Authors: Andrew Corson, Ranjit Philip, Neil Tailor, Abhishek Chakraborty, Kaitlynn Littleford, Grace McCormick, Aaron Walsh
Categories: Cardiometabolic, autism spectrum disorder, congenital heart defect, diet, echocardiography, malnutrition, pulmonary hypertension, right ventricle, thrombosis, thrombus
Source: JACC Case Reports
Authors: Andrew Corson, Ranjit Philip, Neil Tailor, Abhishek Chakraborty, Kaitlynn Littleford, Grace McCormick, Aaron Walsh
Pediatric pulmonary hypertension comprises a variety of etiologies across different age groups, requiring a systematic approach to diagnosis in children.
A 7-year-old boy with nonverbal autism, oral aversion, and resolved muscular ventricular septal defect presented with heart failure and was found to have severe pulmonary hypertension. The initial diagnosis and treatment course was altered after a misleading cause, and he was ultimately found to have undetectable vitamin C levels. After repletion, he was weaned off pulmonary hypertension therapy and received nutritional supplementation via a gastrotomy tube.
Chronic vitamin C deficiency can lead to pulmonary hypertension, and pediatric patients with neurodevelopmental disorders are at a higher risk of developing nutritional deficiencies.
This case emphasizes the importance of having a broad differential for pulmonary hypertension, with a systematic approach to thinking beyond congenital heart disease–related, autoimmune-related, and idiopathic pulmonary hypertension in children.
A 7-year-old boy presented to an outside emergency department with worsening labored breathing after a 1-week history of coughing while lying flat. In the emergency department, he was found to have elevated troponin I (0.22 ng/mL) and B-type natriuretic peptide (856 pg/mL), as well as hypoxemia to 85% without support. He was transferred to our pediatric hospital for concerns of myocarditis and heart failure. His physical examination showed an underweight child in moderate respiratory distress with an ulcer on the upper gum, a normal S1 and S2 without a gallop, no murmurs, scattered rhonchi, hepatomegaly, and no overt skin findings or swollen joints. Echocardiography in the emergency department showed near-systemic pulmonary hypertension with no evidence of left heart involvement. Electrocardiogram showed sinus rhythm with T-wave inversion in the lateral leads.Take-Home Messages•This case emphasizes the importance of having a broad differential for pulmonary hypertension, with a systematic approach to thinking beyond congenital heart disease–related, autoimmune-related, and idiopathic pulmonary hypertension.•With the rise in autism spectrum disorders, physicians should attentively consider nutritional deficiencies as underlying causes for atypical diagnoses.
The patient had a medical history of nonverbal autism, as well as being previously evaluated by a pediatric cardiologist for a ventricular septal defect. He had a recent history of multiple emergency department visits for knee pain and was diagnosed with toxic synovitis and popliteal cellulitis, which was diagnosed on magnetic resonance imaging and was treated with antibiotics. He had now progressed to being nonweightbearing and requiring a wheelchair. An outpatient rheumatology work-up was reportedly negative. One week before his presentation at our hospital, a viral swab was positive for rhinovirus. He was also recently seen at a dentist for bleeding oral ulcers and was placed on amoxicillin. His diet was very limited, only drinking milk and eating cheese puffs. He had previously been in feeding therapy but had been lost to follow-up because of the 2020 coronavirus pandemic.
Our differential diagnoses of the patient's pulmonary hypertension at the time of admission were World Health Organization group 1, group 3, or group 5 causes. The patient did not have echocardiographic findings of group 2 causes. Vitamin deficiencies were also on our differential given the oral ulcers, nonambulatory status, and new onset of pulmonary hypertension. Considering his recent viral infection with elevated troponin, myocarditis was also on the differential.
The patient's initial echocardiogram in the emergency department showed a dilated and hypertrophied right ventricle with qualitatively decreased systolic function, nearly systemic right-sided pressures with a tricuspid valve regurgitation jet of 77 mm Hg, ventricular septal flattening, moderate tricuspid valve regurgitation, and normal left ventricular systolic function. A patent foramen ovale was present and shunting right to left, with a bowing atrial septum to the left. He had no evidence of left-sided obstructions.
The patient was admitted to our cardiac care unit with supplemental oxygen support. We consulted pediatric rheumatology, who had low suspicion of an underlying autoimmune disease. On hospital day 2, the patient's echocardiogram showed worsening pulmonary hypertension, with now systemic right-sided pressures with a small pericardial effusion (Figures 1 and 2). Computed tomography (CT) angiography performed on hospital day 2 showed possible nonocclusive pulmonary emboli in the medial segment of the right middle lobe pulmonary arterial branch and the left basilar subsegmental branch, along with left upper partial anomalous pulmonary venous return, and opacities in the lung bases suspicious for pulmonary edema, infectious etiology, or atelectasis (Videos 1 and 2).Figure 1Initial Echocardiography Findings: Parasternal Long-Axis View(Left) Parasternal long-axis view showing moderate tricuspid valve regurgitation, with a TR jet of 98 mm Hg (systemic blood 100/76 mm Hg). (Right) Parasternal long-axis view showing trivial pulmonary valve insufficiency, with a peak PI gradient of 39 mm Hg. PI = pulmonary insufficiency; TR = tricuspid regurgitation.Figure 2Initial Echocardiography Findings: Apical 4-Chamber and Short-Axis Views(Left) Apical 4-chamber view showing severe right ventricular dilation with atrial septum bowing into the left atrium. A small pericardial effusion is also seen. (Right) Short-axis view showing a pancaked left ventricle due to interventricular septal bowing from right ventricular hypertension.
