Varicella
in Pediatric
Orthotopic
Liver
Transplant
Recipients
Robert
S. McGregor,
MD, Basil J. Zitelli,
MD, Andrew
H. Urbach,
MD,
J. Jeffrey
Malatack,
MD, and J. Canton
Gartner,
Jr,
MD
From the Department of Pediatrics, Children’s Hospital of Pittsburgh
ABSTRACT. From May 1981 to May 1984, 90 pediatric
patients underwent liver transplantation and 65 patients survived as of May 1986. Two of the nonsurvivors died with complications related to clinical varicella. Of these 67 patients (65 survivors and two nonsurvivors who died of varicella-related causes), 51 patients were determined to be varicella susceptible. Clinical disease developed in no patients with serologic evidence or clinical history of varicella prior to transplantation. Eighteen susceptible patients were exposed and received zoster immune glob-ulin and varicella did not develop. Clinical disease
devel-oped in eight patients despite zoster immune globulin, although one patient received it 96 hours after exposure. Six patients received no zoster immune globulin and clinical varicella developed. In all, varicella developed in 14 patients. Thirteen were admitted to the hospital and treated with intravenous acyclovir. Of those treated, two died of causes related to complications of varicella. The remaining patients treated with acyclovir had mild dis-ease. The one patient not treated with acyclovir also had mild disease. We conclude that patients contracting var-icella after liver transplantation while receiving mainte-nance immunosuppressive agents should be treated with intravenous acyclovir. Generally, when treated with acy-clovir while receiving maintenance immunosuppressive drugs, these patients have mild clinical disease. Patients recently treated with high-dose prednisone and cyclo-sporine may have severe clinical disease resulting in death. Pediatrics 1989;83:256-261; variceila, liver trans-plantation, acyclovir.
Varicella zoster infections are potentially life-threatening illnesses in immune-compromised pa-tients.”2 Pneumonitis, encephalitis, and hepatitis
Received for publication Dec 30, 1987; accepted Feb 23, 1988. Reprint requests to (R.S.M.) Children’s Hospital of Pittsburgh, One Children’s P1, 3705 Fifth Ave at DeSoto St, Pittsburgh, PA 15213-3417.
PEDIATRICS (ISSN 0031 4005). Copyright © 1989 by the American Academy of Pediatrics.
are among the complications previously re-ported.’ In contrast to the immunocompetent host, visceral dissemination is much more likely to
occur in the immunocompromised patient, and such
dissemination has led to fatal outcomes.3’4 Varicella has been described in patients who have undergone
renal transplantation and who are receiving
aza-thioprine and corticosteroids; however, there are no similar reports in liver transplant recipients receiv-ing maintenance cyclosporine and prednisone as immunosuppressive agents.
Information concerning the varicella status and clinical course of 65 consecutive survivors of liver transplantation was reviewed. In addition, the courses of two patients whose deaths were related
to varicella were examined.
MATERIALS
AND
METHODS
This project was approved by the local institu-tional review board. From May 1981 to May 1984, 90 pediatric patients underwent liver transplanta-tion,6 and 65 patients survived until May 1986. All survivors were followed up by at least one of the authors during the follow-up period. In addition, a detailed chart review was performed and phone
interviews were conducted with the families of these patients. The clinical courses of the two patients
who died of varicella-related causes were also
re-viewed.
