Protein-Losing Enteropathy and Plastic Bronchitis After the Fontan Operation

Chronic low cardiac output from Fontan circulation and single-ventricle physiology may lead to mesenteric vasoconstriction. Rychik and Gui-Yang⁷  studied the Doppler flow patterns in the superior mesenteric arteries of patients with normal physiology, patients with Fontan physiology without PLE, and patients with Fontan physiology and PLE. Patients with active PLE had absent diastolic flow, suggesting very high mesenteric vascular resistance. The author proposed a paradigm for the mechanism of PLE (Figure 2).⁶  The low cardiac output, high venous pressure, and congestive heart failure in patients with Fontan physiology lead to increased mesenteric vascular resistance, resulting in venous hypertension and congestion. Congestive heart failure and low cardiac output cause inflammation, which results in the release of tumor necrosis factor a, subsequently disrupting intestinal integrity and leading to protein leakage. The release of tumor necrosis factor a alters enterocyte basal membrane glycosaminoglycan makeup and basal membrane heparin sulfate, contributing to the existing protein leak. Patients may have an unknown congenital predisposition to protein leakage that may progress to a disease state when conditions of the Fontan pathway are present.⁶  Meadows and colleagues⁸  have extended the paradigm to consider PLE a disorder of lymphatic insufficiency. Their study found that central venous thrombosis and other forms of central venous obstruction may be contributive or causative factors of PLE. Thus, poor perfusion and dilated lymphatic vessels in combination with inflammation and a genetic predisposition are thought to be responsible for the development of PLE.^6,8  Protein-losing enteropathy is largely a disease of central venous congestion, so patients may have normal systolic function and cardiac output.

Clinical manifestations of PLE include abnormal lymphatic flow, hypoalbuminemia, and coagulopathies. Lymphangiectasia, a hallmark sign of PLE, is a result of increased SVR. Increased SVR causes lymphatic vessels to dilate, leading to loss of protein into the gut and hypoproteinemia. Loss of albumin reduces the transport capacity of calcium, causing hypocalcemia.⁹  Adverse effects of hypocalcemia include osteopenia, poor growth, and (in severe cases) tetany. Protein loss and hypoalbuminemia can also predispose patients to hypogammaglobulinemia and loss of immunoglobulin G. Low serum protein decreases circulating coagulation factors because of deficiencies in basal membrane heparin caused by altered glycosaminoglycan makeup.⁶  Loss of coagulation factors can produce a hypercoagulable state.⁹  Excessive lymphatic fluid contributes to the engorged intestinal lymphatic system in PLE, resulting in lymphopenia and immunodeficiency.⁹ 

The gold standard for diagnosis of PLE is the 24-hour stool α₁-antitrypsin (AAT) clearance study.⁹  α₁-Antitrypsin is a protein produced by the liver and excreted in the stool. The reference value for this study is less than 30 mL of AAT cleared in the stool in 24 hours. In patients with PLE, hundreds of milliliters of AAT are cleared in 24 hours. An increased spot concentration of fecal AAT is also diagnostic of PLE; however, a low concentration should not rule out PLE.⁹  In patients with PLE, the serum albumin level is less than 2.5 g/dL. Patients with PLE become symptomatic because of protein loss and nutrient malabsorption. Symptoms of intestinal protein loss and lowered intravascular oncotic pressure include peripheral edema, pleural effusion, chylothorax, abdominal bloating, ascites, diarrhea, and failure to thrive. Magnetic resonance imaging in patients with single-ventricle Fontan physiology reveals lymphatic abnormalities including thoracic duct dilation, lymphangiectasia, and lymphatic collaterals.¹⁰ 

