Edited by: Oswin Grollmuss, Centre Chirurgical Marie Lannelongue, France
Reviewed by: Dunbar Ivy, University of Colorado School of Medicine, USA; Christian Apitz, Pediatric Heart Center Giessen, Germany; Olivier Sitbon, Université Paris-Sud, France
This article was submitted to Pediatric Cardiology, a section of the journal Frontiers in Pediatrics.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Since the advent of highly active anti-retroviral therapy, HIV-related mortality has decreased dramatically. As a consequence, patients are living longer, and HIV infection is becoming a chronic disease. Patients and caretakers have to deal with chronic complications of infection and treatment, such as cardiovascular diseases, which now represent an important health issue, even in the pediatric population. Prevalence of pulmonary arterial hypertension (PAH) in the adult HIV population is around 0.4–0.6%, which is around 1000- to 2500-fold more prevalent than in the general population. In recent adult PAH registries, HIV has been identified as the fourth cause of PAH, accounting for approximately 6–7% of cases. Therefore, regular screening is recommended in HIV-infected adults by many experts. If HIV-associated PAH is mainly reported in HIV-infected adults, pediatric cases have also been, albeit rarely, described. This scarcity may be due to a very low PAH prevalence, or due to the lack of systematic cardiovascular screening in pediatric patients. As PAH may manifest only years or decades after infection, a systematic screening should perhaps also be recommended to HIV-infected children. In this context, we retrospectively looked for PAH screening in children included in our national Swiss Mother and Child HIV cohort study. A questionnaire was sent to all pediatric infectious disease specialists taking care of HIV-infected children in the cohort. The questions tried to identify symptoms suggestive of cardiovascular risk factors and asked which screening test was performed. In the 71 HIV-infected children for which we obtained an answer, no child was known for PAH. However, only two had been screened for PAH, and the diagnosis was not confirmed. In conclusion, PAH in HIV-infected children is possibly underestimated due to lack of screening. Systematic echocardiographic evaluation should be performed in HIV-infected children.
WHO estimated in 2010 that 34 millions of humans were infected with HIV, 10% being younger than 15 years old (
Since the advent of highly active anti-retroviral therapy (HAART), HIV-related mortality has decreased dramatically both in adults (
Because of the lack of randomized control studies, it is difficult to differentiate the etiological role of the virus itself from the impact of HAART in pulmonary arterial hypertension (PAH), as well as other cardiovascular manifestations. PAH is a serious disease of the pulmonary arteries characterized by vascular remodeling due to dysfunctional proliferation of smooth muscle and endothelial cells (
Despite this, no systematic cardiovascular screening is usually suggested to HIV-infected children. To demonstrate this, we sent a questionnaire to all infectious diseases specialists taking care of HIV-infected children in Switzerland, part of the Swiss Mother and Child HIV (MoCHIV) cohort study to evaluate if they look for PAH symptoms and perform screening procedures. We will first review HIV-related PAH (HIV-PAH) and second describe the results of our questionnaire.
Pulmonary arterial hypertension was described in HIV-infected patients for the first time in 1987 (
Pulmonary arterial hypertension is defined as a resting PAP >25 mmHg, associated with a pulmonary arterial occlusion pressure (PAOP) ≤15 mmHg (
Diagnosis relies on clinical symptoms, such as fatigue and dyspnea, as well as clinical findings, such as an increase in the pulmonary component of the second heart sound, a tricuspid regurgitation murmur or a right fourth heart sound, and signs of right heart failure. Chest X-rays may show cardiomegaly and pulmonary arteries enlargement, and the electrocardiogram shows right ventricular hypertrophy with right axis deviation. When PAH is suspected, echocardiography is the most useful diagnostic tool (
Prevalence of HIV-PAH is around 0.2–0.6% (
HIV-related PAH physiopathology is not completely understood, is probably multifactorial, and includes genetic factors. It is hypothesized that HIV acts as a trigger, maintaining chronic inflammation and immune activation. Histological features, which closely resemble those seen in idiopathic PAH, show in most cases a pulmonary arteriopathy with so-called “plexiform lesions” associated with concentric laminar intimal fibrosis, medial hyperplasia, and white cells. They suggest chronic inflammation (
HIV was never detected – to our knowledge – in the pulmonary endothelial cell using different techniques, such as immunohistochemistry, HIV-DNA hybridization, electron microscopy, or PCR. The absence of virus in endothelial cells, but its presence in alveolar macrophages, suggests an indirect action through mediator release rather than a direct endothelial infection (
Endothelial dysfunction in PAH is characterized by a reduced production of vasodilatators prostacyclin and nitric oxide (NO) and an increased production of endothelin-1 (ET-1) (
The role of viral proteins has also been studied. Despite the absence of virus in endothelial cells, HIV envelope protein Gp120 has been shown to be toxic
Tat is another viral protein secreted by HIV-infected cells, which stimulates endothelial cells, enhancing vascular permeability via IL-6 (
Similarly, HIV-1 proteins expression increased pulmonary vascular resistance among rats exposed to chronic hypoxia compared to wild-type rats (
Levels of asymmetric dimethylarginine (ADMA), an endothelial NO synthase inhibitor, are increased during HIV infection because of sustained inflammation. This may contribute to endothelial dysfunction, as ADMA levels are correlated with PAP in HIV-infected patients (
Other factors may contribute to HIV-PAH pathophysiology. HCV infection or drug use are independent etiologies of PAH; however, as they are more frequent among HIV-infected patients, they may act as confounding factors (
Clinically, symptoms of HIV-PAH are similar to idiopathic PAH. Early HIV-PAH may be misdiagnosed because of non-specific symptoms, such as exercise intolerance, progressive dyspnea (85%), edema (30%), and non-productive cough (19%) (
HIV-related PAH carries a poor prognosis: mortality is mainly due to PAH rather than to HIV complications: PAH is therefore a predictor of mortality by itself (
The relationship between the severity of HIV and PAH is subject to debate. HIV-PAH occurs at all stages of HIV infection. Most authors could not show an association between HIV-PAH and low CD4 T cell count (
Regarding viremia, several studies could not find an association with HIV-PAH (
Because survival is related to NYHA stage, early diagnosis and treatment are paramount (
Oxygen reduces hypoxia-induced pulmonary vasoconstriction, whereas diuretics reduce right ventricular preload, and digoxin increases cardiac output. Oral anticoagulation reduces the possible thrombotic component of PAH (
Prostacyclin analogs can be administered by IV infusion, inhalation, or subcutaneously.
