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Journal of Clinical Virology 36 (2006) 13–16
Disseminate and fatal cytomegalovirus disease with thymitis in a naive
HIV-patient after early initiation of HAART:
Immune restoration disease?
Sonia Gutiérrez a,1 , Silvia Alconchel b , Ezequiel Ruiz-Mateos c,1 , Miguel Genebat a,1 ,
Alejandro Vallejo c,1 , Eduardo Lissen a,1 , Jorge Fernández-Alonso b , Manuel Leal a,∗,1
a
b
Department of Internal Medicine, Virgen del Rocio University Hospital, Seville, Spain
Department of Anatomy Pathology, Virgen del Rocio University Hospital, Seville, Spain
c Department of Biochemistry, Virgen del Rocio University Hospital, Seville, Spain
Received 5 October 2005; received in revised form 10 December 2005; accepted 16 December 2005
Abstract
We describe a naı̈ve HIV-infected patient who developed a Pneumocystis carinii pneumonia and disseminate and fatal cytomegalovirus
disease within 3 months after initiation of HAART, suggesting due to coincidence in time, an immune restoration disease. We propose an
alternative hypothesis.
© 2005 Elsevier B.V. All rights reserved.
Keywords: Immune restoration disease; Thymitis cytomegalovirus; AIDS
1. Introduction
HIV-patients under HAART may experience severe systemic inflammatory reactions that have been defined as
immune restoration disease (IRD). It has been communicated
that IRD has two different patterns; an earlier pattern during
the first 3 months of HAART as an immune response against
viable opportunistic pathogens, and a later pattern as an
immune response against non-viable opportunistic pathogens
months to years after HAART (French et al., 2004). During
the IRD, a baseline CD4 cell count below 100 cells/mm3
has been reported among patients, while after HAART an
increase above 200 cells/mm3 is reached (Price et al., 2001).
Outcomes range from minimal morbidity to fatal progression
(French et al., 2004; Hirsch et al., 2004). In this way, atypical presentations of mycobacterial, cytomegalovirus (CMV),
∗ Corresponding author at: Viral Hepatitis and AIDS Unit, Department of
Internal Medicine, Virgen del Rocio University Hospital, Seville, PC 41013,
Spain. Tel.: +34 955012396; fax: +34 955012390.
E-mail address: [email protected] (M. Leal).
1 Viral Hepatitis and AIDS Unit.
1386-6532/$ – see front matter © 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jcv.2005.12.007
hepatitis B virus, hepatitis C virus and JC virus have been
described after initiating HAART (French et al., 2004; Safdar
et al., 2002).
We here report the case of a naı̈ve HIV-infected patient
who developed Pneumocystis carinii pneumonia as well as
disseminated and fatal CMV infection coinciding with the
initiation of HAART.
2. Case report
In 1993, a 32-year-old woman was diagnosed of HIV
infection in our unit. Then, her CD4 T cell count was 840
cells/mm3 , and HIV plasma viral load (pVL) was above
75,000 copies/mL. The moment that primoinfection occurred
in the past was unknown because it was asymptomatic. Since
she declined to receive antiretroviral therapy, a progressive CD4+ T cell count decrease was taking place during
the following 9 years. In July 2002, she began HAART
with zidovudine, lamivudine, and abacavir, having HIV pVL
above 75,000 copies/mL, CD4+ T cell count of 90 cells/mm3 ,
and a thymic volume (measured by mediastinic computed
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S. Gutiérrez et al. / Journal of Clinical Virology 36 (2006) 13–16
tomography) of 1.2 cm3 . In the next 3 months after the initiation of HAART, the patient developed several infectious
events such as P. carinii pneumonia after 10 days, which was
successfully treated with cotrimoxazole. Seven days later,
the patient showed low level of conscience, convulsions, and
plasmatic Na+ concentration of 102 mequiv./L, recovering
from the neurological events after hiponatremia treatment.