The patient's status continued to deteriorate, and he was transferred to our cardiac intensive care unit on hospital day 3. He required intubation and was placed on vasodilator therapies such as oral sildenafil (10 mg every 8 hours) and inhaled nitric oxide at 20 ppm. Given the findings on CT angiography, the patient was started on systemic anticoagulation with alteplase at a dose of 0.06 mg/kg/h, with concerns for possible chronic thromboembolic disease (CTEPH). Within hours of starting alteplase, he had to be transitioned to systemic heparin given significant oral bleeding. Being a rare entity in pediatrics, the CT images were reviewed with international CTEPH specialists, who disagreed with the diagnosis. Their reasoning was that even though the subsegmental pulmonary artery branches were not well opacified with contrast, this was likely due to artifact or poor contrast timing and did not suggest a diagnosis of CTEPH. This clarification marked a crucial turning point in the patient's clinical management and emphasized the importance of obtaining expert opinions on rare diagnoses. Their suggestion was to continue our work-up for group 1 causes of pulmonary hypertension.
Coagulation and infectious disease causes did not reveal any abnormalities. The patient's nutritional deficiencies included undetectable vitamin C levels, for which he received replenishment with 400 mg (equivalent to 20 mg/kg/d) of ascorbic acid, which was added to his total parental nutrition. Our treatment goal was to administer this amount daily for 1 month or until scurvy symptoms resolved. His laboratory tests also showed low 25-hydroxy vitamin D levels (24.9 ng/mL, reference 30-70 ng/mL). He was treated with cholecalciferol 1,000 IU/d. He was also noted to be iron deficient on admission, having a total iron level of 28.0 μg/dL (reference 53.0-151.0 μg/dL), an elevated total iron binding capacity of 417 μg/dL (reference 162-344 μg/dL), and low normal ferritin level of 10.4 ng/mL (reference 10.0-60 ng/mL). He was treated with ferrous sulfate 220 mg twice daily.
On hospital day 5, a ventilation/perfusion scan showed multiple irregular segmental or subsegmental perfusion abnormalities, with wedge-shaped perfusion defects seen within the right upper lobe apical segment and right middle lobe medial and lateral segments. There was also diffusely decreased perfusion to the left lung compared with the right, which was said to be directly related to pulmonary artery hypertension. These findings provided an intermediate-probability result for pulmonary embolism. The patient continued to clinically improve, and pulmonary pressures decreased on repeat echocardiography. Given the intermediate-probability ventilation/perfusion scan results, repeat CT angiography was performed, which again showed no evidence of pulmonary emboli.
The patient then underwent cardiac catheterization on hospital day 10, which showed dilated branch pulmonary arteries and confirmed the anomalous left upper pulmonary vein (Figure 3). The catheterization data revealed normal hemodynamic pressures without significant shunting or elevation in pulmonary vascular resistance (Table 1). He eventually was extubated and was transferred out of our intensive care unit on hospital day 14.Figure 3Cardiac Catheterization Angiography Findings(Left) Angiogram showing dilated bilateral branch pulmonary arteries. (Right) Angiogram showing anomalous drainage of the left upper pulmonary vein to the innominate veinTable 1Cardiac Catheterization Hemodynamics After Ascorbic Acid ReplenishmentCardiac catheterization data•Hemoglobin: 9.2 g/dL, aVO2: 130 mL/min/m^2^, ABG: 7.57/30/52/27/+5•Catheterization performed intubated, sedated, on 21% FiO2Calculations•Qp:Qs = 1.3:1 (using 82% as mixed venous, 85% as pulmonary artery to account for PAPVR)•Cardiac 8 L/min/m^2^•Transpulmonary 8 mm Hg•PVRi: 0.77 WU/m^2^Pressures•Femoral 82/42, mean 57 mm Hg•Right 11/10, mean 7 mm Hg•Right 30/11 mm Hg•Right pulmonary 25/10, mean 17 mm Hg•Right pulmonary capillary 9 mm Hg•Left pulmonary 25/15, mean 17 mm Hg•Left pulmonary capillary 10 mm HgSaturations•Femoral 95%•Innominate 94%•High SVC: 82%•Low SVC: 85%•Pulmonary 77%•Left pulmonary 77%ABG = arterial blood gas; aVO2 = assumed oxygen consumption; FiO2 = fraction of inspired oxygen; PAPVR = partial anomalous pulmonary venous return; PVRi = indexed pulmonary vascular resistance; Qp:Qs = pulmonary-to-systemic blood flow; SVC = superior vena cava.
