Pediatrics International (2008) 50, 251254 doi: 10.1111/j.1442-200X.2008.02537.

x
2008 Japan Pediatric Society
Various causes have been reported for HIV-related heart disease,
including myocardial infection with HIV itself, opportunistic
infections, and autoimmune response to viral infection.
1 4
Prior
to the highly active antiretroviral therapy (HAART) era, dilated
cardiomyopathy was described in up to 30 40% of AIDS patients
with an estimated annual incidence of 15.9/1000.
5
This condition
frequently leads to left heart dysfunction that becomes the major
cause of heart failure, especially among HIV-infected children.
However, after the introduction of HAART regimens, the preva-
lence of HIV-associated cardiomyopathy has been reduced by
approximately 30% .
6,7
Nonetheless, HAART itself, especially if
the regimen includes protease inhibitors, is associated with an
increase in both peripheral and coronary arterial diseases due to
metabolic syndrome.
6,7
Moreover, some patients who achieve
HIV viral suppression and improved immune function may
develop clinical symptoms of immune restoration disease
(IRD), which constitutes an increased capacity of inammatory
reactions against both infectious and non- infectious antigens.
Most infectious antigens arise from an unmasking of previously
unrecognized infections or a worsening of ongoing opportunis-
tic infections.
8,9
Common pathogens include mycobacterium
spp., cryptococcus, cytomegalovirus, and hepatitis viruses.
9,10

In the present paper we report three cases of HIV-infected chil-
dren who developed dilated cardiomyopathy after initiation of
HAART while their HIV-viral load decreased and CD4 T-cells
increased. We hypothesized that the dilated cardiomyopathy
may be related to IRD. Clinical characteristics of the patients
are given in Table 1 .
Case 1
A 14-year-old HIV-infected girl with a history of cryptococcal
meningitis developed dilated cardiomyopathy after 7 weeks of
HAART. Before initiation of HAART her CD4 T-cell count was
4% (254 cells/ L) and her HIV-RNA level was 45 338 copies/mL.
On admission she had a jugular venous distension, tachycardia,
and S3 gallop, but no friction rub was found. Her liver was
enlarged 6 cm below the right costal margin. At the time of the
episode of dilated cardiomegaly her CD4 T-cell count was 11%
(596 cells/ L) and her HIV-RNA level was <400 copies/mL. Chest
radiography showed marked cardiomegaly, pulmonary venous
congestion with minimal pleural effusion. The echocardiogram
showed a marked enlargement of the left atrium and left ventricle
(left ventricular end diastolic size: 5.3 cm) with poor contraction
of the left ventricle ( Fig. 1a ). The ejection fraction was 22% (nor-
mal: 50 80%). The troponin T STAT immunoassay was negative
and the creatine phosphokinase-MB (CPK-MB) level was normal.
After treatment with i.v. furosemide, dobutamine and enalapril the
patient gradually recovered within 2 weeks. Throughout the epi-
sode HAART was not discontinued. She also received medication
for congestive heart failure, and at the 2 month and 6 month follow
up, the ejection fractions were 48% and 58%, respectively.
Case 2
A 7-year-old HIV-infected boy with a history of excessive oral
candidiasis developed clinical symptoms of heart failure in the
third week of HAART. His CD4 T-cell count before initiation of
HAART was 0% (4 cells/ L). When he developed the symptoms
his CD4 T-cell counts were 1% (9 cells/ L) and 4% (57 cell/ L),
his HIV-RNA levels were 108 and <50 copies/mL, at 3 and
6 weeks, respectively, after initiation of HAART. Chest radiogra-
phy showed marked cardiomegaly. The echocardiogram indicated
an ejection fraction of 27%, and dilated left atrium and left ventri-
cle (left ventricular end diastolic size: 5.1 cm) ( Fig. 1b ). The
troponin T STAT immunoassay was positive at a level of 0.045
(0 0.009), the creatinine kinase -total was 345 U/L (0 195 U/L),
and the CPK-MB level was 19 U/L (0 25 U/L). In addition,
erythrocyte sedimentation rate was 42 mm/h (0 24 mm/h), and C-
reactive protein was 15.3 mg/L (0 5 ). Myositis was ruled out due
to the lack of any clinical symptoms. The patient received i.v.
immunoglobulin (2 gm/kg) in addition to dobutamine and furo-
semide to improve the heart contraction. The serum neutralizing
immunoglobulin for Coxsackie B virus type 3 was positive at
1:160 (cut-off point, <1:20). In addition, blood culture during the
episode was reported later as positive for Mycobacterium kansasii.
Patient Report
Dilated cardiomyopathy in three HIV-infected children after initiation of
antiretroviral therapy
Peninnah Oberdorfer ,
1
Rekwan Sittiwangkul ,
2
Thanyawee Puthanakit ,
1
Yupada Pongprot
2
and Virat Sirisanthana
1