Three weeks after the initiation of HAART, a colonoscopy
was performed due to the development of mucosanguineous
diarrhoea. The biopsy of the colon revealed cytomegalic
inclusion bodies that allowed the diagnosis of CMV colitis, which was treated with ganciclovir and foscarnet, while
HAART was interrupted after 6 weeks of its initiation due
to an apparent IRD. She had not previously suffered a CMVrelated disease, thus, she did not take ganciclovir or foscarnet.
Despite of this new treatment, symptoms as fever, cough,
and disnea turned up, as well as bilateral interstitial infiltrate,
which was evidenced by chest radiography. Since the patient
treated with ganciclovir and foscarnet showed favourable
evolution, empiric CMV pneumonia was diagnosed. Ten days
later, the patient referred lost of vision and fundus ophthalmoscopic examination confirming CMV retinitis, despite the
treatment she had taken. At that moment, CMV plasma viral
load was above 738,000 copies/mL, it was not possible to
achieve the sequence of CMV strain to study the development of drug related resistance to ganciclovir and foscarnet,
so, due to the progression of CMV disease with this drugs we
decided to switch to cidofovir.
Since the patient progressed with adverse clinical events,
IRD was ruled out and a new HAART regimen including zidovudine, lamivudine, and lopinavir/ritonavir was prescribed. Finally, although CD4 T cell count increased to 432
cells/mm3 and CMV viral load decreased to 1000 copies/mL,
the patient developed fatal meningoencephalitis after 12
weeks of initiation of HAART. Necropsy was performed to
further studies.
3. Material and methods
Plasma HIV-1 RNA was measured by a quantitative PCR
(HIV Monitor Test kit version 1.5, Roche Molecular System Inc., Branchburg, NJ) according to the manufacturer’s
instructions. This assay has a detection limit of 50 HIV-1
copies/mL. Frozen plasma samples stored since 1993 were
used to measure CMV viral load by a quantitative PCR
(Cobas Amplicor CMV Monitor test, Roche Molecular Systems Inc., Branchburg, NJ) according to the manufacturer’s
instructions. This assay has a detection limit of 400 CMVDNA copies/mL. Total CD4 cell count was determined in
fresh samples by conventional flow cytometry.
Since the patient was enrolled in a study about the role
of the thymus in T cell repopulation, the following measured
parameters were available: mediastinic computed tomography that was performed with a modified method as previously
described (Choyke et al., 1987); and the quantification of
Fig. 1. Evolution of total CD4 cells counts and TRECs.
TRECs generated during the rearrangement of T cell receptor
genes as one proposed molecular marker for the determination of recent thymic cell emigrants. A PCR-based method
for quantifying ␦Rec-J␣ TREC number has been described
(Douek et al., 1998).
4. Results
Evolution of total CD4 cell counts and TRECs are showed
in Fig. 1. Thymic volume was 1.2 cm3 (score 2), which has
been related with an attrofic thymus and fat infiltration.
Evolution of plasma viral load VIH and CMV are showed
in Fig. 2. Plasma viral load CMV was measured in blood samples since year 1993 and it revealed that CMV was detectable
in plasma 2 months before starting HAART. It increased
until 738,000 copies/mL after initiating first HAART regimen. Despite of second HAART and therapy with ganciclovir, foscarnet and cidofovir were started, CMV was always
detectable in plasma.
4.1. Necropsy
It was procedure as a standard autopsy, with special
looking for thymic remnants. Immunohistochemical thymus
studies were performed by streptavidine-biotine technique
for CD3, CD20 (Dako-labs), CD4, CD8, CD5 (Vitro labs),
and pan-cytokeratins (Menarini lab) antibodies, on paraffin
embedded sections. The scarce lymphocytes presents were
Fig. 2. HIV and CMV plasma viral load evolution. () Plasma viral load
CMV; () plasma viral load HIV.
