Inhaled Tissue Plasminogen Activator for Acute Plastic Bronchitis

Inclusion Criteria (patients with plastic bronchitis):

   1. ≥ 5 years of age but ≤24 years of age and weigh at least 18.6 kg (41 lbs).

   2. Patients with CHD that have a history of PB with previous airway cast production
   and/or present with symptoms of an acute exacerbation (e.g., difficulty breathing,
   dyspnea) of PB that requires hospitalization. An acute exacerbation of PB is defined
   as either respiratory symptoms suspicious for airway cast formation and/or the
   expectoration of, or a bronchoscopy retrieved, fibrin PB cast.

   3. Patients without CHD that present with an acute exacerbation of PB, defined as the
   expectoration of, or a bronchoscopy retrieved, fibrin PB cast that causes acute
   respiratory distress (e.g., severe coughing, difficulty breathing, dyspnea) or a
   history of PB with pathologic evidence of fibrin airway cast production. Either a cast
   sample (at least ½ inch (~4cm)) or a pathology report that documents PB cast fibrin
   content must be submitted to the UM pathology core.

   4. Must be able to use a mouthpiece nebulizer.

   5. Informed consent (with parental if age ≥14 years) or assent for age ≥10 and < 14 years
   old with parental informed consent.

Exclusion Criteria (patients with plastic bronchitis):

   1. Known contraindication(s) to the use of tPA, including:

      - active internal bleeding;

      - history of cerebrovascular accident;

      - recent intracranial or intraspinal surgery or trauma;

      - intracranial neoplasm, intracranial arteriovenous malformation or intracranial
      aneurysm;

      - known bleeding diathesis;

      - and/or severe uncontrolled hypertension

   2. Body weight >/= 100th percentile or BMI > 30

   3. Known cystic fibrosis

   4. Currently receiving dornase-alfa and/or inhaled unfractionated or low molecular weight
   heparin and/or a direct acting oral anticoagulant (e.g., dabigatran, rivaroxaban)

      - Inhaled unfractionated or low molecular weight heparin must be discontinued at
      least 72h. Inhaled dornase alfa should be discontinued no later than the time of
      the start of enrollment in the treatment phase. If the patient is receiving
      inhaled tPA, this regimen must be discontinued and transitioned to the inpatient
      dosing regimen (5mg Q6h) of study drug.

      - Direct acting oral anticoagulants must be discontinued one week prior to the
      start of enrollment in the treatment phase.

   5. Protein losing enteropathy

   6. Liver dysfunction (defined as ≥ 3X the normal levels of one or both liver
   transaminases, AST and AST)

   • Transaminase levels acquired within the last 9 months can be used to assess liver
   function. If previously normal and there is no clinical indication that liver function
   has worsened, the patient can be enrolled. If there are no transaminase values within
   the last 9 months, they need to be acquired as part of screening

   7. Need for concomitant intravenous or sub-cutaneous anti-coagulation with resulting
   anti- Xa levels > 0.5 (low molecular weight heparins) or > 0.3 (unfractionated
   heparin)

   8. International normalized ratio (INR) > 2.0 if not receiving warfarin

   9. Patients being actively treated for thrombosis

10. Concomitant use of a thienopyridine class antiplatelet agent (e.g., clopidogrel)

11. A platelet count of < 100,000 platelets/µL

12. A hematocrit <30%

13. Gross hematuria on screening urinalysis

14. Pregnant or lactating women (negative pregnancy test required for girls/women of
   childbearing potential at the time of inhaled tPA administration). All women of child-
   bearing potential must be willing to practice appropriate contraception throughout the
   study.

15. Subjects who are known positive for, or are hospitalized with COVID-19 caused by the
   new coronavirus, SARS CoV-2, at the start of the treatment phase.

16. Suspected or active concurrent infectious illness.

Inclusion Criteria for Healthy Controls

   1. Healthy children ≥ 5 years of age but ≤18 years of age with no other underlying
   concomitant illness or chronic medication use (with the exception of vitamin
   supplements)

   2. Weigh at least 18.6 kg (41 lbs)

Inclusion Criteria for Healthy non-PB Fontan Controls

   1. Children ≥ 5 years of age but ≤18 years of age with uncomplicated Fontan physiology
   with no history of PB, other Fontan-associated complications (e.g., hepatopathy, PLE),
   or other concomitant illnesses (e.g., asthma).

   2. Weigh at least 18.6 kg (41 lbs)

Inclusion Criteria for PLE Fontan Controls

   1. Children ≥ 5 years of age but ≤18 years of age with Fontan physiology, no history of
   PB and a diagnosis of PLE defined as clinically symptomatic hypoproteinemia and/or
   enteral protein loss.

   2. Weigh at least 18.6 kg (41 lbs)

Exclusion Criteria for Healthy, non-PB Fontan Controls and PLE Fontan Controls

   1. Exceed the 100th percentile for body weight or have a BMI greater than 30.

   2. History of post-operative chylothorax following any palliation surgery (except for PLE
   controls).

   3. Known liver dysfunction per medical record review (e.g., defined as ≥ 3X the normal
   levels of one or both liver transaminases [ALT & AST])

   4. COVID-19 positive within the last 14 days prior to the scheduled visit and/or the
   presence of symptoms consistent with COVID-19 at the time of the visit

   5. Suspected or active concurrent infectious illness