1
Divisions of Infectious Diseases and
2
Cardiology, Department of Pediatrics, Faculty of Medicine, Chiang Mai University,
Chiang Mai, Thailand
Key words AIDS , antiretroviral therapy , cardiomegaly , children , dilated cardiomyopathy , HIV , immune restoration disease ,
myocarditis .
Correspondence: Peninnah Oberdorfer, MD PhD, Division of Infec-
tious Diseases, Department of Pediatrics, Faculty of Medicine, Chiang
Mai University, Chiang Mai 50200, Thailand. Email: aoberdor@mail.
med.cmu.ac.th
Received 11 May 2005; revised 15 February 2006; accepted
6 June 2006.
252 P Oberdorfer et al.
2008 Japan Pediatric Society
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Cardiomyopathy in HIV 253
2008 Japan Pediatric Society
He received medication for congestive heart failure as well as
continued HAART. He also received clarithromycin and etham-
butol for M. kansasii infection. His cardiac function gradually
improved with an ejection fraction of 36% and 55% at 2 month
and 12 month follow up.
Case 3
A 1-year-old HIV-infected boy with a history of systemic
cytomegalovirus infection (colitis, retinitis, encephalitis) devel-
oped symptoms of dilated cardiomegaly at 6 weeks after initia-
tion of HAART. His CD4 T-cell count prior to HAART was 11%
(740 cells/ L) and his HIV-RNA level was >750 000 copies/mL.
At the time of the episode his CD4 T-cell count had risen to 30%
(1310 cells/ L) and his HIV-RNA level decreased to 262 copies/
mL. The echocardiogram showed a markedly dilated left atrium
and left ventricle with severely depressed left ventricular systolic
function (ejection fraction: 30%; Fig. 1c ). He received pred-
nisolone (2 mg/kg per day), furosemide and dobutamine but his
state worsened and he eventually died without re-assessment of
his cardiac function. The blood culture taken when he died was
positive for Pseudomonas aeruginosa . Post-mortem examination
was not permitted.
Discussion
We report three cases of HIV-infected children who developed
clinical symptoms of dilated cardiomyopathy shortly after initia-
tion of HAART. All patients had a CD4 T-cell count <15% and
had opportunistic infections prior to and at the time of HAART.
At the episode of cardiomegaly their HIV-RNA viral levels had
decreased to <400 copies/mL (a decrease in the plasma HIV-RNA
level by >2 log
10
copies/mL) and their CD4 T-cell counts had
increased. They received inotropic drugs to improve cardiac func-
tion and continued on HAART. The clinical symptoms in two of
the three patients improved, but one died from P. aeruginosa
sepsis. Although there is no generally accepted case denition
for IRD, we propose that these episodes of dilated cardiomyopa-
thy may be related to IRD.
French et al. recently proposed criteria for the diagnosis of
infectious IRD in HIV-infected patients on HAART, which
included two major criteria and three minor criteria. The major
criteria are (a) an atypical presentation of opportunistic infec-
tions in patients responding to HAART; and (b) a decrease in the
plasma HIV-RNA level by >1 log
10
copies/mL. Minor criteria are
(i) an increase in CD4 T-cell count after HAART; (ii) an increase
in immune responses specic to the relevant pathogen; and (iii) a
spontaneous resolution of disease without specic antimicrobial
therapy with continuation of anti-retroviral therapy. The diagnosis
of IRD requires both major criteria or criterion A and two minor
criteria.
10

