CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 3, April 2012
e16
AFRICA
spironolactone were introduced and the dobutamine weaned. His
ART was stopped and he was recommenced on prednisone 100
mg daily initially. TB treatment was continued. Broad-spectrum
antibiotics (ampicillin plus amikacin) were prescribed to cover
the possibility of a bacterial pneumonia, but a blood culture
was negative. He was also prescribed intravenous thiamine.
Carvedilol was added later. ART was re-introduced after two
weeks.
During the next two months, two attempts at weaning
prednisone resulted in a return of his night sweats, dyspnoea, dry
cough and worsening of his pre-existing infiltrates (Fig. 1) but
not worsening of heart failure. On both occasions, he had rapid
symptomatic improvement after reintroduction of high-dose
prednisone. At evaluation three months after initial presentation,
he was able to walk two kilometres on the flat, had no signs
of heart failure and a repeat echocardiogram measured his
fractional shortening as 22%. Prednisone was gradually weaned
and he received six months in total. After six months on ART his
CD
4
count was 359 cells/ml, his HIV viral load was undetectable
and his sputum TB culture was negative.
Discussion
Paradoxical TB-IRIS
TB-IRIS affects approximately eight to 43% of patients who
commence ART while on treatment for active TB, and it
manifests with recurrence or new symptoms, clinical signs and/
or radiographic features of TB despite effective TB treatment.
2
A
recent meta-analysis reported the pooled cumulative incidence
across studies as 15.7%.
3
Onset is typically within the first
four weeks of ART. IRIS is thought to result from rapid but
dysregulated restoration of antigen-specific immunity during
early ART.
4
In paradoxical TB-IRIS this results in inflammation
at the sites of TB disease directed at the residual MTB antigen.
5
In addition, TB-IRIS has been shown to be accompanied by
marked cytokine elevation in peripheral blood, in particular the
pro-inflammatory cytokines IL-6, TNF-
α
and IFN-
γ
.
6
Since high levels of these pro-inflammatory cytokines have
been implicated in the pathogenesis of HIV-associated dilated
cardiomyopathy (DCMO),
6
it would be plausible to expect that
patients who experience severe TB-IRIS accompanied by high
pro-inflammatory cytokine concentrations and have pre-existing
subclinical DCMO could develop overt heart failure as a
consequence. Both TNF-
α
and inducible nitric oxide synthetase
(the production of which is increased in the presence of TNF-
α
and IL-6) have been implicated in the pathogenesis of DCMO
in patients with and without HIV infection.
6
It is thought that
by a similar cytokine-mediated mechanism, bacterial sepsis may
precipitate myocardial depression, particularly in patients with
underlying cardiac disease.
7
The cytokine-mediated upregulation
of inducible nitric oxide synthetase in sepsis results in increased
production of reactive oxygen species and interference with
calcium homeostasis, thereby impairing myocyte contractility.
8
HIV cardiomyopathy
DCMO is common in late-stage HIV infection. A Rwandan study
found the prevalence of echocardiogram-diagnosed DCMO to be
17.7% among 416 consecutively screened HIV-infected patients
without a previous history of heart disease.
9
In autopsy studies,
myocarditis is present in nine to 52% of HIV-infected patients. In
only 10 to 15% of these cases of myocarditis can evidence of a
bacterial, fungal or protozoal infection be found.
10-12
The majority
of other cases of DCMO are thought to be a result of the direct
or immune-mediated effects of HIV itself.
A direct role for HIV infection in the development of DCMO
was suggested by a study of 952 asymptomatic HIV-infected
patients who were followed for 60 months.
13
DCMO was
diagnosed by echocardiogram in 8%, most of whom had
evidence of a myocarditis on endomyocardial biopsy. Among
these patients, 76% had HIV nucleic acid sequences present
in the myocytes, while 26% had evidence of Coxsackie virus,
cytomegalovirus, or Epstein-Barr virus infection.
HIV may induce myocardial injury through three putative
mechanisms.
14
Firstly, HIV may have a direct cytotoxic effect on
the myocytes.
15
Secondly, HIV-related immune activation may
result in high levels of pro-inflammatory cytokines, which result
in dysfunction and apoptosis of cardiac myocytes. Thirdly, this
immune activation may drive an auto-immune reaction targeting
host myocardial cells.
IRIS myocarditis
IRIS may affect any organ system and has been described in
association with a wide variety of pathogens as well as auto-
immune conditions and with HIV itself.
3
To our knowledge, there
has been one published case of IRIS-associated myocarditis. The
patient was a 29-year-old HIV-infected man with a CD
4
count
of 56 cells/ml who presented five weeks after commencing
ART, with acute myocarditis complicated by fatal polymorphic
ventricular tachycardia.
16
At post mortem, he was found to have evidence of a
cytomegalovirus (CMV) pneumonia and a predominantly CD
8
lymphocytic infiltrate of his myocardium and conduction system.
Immunohistochemical staining for CMV in his myocardium was
negative. The myocarditis was attributed to IRIS, given the
timing of the presentation, the marked reduction in HIV viral
load on ART and the prominent inflammatory infiltrate of the
myocardium. The antigenic target of the IRIS was likely HIV
itself or an undiagnosed pathogen.
In the case we present here, it was not possible to exclude a
cellular infiltrate of the myocardium due to IRIS myocarditis
because we did not perform an endomyocardial biopsy, but the
MRI findings did not suggest myocardial inflammation, making
this unlikely.
17
We also considered the possibility that our patient’s
heart failure resulted from inflammation in the myocardium due
to TB-IRIS myocarditis. However, because of the MRI showing
no evidence of inflammation in the myocardium, we think this
unlikely. We would expect TB myocarditis to be characterised by
areas of focal gadolinium enhancement on cardiac MRI.
18
Conclusion
This patient had no symptoms of heart failure prior to ART. After
starting ART he developed paradoxical TB-IRIS, a diagnosis
that we made on the basis of the characteristic clinical features
described above and which was supported by his having
exacerbations of TB-IRIS symptoms on weaning prednisone but
improvement when recommenced on higher doses. Prednisone
has been shown to result in symptomatic improvement in
TB-IRIS.
19