All patients undergoing pretransplantation
eval-uation had varicella antibody titers determined by indirect immunofluorescent antibody testing as de-scribed by Schmidt et al.7 Information pertaining to varicella exposure of patients in the
posttrans-plantation period and subsequent administration of
TABLE. Clinical Data From Patients Contract ing Varicella A fter Liver Transplantation*
Patient Interval Medications at Medication Severity Varicella
No. After Time of Changes Treatment of Score Titer
Transplan- Varicella During Varicella After
tation
Infe:tion
(mg/kg/d) Clinical
Varicella
Infection
Zoster Immune Acyclovir Globulin
(1 vial/lO kg) Cyclosporine Prednisone
190 29 mo 10.5 0.26 None + + Mild NA
191 47 mo 7.4 0.25 None + + Mild +>1:50
226 31 mo 7.1 0.15 None + + Mild Nonimmune
286 35 mo 10.7 0.12 None + + Mild +1:50
301 31 mo 9.4 0.31 None - + Mild +1:40
306 35 d 26.3 0.69t None - + Mild Nonimmune
308 21 d 16.8 1.0 Prednisone
decreased 50%
- + Mild Nonimmune
313 20 mo 10.0 0.6 None + + Mild +1:50
317 30 mo 11.8 0.26 None + (given 96 h +
after expo-sure)
Mild +1:200
327 18 mo 13.7 0.29 None - + Mild +1:50
355 29 mo 7.6 0.26 None + - Mild +1:40
368
379
18 wk
15 mo
21.0 1.2
7.8 0.79
Cyclosporine stopped
None
- +
- +
Severe (died)
Mild +>1:128
420 10 mo 15.8 0.79 Cyclosporine
stopped
+ + Severe
(died)
* Patient No. comes from consecutive pediatric liver transplantation system from Denver-Pittsburgh series. Severity
score is from Feldhoff et al.5 Symbols: +, treated; -, not treated; NA, information not available/patient alive.
t Methylprednisolone, 13 mg/kg IV, nine days prior to varicella.
:1:Methylprednisolone, 10 mg/kg IV, 15 days prior to varicella.
contracted varicella were further questioned as to the clinical course, the pre-varicella immunosup-pressive drugs and dosages, and whether any changes in these drugs or dosages had occurred within a month of contracting varicella. Informa-tion regarding treatment of varicella with acyclovir
and possible reductions in doses of
immunosup-pressive agents was obtained from a parent and then confirmed from hospital records if
hospitali-zation occurred. Clinical severity was assigned by
using the guidelines of Feldhoff et al5 which define varicella as being severe if two of the following criteria are met: (1) fever >38.3#{176}C for more than six days, (2) new rash more than six days from onset of illness, (3) mucous membrane involvement,
and (4) death.
RESULTS
Of this group of 67 patients (65 survivors plus
two nonsurvivors who died of varicella-related
causes), 11 had serologic evidence of varicella infec-tion and five had a history of clinical varicella pretransplantation. Of 51 varicella-susceptible
pa-tients, 47 were successfully contacted by telephone or in person.
Of the 47 susceptible patients, 15 had no known
exposures to varicella and varicella did not develop.
Eighteen patients had one or more known
expo-sures to varicella and received zoster immune glob-ulin within three days of exposure without clinical
varicella developing. Clinical varicella developed in
14 patients. Of these 14 patients, seven received zoster immune globulin within 72 hours but
van-cella still developed, six received no zoster immune
globulin, and one received zoster immune globulin
later than the recommended 72-hour period (96
hours). With the exception of orthotopic liver transplantation patients OLTx (consecutive
pedi-atric liver transplantation patients from
Denver-Pittsburgh series) 306 and 308 (Table), all of the
surviving patients contracting vanicella were receiv-ing maintenance immunosuppression6 consisting of
cyclosponine and prednisone (average doses:
cyclo-sponine 9.6 mg/kg/d divided in two doses per day and prednisone 0.33 mg/kg/d each morning).
The clinical data for 14 patients contracting
var-icella are summarized in the Table. All but one
patient, OLTx 355, were admitted to their local
a dose of 500 mg/m2 per dose three times a day for
a five- to ten-day course. Thus far no cases of
recurrent vanicella have occurred.
Four patients contracted varicella while receiving
higher than usual maintenance doses of
immuno-suppression. Patients OLTx 306 and 308 were in
the immediate posttransplantation period. Patient
306 had finished decreasing daily doses of intrave-nous methyiprednisolone beginning with 13 mg/kg!
d and ending with 1 mg/kg/d four days prior to a
vanicella outbreak. Similarly, 308 had finished
de-creasing daily doses of intravenous
methylpredni-solone beginning with 10 mg/kg/d and ending with 1.5 mg/kg/d 16 days prior to a vanicella outbreak.