Treatment strategies are directed toward altering the underlying cardiac hemodynamics, correcting hypoproteinemia, and improving protein homeostasis through nutritional support and protein replacement therapy (Table 1). Dietary interventions to promote protein homeostasis include increasing dietary protein and medium-chain triglycerides and reducing sodium and fat. Clinicians should monitor this diet’s effect on the serum albumin level. Fluid restriction may also be indicated for patients with peripheral edema, fluid overload, and ascites. Adherence to dietary restrictions is a concern because families often struggle to follow the rigid daily nutritional regimen. Albumin replacements are recommended when serum albumin levels fall below 2.5 g/dL; however, treatment should be aimed at controlling protein leakage that leads to hypoalbuminemia.⁹  Frequent albumin replacements may be required for symptomatic relief if protein loss is not well controlled. Intravenous immunoglobulin replacements are useful to treat hypogammaglobulinemia associated with low immunoglobulin G levels and to increase serum albumin levels.¹¹ 

Pharmaceutical therapy options are patient specific (Table 1). Diuretics and pulmonary vasodilators can decrease central venous pressure and optimize cardiac output. Diuretics may be used to alleviate peripheral edema and fluid overload. Pulmonary vasodilators such as sildenafil citrate have been found to decrease PVR in the pulmonary bed and reduce SVR to optimize the Fontan circulation. Inflammation caused by congestive heart failure can be controlled with corticosteroids and heparin sulfate. Corticosteroids and heparin sulfate can decrease inflammation by targeting intestinal mucosa and reducing enteric protein losses. Oral budesonide, a potent synthetic glucocorticoid that is delivered primarily to the small intestine, is effective in some patients.¹²  Systemic absorption of budesonide can lead to adrenal suppression and verruca vulgaris. My clinical experience has shown that symptoms are likely to return when the patient is weaned off corticosteroids. In addition to preventing thromboembolic events, heparin may decrease inflammation by inhibiting mast cell degeneration in the intestine. Octreotide mimics somatostatin and may decrease thoracic duct lymphatic drainage associated with chylothorax and lymphangiectasia.¹³  Heparin and octreotide are not primary treatments for PLE but are used to treat patients with refractory PLE.¹³ 

Fontan fenestration may be performed in the cardiac catheterization laboratory to relieve pressure due to obstruction within the systemic venous to pulmonary artery pathway (Table 2). The fenestration allows desaturated blood to shunt to the atrial cavity, providing additional preload to the systemic ventricle and increasing cardiac output and ventricular filling.¹⁴  The increase in cardiac output also improves overall central venous congestion. Arterial desaturation should be anticipated following a fenestration; however, overall tissue delivery improves. Indications for fenestration are acute postoperative hemodynamic deterioration, chronic pleural effusion, and exercise intolerance.¹⁴  If PLE symptoms occur following a fenestration, a spontaneous closure of the fenestration or occlusion should be suspected. Atrial pacing can be considered for PLE treatment in patients who have lost sinus node function or experienced a junctional rhythm following the Fontan procedure. Atrial pacing can correct cardiac hemodynamic instability by restoring atrioventricular synchrony and maximizing cardiac output.

Surgical intervention with a Fontan revision or heart transplant may be indicated in patients with refractory or recurrent conditions. Fontan revision is usually required for patients who receive an atriopulmonary connection because this classical surgical repair can lead to low cardiac output, thrombi, and refractory atrial tachyarrhythmias.¹⁵  When intervention is indicated, the atriopulmonary connection is surgically revised to an extracardiac circulation. Historically, mortality has been as high as 50% in patients with PLE undergoing Fontan conversion.^15,16  Heart transplant is a consideration for patients with severe PLE whose condition is stable and refractory to medical and other surgical interventions.¹⁷  The resolution of symptoms may take several months following heart transplant.¹⁷  Patients with PLE are not ideal transplant candidates because they have poor nutrition, elevated antibody titers, multiple prior operations, increased risk of infection because of immunodeficiency, and single-ventricle physiology. Chronic malnutrition combined with asplenia may increase the risk of immunodeficiency and lead to more infections after transplant. Sensitization is more common in patients with repaired congenital heart disease, but detecting antibodies may be difficult because they are lost in the intestine. Standard testing for sensitization may result in a false-negative result, which then becomes a problem after transplant.

