DOI: 10.1542/peds.

2011-1246
; originally published online August 13, 2012; 2012;130;e710 Pediatrics
Julie Martin, Aditya Kaul and Robert Schacht
Reconstitution Inflammatory Syndrome
Acute Poststreptococcal Glomerulonephritis: A Manifestation of Immune

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of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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Acute Poststreptococcal Glomerulonephritis:
A Manifestation of Immune Reconstitution Inammatory
Syndrome
abstract
Immune reconstitution inammatory syndrome (IRIS) is a well-
described complication of initiation of highly active antiretroviral
therapy in HIV-infected patients. As the immune system recovers, an
inappropriate inammatory response often occurs that causes signif-
icant disease. It is most commonly seen in patients nave to therapy
with CD4+ T-lymphocyte counts ,100 cells/cmm and usually presents
as a are of mycobacterial, cytomegalovirus, or herpes zoster infec-
tions. Less commonly, this syndrome occurs in response to noninfec-
tious triggers and results in autoimmune or malignant disease. Here
we present the rst case of acute poststreptococcal glomerulonephri-
tis associated with varicella zoster virus and IRIS in an adolescent
with perinatally acquired HIV and hepatitis C virus infections. Our
patient was not nave to therapy but was starting a new regimen
of therapy because of virologic failure and had a relatively high CD4+
T-lymphocyte count. This case report indicates that IRIS remains
a concern after initiation of a new highly active antiretroviral therapy
regimen in HIV-infected patients with high viral loads, even in the
presence of CD4+ T-lymphocyte counts .100 cells/cmm. It may pres-
ent as infectious, malignant, or autoimmune conditions including
poststreptococcal glomerulonephritis. Pediatrics 2012;130:e710e713
AUTHORS: Julie Martin, MD,
a
Aditya Kaul, MD,
a
and Robert
Schacht, MD
b
a
The Saul Krugman Division of Pediatric Infectious Diseases, and
b
Division of Pediatric Nephrology, Department of Pediatrics, New
York University School of Medicine/Bellevue Hospital, New York,
New York
KEY WORDS
immune reconstitution inammatory syndrome,
glomerulonephritis, HIV, Streptococcus, varicella
ABBREVIATIONS
APSGNacute poststreptococcal glomerulonephritis
ASOantistreptolysin O antibody
HAARThighly active antiretroviral therapy
IRISimmune reconstitution inammatory syndrome
VZVvaricella zoster virus
All authors have made substantive intellectual contributions to
the case report and take full responsibility for the entire content
of the case report.
www.pediatrics.org/cgi/doi/10.1542/peds.2011-1246
doi:10.1542/peds.2011-1246
Accepted for publication Mar 14, 2012
Address correspondence to Julie Martin, MD, Pediatric Infectious
Disease, NYU Medical Center, 550 First Ave, New York, NY 10016.
E-mail: julie.martin@nyumc.org
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2012 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no nancial relationships relevant to this article to disclose.
FUNDING: No external funding.
e710 MARTIN et al
at Indonesia:AAP Sponsored on December 7, 2013 pediatrics.aappublications.org Downloaded from
Reconstitution of the immune system
occurs once patients are started on
effective highly active anti-retroviral
therapy (HAART). In children, this pro-
cess continues years after the therapy
is initiated and the patients viral load
becomes undetectable.
1
Immune recon-
stitution inammatory syndrome (IRIS)
is an acute process in which a subset of
patients experiences clinical deterio-
ration from rapid and dysregulated
restoration of antigen-specic immune
responses. This creates a paradoxical
inammatory reaction to previously
treated or subclinical infections, as well
as noninfectious stimuli causing auto-
immune and malignant diseases.
2
Renal manifestations of IRIS are un-
common and have been primarily
described in adult patients with Myco-
bacterium tuberculosis.
35
Other causes
of IRIS-associated renal pathology in-
clude granulomatous interstitial ne-
phritis without evidence of tuberculosis,
sarcoidosis, and cryptococcal infection.
68
In pediatrics there are only a few case
reports of renal IRIS.
7,9,10
To date, there
have been no published cases of acute
renal insufciency secondary to acute
poststreptococcal glomerulonephritis
(APSGN) in the setting of IRIS. Here, we
present a patient with perinatally ac-
quired HIV and Hepatitis C who de-
veloped varicella zoster virus (VZV) and
ASPGN after initiation of a new HAART
regimen for virologic failure.