The two other patients, OLTx 420 and OLTx 368,
contracted vanicella 7 months and 4 months,
re-spectively, posttransplantation. The following are
summaries of their clinical courses.
A
10-year-old white boy, OLTx 420, 10 monthsposttransplantation for intrahepatic biliary atresia,
received zoster immune globulin within 24 hours of
exposure to an infected sibling. Ten days after
exposure he had laboratory findings of abnormal
liver function (SGOT 150 lU/L, SGPT 200 lU/L)
and received a single intravenous dose of
methyl-prednisolone for presumed rejection. Seventeen
days after exposure, one single vesicle developed on his back which persisted without scabbing for the
next five days with no medical intervention. Four
additional vesicles then developed over his back
and he was transferred to Children’s Hospital of
Pittsburgh 3 weeks after having received zoster
immune globulin. When admitted, he was noted to
be lethargic and in marked respiratory distress. His temperature was 39.7#{176}C,and he had vesicular
le-sions on his oral mucosa as well as his trunk.
Bilaterally, his breath sounds were decreased.
Lab-oratory findings at the time of admission included
SGOT 198 lU/L and SGPT 239 lULL. Chest
radio-graph initially showed a right-sided pleural effusion but progressed to bilateral pneumonitis. His respi-ratory distress rapidly progressed to respiratory
failure, and mechanical ventilation was required.
Subsequently, hypotension, renal failure and a din-ical course consistent with adult respiratory distress
syndrome occurred. Despite treatment for ten days
with acyclovir, broad-spectrum antimicrobial
agents, vigorous respiratory support, and peritoneal
dialysis, he died of intractable respiratory failure
16 days after admission. Postmortem examination
revealed extensive damage to the lungs consistent
with adult respiratory distress syndrome, renal
tu-bular damage, and focal areas of hepatic necrosis;
however, no organisms or evidence of viral
inclu-sions were found.
Patient OLTx 368, a 4”/i2-year-old Hispanic girl
18 weeks posttransplantation for biliary atresia,
had returned to her home in South America. She
did not have a known varicella contact. Twenty
days prior to a vanicella outbreak, she finished a
repeat “cycle”9 of oral prednisone because her liver
enzyme values were elevated (SGOT 122 IU/L,
SGPT 315 IU/L) and rejection was presumably
occurring. Nine days prior to a varicella outbreak,
she received 1 g of intravenous hydrocortisone, after
which the following values were recorded: SGOT
40 lU/L and SGPT 154 lU/L. Clinical varicella
then developed. Because of the lack of availability
in her home country, she received neither zoster
immune globulin nor acyclovir until her transfer to
our hospital two days after onset of vanicella. When
admitted she was noted to have decreased mental
status. She had oral vesicles and multiple
hemor-rhagic trunk vesicles. SGOT and SGPT values were
both >1000 lU/L. Her clinical course was that of
increasing tachypnea and hypotension requiring
admission to the intensive care unit. Despite
treat-ment with zoster immune globulin, acyclovir, and
-y-globulin, her condition rapidly deteriorated.
Re-fractory metabolic acidosis and intractable
hyper-kalemia led to a fatal dysrhythmia within 24 hours
of admission. Hepatic necrosis and vanicella
hepa-titis were found during autopsy.
DISCUSSION
A
normal host response to vanicella zoster virusinfections involves both humoral and cell-mediated immunity.’#{176}’9 Cradock-Watson et al’2 found that
IgG, IgA, and 1gM antibodies appear two to five
days after onset of the rash and peak 14 to 21 days
into the illness. IgG then decreases to low levels
but remain indefinitely and IgA and 1gM disappear
by 12 months.’2 The protective significance of these
titers has been questioned because patients with
congenital pure humoral immunodeficiency states,
such as primary a--y-globulinemia, respond to
van-cella as normal hosts.1#{176}
Cell-mediated immune responses to varicella
have been studied by numerous investigators,’3’7 and vanicella zoster virus exhibits specific response
patterns when studied in lymphocyte
transforma-tion tests.’5 In addition, Bogger-Goren et al’4 iden-tified several patients without a history of varicella
who were seronegative for varicella zoster virus20
yet had demonstrable vanicella zoster virus-specific proliferation in their lymphocytes. They concluded
that a host’s humoral and cell-mediated immune
responses to varicella may be independent.