Plastic bronchitis is a complex disease in which bronchial casts form in the airway and throughout the tracheobronchial tree. Casts can be classified as inflammatory or acellular. Inflammatory casts are composed mainly of fibrin and cellular infiltrates, and acellular casts are composed mainly of mucin and fibrin.¹⁸  Plastic bronchitis following the Fontan procedure is usually associated with acellular casts, which result in serious pulmonary obstruction and possible death.¹⁸  Hence, PB can present as a more acute, life-threatening disease than PLE.

Plastic bronchitis is thought to have a pathway similar to that of PLE. Altered hemodynamics consist of declining ventricular function with high central venous pressure due to the Fontan pathway, as described by Rychik.^6,9  Chronic high lymphatic pressures from Fontan physiology lead to the development of acellular bronchial casts, although some patients with Fontan physiology have both acellular and inflammatory casts. The acellular casts produce large, rubbery plugs of mucous and fibrin in the tracheobronchial airway. Intrathoracic pressures increase with cast development, resulting in interstitial pulmonary edema or lymphedema. The leakage of fluid into the thorax or pericardium leads to pericardial effusion and/or chylothorax. Surgical damage of the thoracic duct predisposes a patient to PB because of abnormalities in excessive production or drainage of lymphatic fluid.¹⁹  Risk factors for PB are prolonged duration of chest tube drainage after surgery, chylothorax, and development of significant cardiopulmonary collateral vessels.¹⁹ 

Lymphatic insufficiency and excessive lymphatic fluid may cause lymphopenia and immunodeficiency. Lymphangiectasia is present in patients with PB; however, small amounts of protein are lost into the airway, not the gut as in PLE.⁸  Hypoalbuminemia and hypogammaglobulinemia may be present in PB, but the dominant clinical manifestation is respiratory distress related to obstruction in the airway.

Symptoms in patients with PB include decreased breath sounds and airway obstruction due to bronchial hyper-secretions. Patients with substantial airway obstruction from bronchial casts have coughing, shortness of breath, wheezing, and chest pain, and they may expectorate casts. Diagnosis of PB is confirmed by a history of expectoration of bronchial casts.²⁰  Bronchoscopy should be performed in patients with suspected PB who have dyspnea or signs of respiratory distress without expectoration of bronchial casts. Bronchoscopy also allows removal of casts during the diagnostic procedure. However, acellular casts tend to be friable and can be difficult to remove with bronchoscopy because the casts tend to adhere to the bronchial airways. High-resolution computed tomography shows patchy atelectasis of the involved bronchial airway and pulmonary segments.²⁰ 

Treatments for PB include dietary, pharmacological, surgical interventions and interventional catheterization (Table 3). The dietary modification is a high-protein, low-fat diet. Mucus-thinning agents such as nebulized acetyl-cysteine may help treat bronchial casts. A bronchoscopy regimen may promote airway clearance of bronchial casts when using mucus-thinning agents and chest physiotherapy. Airway clearance using standard pulmonary toileting techniques and a high-frequency chest compression vest seems to be the safest and most effective treatment.²¹  Pharmacologic treatment can be optimized with pulmonary vasodilators, aerosolized fibrinolytics, mucolytics, and inhaled steroids.²⁰  Budesonide and sildenafil citrate may be used in combination; their mechanism of action is the same as in treatment of PLE.^6,9,22  Oral budesonide may not be as effective for PB as for PLE because protein leakage occurs in the lungs and not the intestines. Aerosolized tissue plasminogen activator has also been used with some success to dissolve bronchial casts so they may be eliminated or more easily expectorated.^4,23  A combination of sildenafil citrate (a potent pulmonary vasodilator) and aerosolized tissue plasminogen activator to help lyse acellular casts is an effective treatment.^21,22  However, this therapy is associated with a risk of airway hemorrhage. Aerosolized heparin has recently been shown to have anti-inflammatory properties that can decrease mucin secretion and prevent activation of the fibrin pathway for treatment of acellular casts.²¹  In addition to their mucoregulatory effect, macrolides are thought to have an anti-inflammatory effect through modulation of inflammatory cytokines.²⁴ 