CASE REPORT
An 18-year-old male Hispanic patient,
perinatally infected with HIV and hep-
atitis C, has been followed in our clinic
since birth. He is a long-term non-
progressor, having maintained a high
CD4+T-lymphocyte count for most of his
life, despite having an elevated viral
load in the range of 2000 to 17 000
copies/mL. Because of an unstable so-
cial situation, he had a history of poor
adherence to HAART. Starting at age 6
years, he was diagnosed with 1 to 3
episodes of symptomatic streptococcal
pharyngitis per year. He had docu-
mented intercurrent negative throat
cultures when well. The patient un-
derwent tonsillectomy at age 10, after
a peritonsillar abscess secondary to
Streptococcus pyogenes. Otherwise, he
has been healthy with normal liver and
kidney function and normal urinalyses.
At 14 years of age, in the month of June,
he was noted to have an increasing
HIV viral load with .100 000 copies/mL;
CD4+ T-lymphocyte count remained high
at 721 cells/cmm. In August, his HAART
regimen was changed from stavudine,
lamivudine, and nelnavir to zidovudine,
didanosine, and lopinavir/ritonavir. In
October, he was diagnosed with culture-
positive streptococcal pharyngitis, which
was treated with antibiotics. He pre-
sented with back pain in November,
3 months after his medication change
and was diagnosed with bilateral her-
pes zoster infection, which was treated
for 7 days with acyclovir. Further labo-
ratory testing at that time revealed
hematuria and proteinuria, elevated
creatinine, and a decrease in hemo-
globin. His CD4+ T-lymphocyte count
decreased but his viral load was un-
detectable (Table 1). The patient sub-
sequently developed gross hematuria.
Additional testing revealed a markedly
elevated antistreptolysin O antibody
(ASO) titer and mild decrease in com-
plement levels. He never developed
swelling, edema, or hypertension. Ab-
dominal ultrasound revealed echogenic
kidneys consistent with medical renal
disease. Kidney biopsy was suggestive
of postinfectious glomerulonephritis
without evidence of membranoprolifer-
ative disease. It also revealed collapsing
glomerulopathy, a condition sometimes
seen in HIV and other viral infections.
Liver enzyme tests remained normal
and hepatitis C viral load was unchanged
from baseline.
The patient was continued on his HAART
therapy. He was not treated with steroids
or any other form of immunosuppres-
sion. His gross hematuria resolved and
creatinine normalized within 6 months
but microscopic hematuria persisted
for more than 2 years. He required
supplemental erythropoietin briey for
anemia related to acute renal failure.
The peripheral blood smear showed no
evidence of microangiopathic hemolytic
anemia. Repeat throat cultures done
3 months and 2 years after onset of
hematuria were both negative. His ASO
titer on presentation was extremely
elevated at 1927 IU/mL and remains
elevated 36 months later at 476 IU/mL.
He has otherwise been healthy with good
virologic control of his HIV infection.
DISCUSSION
Establishing a denitive diagnosis of
IRIS can be challenging, as there is no
specic laboratory test and diagnostic
criteria for IRIS have not been standard-
ized. Although there are several atypical
features in this case in terms of IRIS
presentation, including normal CD4+
T-lymphocyte count and prior HAART
therapy, we feel that our patients clinical
course is highly suggestive of IRIS by
fullling previous criteria established
by Shelburne et al
11
and French et al.
12
These criteria include the following:
HIV-infected patient, receipt of effective
HAART as shown by a decrease in HIV
RNA concentration frombaseline, clinical
symptoms consistent with an inamma-
tory process, short interval between ini-
tiation of symptoms and change of HAART
regimen, clinical course not consistent
with expected course, and spontane-
ous resolution of disease with contin-
uation of HAART. For this patient, IRIS
likely occurred by 2 mechanisms: exag-
gerated activation of the immune system
against persistent streptococcal antigen
(paradoxical IRIS) and response to viable
pathogens (unmasking IRIS); in this case,
the herpes zoster infection. Decrease
in viral load was associated with a drop
in CD4+ T-lymphocyte count, perhaps
CASE REPORT
PEDIATRICS Volume 130, Number 3, September 2012 e711
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because of immune dysregulation lead-
ing to IRIS.
9
In terms of renal disease, both the renal
biopsy and clinical course were most
consistent with APSGN. He had sudden
onset of hematuria and proteinuria,
a history of recent streptococcal infec-
tion 1 month before onset of symptoms,
with conrmatory markedly elevated
ASO and mild decrease in complement
levels. He also demonstrated renal
functional impairment manifested by
a threefold increase in serum creati-
nine. Themorphologic features onlight
microscopy revealed diffuse mesangial
proliferative glomerulonephritis with
endocapillary and extracapillary pro-
liferation, as is seen in APSGN.