Epoprostenol, the intravenous form of a prostacyclin analog, has been shown to induce clinical (
Sildenafil, a phosphodiesterase inhibitor type 5, is the most frequently used medication in idiopathic PAH. In HIV-PAH, its use is limited because of its interaction with protease inhibitors (PIs), through the 3A4 P450 cytochrome pathway (
Bosentan, an oral dual endothelin receptor antagonist, acts by inhibiting the potent vasoconstricting properties of endothelin. Bosentan has been shown to induce a clinical and hemodynamic improvement among HIV-infected patients (
A treatment algorithm was recently proposed for HIV-PAH (
The role of HAART in PAH is unclear. As chronic inflammation probably contributes to HIV-PAH pathophysiology, one may suspect a beneficial effect of HAART on HIV-PAH by reducing inflammation. In rats, PIs reverse or decrease PAH progression by reducing remodeling and smooth muscle cell proliferation (
On the other hand, other studies have shown a deleterious effect of HAART on HIV-PAH, possibly secondary to PI-induced endothelial dysfunction (
In general, HIV-PAH prevalence has not changed significantly since HAART was introduced. This may suggest that antiviral drugs have a little effect on sites where the virus affects vascular cells. However, a protective effect of HAART on survival and incidence may explain a stable prevalence, as patients are now living longer. In clinical practice, since the Opravil et al. study showing an improvement of the pressure gradient when the patients were treated, experts recommend to introduce HAART at the time of HIV-PAH diagnosis, regardless of CD4 T-cell counts (
While HIV-PAH mainly concerns HIV-infected adults, pediatric cases have also been described (
In a recent registry study of more than 360 children in 19 countries – including Switzerland – with confirmed PAH, there was no HIV-infected child (
To demonstrate a correlation between HIV and PAH in HIV-infected children, we retrospectively analyzed cardiovascular and, in particular, PAH screening of children in the Swiss MoCHIV cohort study.
The MoCHIV Cohort Study is a merger of the former Neonatal HIV Study and the Swiss HIV and Pregnancy Study. Initially, the main goal was to collect a maximum of data in children born to HIV-infected mothers and HIV-infected children to gain epidemiological information and to study vertical transmission and natural history of disease. In 1998, a merged project was built named The Swiss MoCHIV Study. In 2004, a permanent link was established between the Swiss HIV Cohort Study (SHCS) and MoCHIV. Thus, longitudinal data in women included in both cohorts became available for research, making MoCHIV a very unique mother–child cohort. All mothers and children are given a cohort number, which is then used to collect data in both cohorts anonymously. Women and children are followed according to good clinical practices, as defined by the respective guidelines for adults, pregnant women, and children. These have been regularly adjusted according to growing knowledge.
It is estimated that approximately 75% of HIV-infected children living in Switzerland are part of MoCHIV. All Swiss pediatric infectious disease experts following HIV-infected children in the cohort received a person-specific questionnaire. The questions concerned symptoms suggestive of PAH and which cardiovascular screening was performed. In addition, questions concerning HIV status (CD4 T-cell count, viremia, HAART treatment or not) were recorded (Figure
Among the 83 children currently included in the MoCHIV cohort study, the questionnaire was retrieved for 71 (86%) children. As suspected, no child of the MoCHIV cohort was known for PAH. Only two children (3%) had been screened for PAH, one because of thoracic pain and one because of dizziness, but diagnosis was not confirmed. Echocardiographic studies have reported higher prevalence of PAH (
Increased PAH risk in HIV-infected children, due to HIV infection and/or anti-retroviral treatment, creates new challenges and has serious implications for the quality of life and the survival of this population. However, despite a clearly increased risk, PAH detection is neglected in HIV-infected children. The true impact of PAH can only be appreciated after years or decades because of its silent and slow progression. Survival among HIV-infected children will probably continue to increase with more potent treatment options. As demonstrated in several studies, the prevalence of echocardiographic signs of increased PAP despite being below PAH definition level is more frequent than expected, even in children. Therefore, a systematic PAH screening should be proposed in this at-risk population (
The Review Editor Dunbar Ivy declares that, despite having collaborated on publications in the last 2 years with author Maurice Beghetti, the review process was handled objectively. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors acknowledge all members of the MoCHIV cohort study who answered our questionnaire, especially Jean-Jacques Cheseaux, Claire-Anne Wyler, David Nadal, Christian Kahlert, Andrea Duppenthaler, and Christoph Rudin.