A 19% incidence of IRD after initiating HAART in advanced-
stage HIV-infected children was found in a recent report.
9
The
denition of IRD used in that report covers HIV-infected patients
whose antiretroviral treatment has led to an increase in CD4 lymph-
ocyte count and decrease in plasma HIV-RNA level, and who
have a disease event caused by microorganisms or conditions
that have previously been associated with IRD.
9
Although there
was no clear evidence for the causative organism of the cardio-
myopathy and this condition has never been reported to be one of
the manifestations of IRD, we propose that the three patients in
the present study could have had dilated cardiomyopathy IRD.
Further studies on the causes and associated factors of cardiomy-
opathy are needed in order to draw rmer conclusion. Because of
the short onset of the dilated cardiomyopathy episode, the effect
of antiretroviral therapy on coronary arterial disease was unlikely
in these patients. Nevertheless, we recommend a careful cardio-
logic evaluation of HIV-infected children both before and after
initiation of HAART.
Acknowledgment
We thank Martyn A. French from the Department of Clinical
Immunology and Biochemical Genetics, Royal Perth Hospital
and School of Surgery and Pathology, University of Western
Australia, Perth, Australia for his comments on the last version
of this manuscript.
References
1 Grody W , Cheng L , Lewis W . Infection of the heart by the human
immunodeciency virus . Am. J. Cardiol . 1990 ; 66 : 203 6 .
2 Herskowitz A , Willoughby S , Vlahov D , Ahmed-Ansari A ,
Beschorner W , Baughman K . Myocarditis and cardiotropic viral
infection associated with severe left ventricular dysfunction in
late-stage infection with human immunodeciency virus .
J. Am. Coll. Cardiol . 1994 ; 24 : 1025 32 .
3 Kan H , Xie Z , Finkel MS . HIV gp120 enhances NO production
by cardiac myocytes through p38 MAP kinase-mediated NF-kB

Fig. 1 Echocardiograms of patients (a) 1, (b) 2, and (c) 3.
254 P Oberdorfer et al.
2008 Japan Pediatric Society
activation . Am. J. Physiol. Heart Circ. Physiol . 2000 ; 279 :
H3138 43 .
4 Currie PF , Boon NA . Immunopathogenesis of HIV-related heart
muscle disease: Current perspectives . AIDS 2003 ; 17 : S21 8 .
5 Barbaro G . Cardiovascular manifestations of HIV infection .
J.R. Soc. Med . 2001 ; 94 : 384 90 .
6 Barbaro G , Klatt EC . Highly active antiretroviral therapy and
cardiovascular complications in HIV-infected patients . Curr.
Pharm. Des . 2003 ; 9 : 1475 81 .
7 Barbaro G . Reviewing the cardiovascular complications of HIV
infection after the introduction of highly active antiretroviral ther-
apy . Curr. Drug. Targets Cardiovasc. Haematol. Disord . 2005 ; 5 :
337 43 .
8 Hirsh H , Kaufmann G , Sendi P , Battegay. Immune reconstitution
in HIV-infected patients . Clin. Infect. Dis . 2004 ; 38 : 1159 66 .
9 Puthanakit T , Oberdorfer P , Akarathum N , Wannarit P , Sirisanthana
T , Sirisanthana V . Immune reconstitution syndrome after highly
active antiretroviral therapy in HIV-infected Thai children . Pedi-
atr. Infect. Dis. J . 2006 ; 25 : 53 8 .
10 French M , Price P , Stone S . Immune restoration disease after
antiretroviral therapy . AIDS 2004 ; 18 : 1615 27 .