Although many features of this case are
consistent withtypical APSGN, there are
several atypical features suggesting
IRIS played a role in the disease pro-
gression. Both the length of time for the
acute glomerulonephritis to resolve
and the length of time for the ASO titer
to normalize were much longer than
what is expected for typical APSGN. This
prolonged time to normalization is likely
related to immune dysregulation with
inability to clear antigen.
13
With ASPGN,
the urine is expected to normalize within
the rst 3 months after onset of symp-
toms.
14
Although this patients creatinine
normalized within 6 months, he contin-
ued to have microscopic hematuria for
more than 2 years. The fact that our
patient developed glomerulonephritis at
age 14 years despite multiple previous
streptococcal infections may point to
a more virulent streptococcal strain or
may be related to relative immunologic
dysregulation secondary to HIV infection.
In addition, interstitial inammation and
edema, as well as acute tubular injury
with regenerative changes and neutro-
philic tubulitis, were noted histologically.
These ndings have been described in
IRIS without APSGN.
3
IRIS is a complication of antiretroviral-
induced immune recovery. It occurs as
the result of an exaggerated activation
of the immune system against persis-
tent antigen (paradoxical IRIS) or viable
pathogens (unmasking IRIS).
2
One pos-
sible explanation for this is an imbal-
ance of effector and regulatory cellular
immune responses during the restora-
tion of pathogen-specic responses of
the immune system during reconstitu-
tion.
9,15,16
Disease is typically seen after
an increase in the CD4+ T-lymphocyte
count; however, IRIS may occur after
reduction of viral load before an in-
crease in CD4+ T lymphocytes, which
is what we believe to have occurred
in our patient. This may be related
to improved functioning of the CD4+
T lymphocytes as well as other parts of
the immune system.
9
In the pediatric population, the inci-
dence of IRIS is estimated to be 20%in
resource-limited countries.
17,18
There
are no studies reporting incidence rates
in resource-rich areas. IRIS is most often
seen with mycobacterial infections,
including tuberculosis, atypical myco-
bacteria, and bacille Calmette-Guerin
vaccine, herpes simplex, and herpes
zoster.
1820
As seen in adult patients,
children with opportunistic infections
before beginning treatment with anti-
retroviral therapy have increased in-
cidence of IRIS.
21
Multiple studies have
shown that a CD4+ T-lymphocyte count
,100 cells/cmm is a major risk factor
for developing IRIS.
16
This case sug-
gests that IRIS may occur with CD4+
T-lymphocyte counts much higher
than previously thought.
Optimal management of IRIS has not
been well established. In paradoxical
IRIS, which is triggered by dead and
dying infective antigen particles, HAART
should be continued. In the setting of
unmasking IRIS (viable replicating in-
fective antigen) in a critically ill patient,
it is less clear whether HAART should
be continued. Anecdotal evidence sup-
ports the use of corticosteroids with
severe manifestations.
22
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e712 MARTIN et al
at Indonesia:AAP Sponsored on December 7, 2013 pediatrics.aappublications.org Downloaded from
not treated with steroids, his HAART
therapy was continued, and he improved
over time.
Although renal IRIS is relatively rare,
renal pathology is very common in HIV-
infected patients over the course of
their lifetimes with a wide differential
diagnosis including HIV and nonHIV-
related diseases.
23
IRIS has previously
been associated with renal pathology
in pediatrics patients in the cases of
nephrotic syndrome and renal crypto-
coccal infection.
7,10
No cases of renal
immune complex deposition associated
with IRIS have been reported. Primary
varicella infection has been described
in the literature to cause both immune
complex deposition and exacerbations
of APSGN.
24,25
This association has not
been reported with varicella zoster
nor has it been described in the HIV-
infected population. Here we pro-
pose that immune reconstitution after
change in antiretroviral treatment
regimens led to reactivation of VZV
and subsequent prolonged course of
APSGN.
In summary, we report the rst case
of an adolescent with an association
of VZV, protracted APSGN, and IRIS,
the former 2 probably caused by the
latter. Although IRIS has most com-
monly been described in patients with
very low CD4+ T-lymphocyte counts
who were previously naive to anti-
retroviral therapy, this case is highly
suggestive of IRIS occurring in the
setting of a normal CD4+ T-lymphocyte
count at the time of HAART regimen
change because of treatment failure.
As experience with prolonged HAART
treatment and management of treat-
ment failures continues, we are likely
to see more patients with this type of
IRIS presentation.
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DOI: 10.1542/peds.2011-1246
; originally published online August 13, 2012; 2012;130;e710 Pediatrics
Julie Martin, Aditya Kaul and Robert Schacht
Reconstitution Inflammatory Syndrome
Acute Poststreptococcal Glomerulonephritis: A Manifestation of Immune

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