Pulmonary arterial hypertension (PAH) affects approximately 0.5% of human immunodeficiency virus (HIV)-infected adult patients at all stages of the disease and carries a poor prognosis.1 The effectiveness of highly active antiretroviral therapy (HAART) in patients with HIV-related PAH (HIV-PAH) remains controversial.2,3 Little is known about the incidence and clinical course of, and therapy options for PAH in HIV-1 infected pediatric patients.4,5 Here, we report on a 3-month-old, HIV-infected immature preterm infant with unexplained acute respiratory distress syndrome (ARDS) and life-threatening HIV-PAH, which completely resolved on HAART administration.
A 30-year-old gravida II from Sambia with unknown HIV-antibody status was admitted to the hospital with premature rupture of membranes at 23 6/7 weeks of gestation. Two days later, after receiving betamethasone to induce fetal lung maturation she delivered a female preterm infant by emergency cesarean section. The birth weight was 708 g, and APGAR scores were 1, 4, and 8 at 1, 5, and 10 minutes, respectively. The infant was intubated, received surfactant, and was mechanically ventilated until day 31. A patent ductus arteriosus was ligated on day 24 after 2 unsuccessful attempts of pharmacological closure with indomethacin. After extubation on day 31 and 5 more days of nasal continuous positive airway pressure ventilation, the infant continued to require supplemental oxygen until day 70. Two episodes of nosocomial infections with positive blood cultures for Candida albicans (day 16) and Staphylococcus aureus (day 29) were successfully treated. From day 28 to day 57, the patient received spironolactone and hydrochlorothiazide for the treatment of suspected bronchopulmonary dysplasia.
On day 93, the clinical status deteriorated as evidenced by recurrent episodes of apnea and arterial hypoxemia requiring supplemental oxygen (Fig. 1C). In addition, peripheral lymphadenopathy was noted. Chest radiograph revealed mild patchy pulmonary infiltrates and a boot shaped heart silhouette (Fig. 1A), possibly the first signs of right ventricular dysfunction. White blood cell counts, C-reactive protein, and interleukin-6 values were normal. Serologic tests for Mycoplasma pneumonia, Chlamydiapneumonia and Epstein-Barr virus, and the polymerase chain reactions for cytomegalovirus in urine and respiratory syncytial virus in respiratory secretions were negative. However, HIV-1-antibodies were detected in infant and mother, and HIV-1-infection was subsequently confirmed by polymerase chain reactions. On day 100, the infant had a CD4 cell count of 1739/μL (29%) and a HIV-1 RNA plasma viral load of >100,000 copies/mL. Pneumocystisjirovecii prophylaxis with trimethoprim-sulfamethoxazol was initiated, while HAART was deferred.
After transient respiratory improvement in response to treatment with diuretics, increasing arterial hypoxemia developed on day 120 requiring mechanical ventilation which was resumed with increasing ventilator settings [fraction of inspired oxygen (FiO2) 1.0, peak inspiratory pressures up to 36 mbar]. Chest radiograph showed cardiomegaly and extensive patchy infiltrates in both lungs. Echocardiography revealed severe PAH and right heart failure (Fig. 1B). Right ventricular systolic pressure, as estimated by tricuspid regurgitant velocity (4 m/s) was similar to systemic systolic blood pressure (60–80 mm Hg versus 70 mm Hg). The main pulmonary artery was dilated, right artrial and ventricular diameters were extremely enlarged and showed critically reduced right-ventricular contractility. There was no evidence of left ventricular dysfunction or congenital heart malformation. Despite inhaled nitric oxide, iloprost, diuretics, and digoxin, the infant's hemodynamic and respiratory condition remained critical. Ventricular fibrillation on day 124 responded to cardiopulmonary resuscitation and electrical defibrillation.
The inflammatory indices, C-reactive protein, and interleukin-6 were normal and repeated cultures of blood, urine, and pleural effusions (bilateral chest drainages on day 122) were negative for bacteria or fungi. Tracheal aspirates were negative for cytomegalovirus, Epstein-Barr virus, fungal pathogens, and Pneumocystisjirovecii antigen but there was growth of Staphylococcus aureus and Klebsiellapneumonia, a result of questionable significance. The institution of empiric broad spectrum antibiotics (ceftazidime, vancomycin, and meropenem), systemic antimycotics (liposomal amphotericin B, flucytosine), and high-dose trimethoprim-sulfamethoxazol against suspected Pneumocystisjirovecii pneumonia did not lead to any noticeable improvement of the clinical status.