Al-though the role of cell-mediated immunity in
ad-quired immunodeficiencies, malignancies, or
im-munosuppressive drugs’8 affecting T cell function
are also associated with increased complications with varicella. Because both cyclosporine and
pred-nisone are known to depress cell-mediated
immunity2#{176}22 our patients seem to be at particular
risk for complications of varicella zoster virus
in-fection.
Corticosteroids have frequently been implicated
as a significant risk factor for complications and
fatalities associated with varicella.2326 Falliers and
Ellis27 suggested that steroid use in pediatric pa-tients with asthma, at the equivalent dosage of
prednisone 5 to 10 mg/d (mg/kg doses unavailable),
if unassociated with underlying immune disease,
does not pose exceptional problems in patients
con-tracting varicella. Feldhoff et al5 concluded that
prednisone at doses of 0.25 to 0.5 mg/kg/d did not
affect severity or outcome of varicella infections in
renal transplant recipients. Ten of our 14 patients contracting varicella were receiving “maintenance” doses of prednisone (0.12 to 0.36 mg/kg/d, mean 0.28 mg/kg/d). Nine ofthe ten patients were treated
with acyclovir, with or without previous zoster
im-mune globulin and all responded to vanicella in a
similar manner as nonimmunocompromised hosts. Although our results are consistent with the
expe-rience of Feldhoff et al5 and Falliers and Ellis27 in
that “low-dose” prednisone may not significantly
effect outcome of the clinical course of varicella, it should be highlighted that seven of these patients receiving “low-dose” prednisone also received zoster
immune globulin which may have blunted the
“nat-ural” course of their vanicella zoster virus
infec-tions.
Evaluating the role of cyclosponine in altering
the hosts response to viral infections is difficult
because there are no published studies in which
patients receiving cyclosporine alone were
evalu-ated. However, in a population of patients with
nephrotic syndrome receiving cyclosporine without
prednisone, only one patient contracted vanicella
while receiving cyclosporine (6 mg/kg/d) alone.
Treatment consisted of withholding cyclosporine
which resulted in relapse of the nephrotic syndrome
but no complications from vanicella (Dr Emir
Te-jani, personal communication, November 1987).
The effect of cyclosporine in our patients was
evaluated via dosages rather than cyclosporine
1ev-els, because levels were not available for these
pa-tients. Future studies should address this.
With respect to cyclosponine, we studied two
groups of patients: ten patients receiving low doses
of cyclosporine (7.1 to 13.7 mg/kg/d, mean 8.6 mgI
kg/d) and the four patients, OLTx 306, 308, 368,
and 420 receiving higher doses (15 to 26 mg/kg/d,
mean 19.9 mg/kg/d). The patients receiving
low-dose cyclosporine did well clinically with zoster
immune globulin and acyclovir therapy, suggesting
that low-dose cyclosponine when combined with
low-dose prednisone may not adversely affect
van-cella outcome if patients are treated with specific
antiviral therapy and/or zoster immune globulin.
One patient, OLTx 355 (Table) receiving
low-dose prednisone and low-dose cyclosporine received
zoster immune globulin after a known vanicella
exposure but did not seek medical attention during his vanicella infection. Although he did not receive
acyclovir, he behaved no differently than the other
nine patients receiving similar doses of
immuno-suppressive agents. Two possible explanations for
this patient’s benign course are proposed. First, and
most likely, zoster immune globulin could have
altered his clinical course and ameliorated what
may have been a more serious disease. Second, he
may have had cell-mediated immunity to vanicella
without measurable serum antibody, similar to
pa-tients described by Bogger-Goren et al.’4
Cyclo-sporine and prednisone may have depressed
cell-mediated immunity enough to allow infection or
reinfection to occur, while his remaining
cell-me-diated immunity provided some residual protection accounting for his mild clinical course.