The patient improved clinically and underwent gastrostomy tube placement for continued nutritional support. He was weaned off all pulmonary hypertension therapy before being discharged and remained on thrombus prophylaxis as a precaution, given his initial diagnosis. His vitamin C level at the 3-month outpatient follow-up was 0.9 mg/dL (reference 0.2-2.1 mg/dL). He followed up with hematology in the outpatient setting and is now off thrombus prophylaxis. At outpatient cardiology follow-up, he continues to show no evidence of elevated right-sided pressures.
Vitamin C deficiency, thought to be an ancient disease, still has prevalence in certain pediatric patient populations, particularly those who experience feeding challenges such as food aversion in autism spectrum disorders. The prevalence of vitamin C deficiency is not currently known in high-income countries. A survey performed in 2003 to 2004 showed vitamin C deficiency in 1.6% of children between the ages of 6 to 11 and <4% in adolescents; however, in low-income countries, deficiency can be seen in up to 23% of school-aged children. The most common presenting manifestations of vitamin C deficiency are musculoskeletal issues, mucosal involvement, and cutaneous lesions, with rare clinical manifestations of pulmonary hypertension only being seen in 3%.^1^ With regard to autism, a recently published study showed a significant increase in autism spectrum diagnoses, with an association surrounding the pandemic shutdowns and lack of health care services.^2^
There have been only a few case reports of pediatric patients presenting with pulmonary hypertension secondary to vitamin C deficiency. One case report described a 9-year-old with autism and a limp who was found to have undetectable vitamin C levels as well as other vitamin deficiencies, and severe pulmonary hypertension, which resolved with resupplementation.^3^ Another reported 2 cases of severe pulmonary hypertension resulting from severely restrictive diets, in a 2-year-old who experienced cardiac arrest and in a 6-year-old boy who had cardinal symptoms of heart failure.^4^ There was also a case report of a 3-year-old who experienced a pulmonary hypertensive crisis while undergoing anesthesia induction, who was then diagnosed with scurvy.^5^ A recently published systematic review of case reports showed that pulmonary hypertension and right-sided heart failure can be attributed to scurvy.^6^
Systematically, we went through our differential with the information at hand for pulmonary hypertension causes using World Health Organization classifications. With the initial presenting symptoms of heart failure and potential myocarditis, group 2 pulmonary hypertension was on our differential; however, echocardiography did not show any evidence of left-sided heart failure, mitral valve stenosis, or pulmonary vein stenosis. The initial CT angiography was read as showing bilateral nonobstructive pulmonary emboli, which led us to treat this patient as within the group 4 category of pulmonary hypertension. He was initially treated with systemic anticoagulation, but he experienced side effects of bleeding. Later, this diagnosis was disputed by the international CTEPH specialists. Follow-up angiography did not show evidence of pulmonary emboli. The patient's age of presentation, along with lack of prematurity or lung disease history, did not make us suspect a group 3 diagnosis.
Our patient did have dilated right-sided structures with anomalous left upper pulmonary venous return. However, as documented on our cardiac catheterization, the pulmonary-to-systemic blood flow (Qp:Qs) was only 1.3:1, so chronic pulmonary overcirculation or congenital heart disease was not a factor in his presenting illness. The patient's indexed pulmonary vascular resistance was 0.77 WU/m^2^. His history of ventricular septal defect was not the cause of his presentation either, and there was no evidence of Eisenmenger syndrome. There was no family history of connective tissue disorders, and rheumatological laboratory work-ups (rheumatoid factor; antibodies to antinuclear, ribonucleoprotein, myeloperoxidase, proteinase, and Sjögrens) were all negative. There was also no family history of pulmonary hypertension or medication or drug exposure; therefore, we did not suspect a group 1 cause.
We were then left with a group 5 cause of pulmonary hypertension, and we attributed this to the patient's vitamin C deficiency. Ascorbic acid plays an essential role in smooth muscle–mediated vasodilation by recycling tetrahydrobiopterin (BH4), which is then used in the synthesis of nitric oxide. It is also involved in reducing nitrite to nitric oxide, releasing nitric oxide from nitrosothiols, and acting as a catalyst to increase production of cGMP (cyclic guanosine-3′-5′-monophosphate).^7^ Huang et al^8^ concluded that ascorbic acid enhances the production of endothelial cell nitric oxide, as well as improving the overall bioactivity of nitric oxide. From a biochemical standpoint, ascorbic acid plays an indirect but necessary role in reducing pulmonary artery pressures by increasing the levels of nitric oxide in our bodies.^8^
Chronic vitamin C deficiency in children can present as a constellation of examination findings such as gingival hyperplasia/bleeding, petechiae, and gait disturbances. As shown in a few case reports as well as our case, it can rarely be a cause of pulmonary hypertension. Although known to be a historic disease, neurodevelopmental disorders in pediatric patients put them at risk for malnutrition, leading to scurvy.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.