On day 132, plasma HIV-RNA viral load was 213.600 copies/mL and CD4 cell count fell to a nadir of 111 cells/μL (25%). HAART was initiated on day 135, consisting of zidovudine (180 mg/m2 twice a day), lamivudine (4 mg/kg twice a day), and nevirapine (5 mg/kg once daily for the first 14 days followed by 7 mg/kg twice a day). After 4 weeks, zidovudine was replaced by stavudine (1 mg/kg twice a day) because of gastrointestinal side effects which resolved after changing therapy.
Two days after initiation of HAART, on day 137, clinical status including arterial hypoxemia improved dramatically and inhaled nitric oxide, iloprost, and mechanical ventilation could be discontinued gradually until day 140. On day 174, the infant was discharged from the hospital in stable condition. Oxygen supplementation was continued until 6 months of age. Echocardiographic examinations showed a significant reduction of right ventricular systolic pressure and right ventricular diameter, and an improvement of right ventricular function. Digoxin and diuretics were finally discontinued at 24 months of age. By 44 months of age, echocardiography showed only mild right ventricular and pulmonary artery dilatation with normal right ventricular function.
Within 5 weeks after initiation of HAART, the plasma HIV-RNA viral load had decreased from 180,600 to 526 copies/mL, and the CD4 cell count had increased from 111 cells/μL (25%) to 1498 cells/μL (35%). After 12 weeks, the plasma viral load was below the limit of detection (<50 copies/mL), which has been sustained during a follow-up period of 42 months. During the same time, the CD4 cell count has remained within normal limits. The patient remained in good health and showed a psychomotor development (Bayley Scales of Infant development II at 28 months corrected age: mental development index of 86) corresponding to former preterm girls of 24 weeks gestational age.6 Except for respiratory syncytial virus pneumonia at 27 months of age, no further hospital admissions were required.
In adult and pediatric patients, HIV-PAH is a serious cardiovascular complication with insidious onset and typically rapid disease progression.7 This seems to be the first report of a case of an extremely immature preterm infant with HIV-PAH presenting in conjunction with a pneumonia-like disease that met criteria of ARDS.8 Both HIV-PAH and ARDS promptly resolved after institution of HAART.
A series of events before the onset of HIV-PAH and ARDS may have damaged the infant's lungs including the vasculature, such as extreme preterm birth, a patent ductus arteriosus, prolonged mechanical ventilation, and systemic bacterial or viral infections. However, despite the infant's extreme immaturity and prolonged mechanical ventilation, her bronchopulmonary dysplasia, according to the National Institutes of Health criteria, could only be classified as “mild.”9 Moreover, during the weeks preceding the onset of PAH and the pulmonary pathology, the infant was doing well without supplemental oxygen.
Even after extensive sampling, an infectious etiology could not be identified and empirically instituted broad spectrum antibiotics and antimycotics did not result in clinical improvement. We did not test, however, for human herpes virus-8 (HHV-8), which recently has been reported to be associated with HIV-PAH.10
The pathogenesis of HIV-related PAH is still unknown. The pathologic lung lesions are characterized by intimal fibrosis, medial hypertrophy, and plexiform lesions. Given that neither HIV nor other infectious agents have been identified in these lesions, it has been suggested that the HIV infection may damage the pulmonary endothelium by a mechanism unrelated to direct infection.11,12 The infant's condition, however, strikingly improved after initiation of HAART and ultimately resolved. Clinical improvement was accompanied by sustained suppression of HIV viral load and immunologic recovery. Although the course of HIV-PAH tends to improve with antiretroviral therapy in adult patients,3,13 there is to date only 1 report of complete regression of HIV-PAH and long-term survival after antiretroviral therapy with a combination of lamivudine, stavudine, and nelfinavir.14
In conclusion, untreated HIV-infection may have precipitated severe lung disease and life-threatening pulmonary hypertension in this extremely preterm infant. The clinical, virologic, and immunologic responses to HAART of our infant are very encouraging and, until larger case series become available, support the use of HAART even in young infants with severe HIV-PAH. PAH should be considered in any HIV-infected pediatric patient with severe cardiopulmonary dysfunction. Early diagnosis of the disease is essential for initiation of appropriate therapy.
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