We surveyed seven other pediatric liver
trans-plantation programs in North America during
March 1987 and found only one additional patient
with post-liver transplantation-acquired vanicella
while receiving maintenance cyclosponine and
pred-nisone who received neither zoster immune globulin
nor acyclovir. His cyclosponine dose, however, was
empirically decreased, and he had no complications
from vanicella. Three other patients could be
iden-tified with post-liver transplantation-acquired
van-icella who received zoster immune globulin and
acyclovir while receiving maintenance prednisone
and cyclosporine. Their courses paralleled our
pa-tients with mild cases.
The two patient deaths (patients 368 and 420)
reaffirm the general fear of varicella in the patient
receiving immunosuppressive agents. The fact that
that the deaths occurred in patients receiving high
doses of immunosuppressive agents suggests that
recent high doses of steroids combined with higher
cyclosponine doses may have predisposed our
pa-tients to more serious complications and death.
Two patients’ (OLTx 306 and 308) clinical courses
were much like our patients receiving maintenance
dose immunosuppression, despite higher
immuno-suppressive doses. This may be explained by the
duration of immunosuppression and the duration
and prednisone for 35 days and 21 days,
respec-tively, and varicella developed in both while they
were being observed in the hospital, diagnosis was
made within 24 hours of the rash, and treatment
with ten days of acyclovir was instituted early in
the disease. Patients 368 and 420 were seen two
days and five days, respectively, into their illnesses,
after 40 weeks and 18 weeks, respectively, of
im-munosuppressive medications.
Although varicella titers were not obtained for
all of these patients after infection, three of the 11
patients for whom this information is known have
nondetectable vanicella titers more than 2 months
after infection. (Vanicella was confirmed clinically
by one of the authors in all three patients and in
the two patients tested, No. 306 and No. 308, Tzank
tests were positive.) This suggests that humoral
immunity did not occur or at least antibodies did
not develop in measurable quantities in a
signifi-cant percentage of patients receiving
immunosup-pressive drugs. None of these 11 patients have been
reinfected, even though two of them have had
known reexposures. Recurrent vanicella has been
noted in other immunocompromised patient
groups.’ We are currently in the process of
eva!-uating cell-mediated immunity specific to vanicella zoster virus in these patients.
Based on our sample of 14 patients, it seems that, in the child receiving low doses of
immunosuppres-sion treated with intravenous acyclovir, vanicella
should be tolerated without complications. Zoster
immune globulin may further contribute to a milder
clinical course. Patients treated with high doses of
steroids and cyclosponine within 3 weeks of clinical vanicella are at high risk for dissemination and fatal complications, and they require prompt treatment.
Currently, we recommend the administration of
zoster immune globulin within 72 hours of vanicella
exposure in patients with no documented history of
vanicella pretransplantation or no demonstrable
serum antibody regardless of immunosuppressive dosages. Should clinical vanicella develop, intrave-nous acyclovir at doses of 500 mg/m2 per dose every
eight hours should be started within 24 hours of
eruption of the skin rash and continued for seven
to ten days. With this regimen, liver transplant
recipients receiving maintenance immunosuppres-sion should tolerate vanicella infection without se-rious complications. It is unclear whether patients
receiving maintenance immunosuppressive
regi-mens can tolerate infection without specific
anti-viral therapy, although the small collective
expeni-ence of two patients is promising. Perhaps the best
hope to protect against varice!la infection, however,
would be administration of vanicella vaccine to sus-ceptible individuals prior to transplantation.3#{176}
ACKNOWLEDGMENT
We thank Melinda A. Suska for her expert secretarial
assistance and Sharon A. McGregor, MD, for her editorial assistance.
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INTRAVENTRICULAR
HEMORRHAGE
IN UTERO
The authors report three cases of unexplained prenatal intraventnicular
haemorrhage (IVH) in three term infants. In the first two cases the suspected diagnosis of prenatal IVH was made a few hours after delivery, in accordance
with the ultrasonographic feature of clots in the ventricles, whereas in the third
case prenatal ultrasonography was suggestive of hydrocephalus with intraven-tnicular clots.
Noted by J.F.L., MD
From Zorzi C, Angonese I, Nardelli GB, et al: Spontaneous intraventnicular