Percutaneous thoracic duct coil embolization or thoracic duct ligation may be a treatment option for chronic chyle leakage and inflammation, although bronchial casts may redevelop after either procedure.²⁵  Heart transplant should be considered a treatment option for unresolved PB that has not responded to medical treatment. Several studies have reported long-term survival following heart transplant in patients with PB.^26,27  One institution reported 2 patients who are long-term survivors of heart transplant after failure of the Fontan procedure and development of PB.²⁶  Gossett et al²⁷  reported a 70% survival rate with no reoccurrence of bronchial casts following transplant.

Protein-losing enteropathy fits into 3 treatment categories based on the patient’s serum albumin level. Albumin levels of 2.5 to 3.5 g/dL are considered mild disease.⁹  Albumin levels of 2.0 to 2.5 g/dL indicate moderate PLE, and levels less than 2.0 g/dL indicate severe PLE (Table 4).⁹  A nurse caring for a patient with PLE should be aware of disease severity and anticipate interventions based on severity. Patients with serum albumin levels less than 2.5 g/dL may require frequent albumin replacements, but control of protein leakage is essential to prevent further hypoproteinemia. Infusion centers that provide albumin replacements can help prevent frequent hospitalizations. Central catheter duration and placement should be carefully considered in patients with signs of PLE because thrombosis from a central catheter can worsen the symptoms.⁸  Patients may benefit from a peripherally inserted central catheter to allow for outpatient replacement therapy at infusion centers or at home. Families need to be taught meticulous central catheter care to prevent infection and avoid unnecessary hospitalization for central catheter–associated infections. Teaching families the importance of dietary modification can improve adherence to fluid restriction and the low-fat, high-protein diet. Adherence to dietary modifications may also prevent frequent hospitalizations.

Pulmonary toileting and chest physiotherapy should be regularly scheduled for patients with PB. The presentation of PB is similar to that of foreign body aspiration. Acute changes in ventilator capacity can lead to tachypnea and increased intrapulmonary pressures. Acute interstitial pulmonary edema and respiratory failure may result in rapid decompensation and possible cardiopulmonary failure. Nurses may need to respond quickly to decompensation and initiate cardiopulmonary resuscitation in patients with PB. The interdisciplinary team should prepare the patient and family for mechanical assist device therapy such as extracorporeal membrane oxygenation.

Symptoms of PLE and PB may be controlled well with individualized medical treatment, but patients with these conditions may have frequent exacerbations. These exacerbations can lead to frequent readmissions, so patients and families may need psychosocial support because of the chronic nature of these diseases. Palliative care should be considered for all PLE and PB patients because the trial-and-error approach to treatment can affect quality of life. Interdisciplinary care should focus on minimizing symptoms, decreasing hospitalizations, and maximizing quality of life. Care teams should include nurses, social workers, child life specialists, dieticians, and psychologists to support families’ psychosocial needs. Formal discharge education to reinforce medical treatments and diet can improve adherence among patients and families. Patients and families can also benefit from structured care coordination to promote successful discharge to home.

Protein-losing enteropathy and PB after Fontan repair are challenging to treat despite advances in surgical and medical therapy. Recently proposed paradigms provide guidelines to better understand PLE and PB disease processes. Patients with PLE and PB can be treated with a wide variety of medical and surgical options; however, individual patient response remains a challenge. Clinical pathways need to be established and tested with randomized multicenter clinical trials or quality improvement collaboratives. Protein-losing enteropathy and PB are chronic diseases that expose patients and families to many psychosocial stressors. Treatments for both diseases are aimed at controlling symptoms and improving quality of life.

The author would like to thank Jack Rychik, MD, for his contributions to research and the development of a paradigm for protein-losing enteropathy and plastic bronchitis.