S. Gutiérrez et al. / Journal of Clinical Virology 36 (2006) 13–16
Fig. 3. Cytomegalic inclusion bodies in the medullar epithelial cells of thymus.
stained with CD3, CD4, CD8, and CD5, with sparse CD20
positive lymphocytes placed between them. Pan-cytokeratins
stained most of the cells with intranuclear cytomegalic inclusions.
Macroscopic findings were no relevance. Microscopic
study showed generalized infection with cytomegalovirus
inclusions, mainly in lungs, with lymphocytic interstitial
pneumonitis, and adrenal glands, which showed massive
necrotizing adrenalitis. Both serious adrenalitis as the pneumonitis explained the cause of death. Other affected organs
were the liver, brain, and heart.
Thymus showed diffuse cortical atrophy with scarce lymphocytes, and frequent cytomegalic inclusion cells in the core
of the medulla (Fig. 3). Neither necrosis nor plasma cell infiltration were presented. Microscopical changes found were
according with changes reported in later stages of the thymic
process in AIDS patients (Davis, 1984). Cytomegalic inclusion bodies in the medullar epithelial cells were a relevant
finding.
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On the other hand, it has been reported that the loss of
CMV-specific CD4 T cell response cause recurrences of
CMV retinitis despite of the increase of CD4 cell counts after
HAART (Johnson et al., 2001; Komanduri et al., 2001). To
the best of our knowledge, there are no reported cases of death
for disseminated CMV disease in HIV-positive patients after
HAART.
Initially, we thought that the patient developed IRD
because the presence of P. carinii pneumonia and CMV colitis, coinciding with the introduction of HAART. Moreover,
CD4 cell count at baseline was low but increased after treatment. Subsequently, CMV disease was hard to be explained
as a IRD due to the increase of CMV plasma viral load 2
months before initiation of HAART, the sudden clinical evolution and the disseminate infection by viables pathogens
found after necropsy. Thus, an alternative hypothesis was
needed to formulate.
In this way, as revealed by the presence of a later AIDS
stage thymus with cytomegalic inclusion bodies, there was a
serious thymic dysfunction. This might impair the regeneration of new complete peripheral T cell receptor repertoire that
could enhance opportunistic infectious diseases, as P. carinii
and CMV infection, despite antiretroviral treatment.
Despite thymic impairment, thymic function-related
markers as, total CD4 cell counts and TREC levels, increased
after HAART. We suggested that, CD4 cell counts could have
increased by redistribution of the cells within lymph nodes,
while decreased T-cell turnover after HAART could explain
the increment in TREC levels (Lempicki et al., 2000).
Cytomegalic inclusion bodies found in thymic medullar
epithelial cells is a relevant finding since these cells have
been reported to be prominent targets of viral replication in
different cultures, although it has not been studied in animal
models (Mocarski et al., 1993; Numazaki et al., 1989).
In conclusion, this case report stands out the difficulty
to make an IRD diagnosis. In this way, the development
of opportunistic infectious coinciding early after initiating
HAART should be considered in the differential IRD diagnosis since they have different management and prognosis.
5. Discussion
Acknowledgements
Our report describes a serious thymic dysfunction in a
naı̈ve HIV-infected patient who developed P. carinii pneumonia and disseminate and fatal cytomegalovirus disease within
3 months after initiation of HAART suggesting, since their
coincidence in time, an immune restoration disease.
Nowadays, most of the atypical manifestations of infectious diseases after HAART are included as IRD. In this
way, CMV IRD has frequently been reported as eye disease,
including recurrent CMV retinitis or uveitis (Deayton et al.,
2000; Stone et al., 2002). Other less common forms of CMV
IRD have been reported, such as, pancreatitis, submaxillitis,
pseudotumoral colitis, and isolated fever with positive CMV
viraemia (Gilquin et al., 1997). Resolution has been observed
in all patients after therapy with ganciclovir and foscarnet.
This work was supported by Red de Investigaciones en
Sida (RIS) from the Ministerio de Sanidad y Consumo, Spain.
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