Diffuse Immune-Mediated Pulmonary Hemorrhage

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Welcome to our Episode a 16-year-old who is coughing up blood.

Here's the case:

A 16-year-old female with h/o SLE was transferred to the PICU due to hypoxia requiring increasing FIO2. A few hours prior to admission to the PICU patient also started coughing up blood and had difficulty breathing. The patient was admitted to the general pediatric floor 2 days earlier for pneumonia requiring an IV antibiotic and O2 via NC. Once transferred to the PICU, she had a rapid deterioration with progressive hematemesis, worsening respiratory distress, and saturations in the low 70s requiring escalating FIO2. The patient was emergently intubated using ketamine + fentanyl and rocuronium. Chest radiograph showed: Worsening bibasilar alveolar and interstitial airspace disease concerning pulmonary hemorrhage. The patient was initially placed on HFOV Paw 26, FIO2 70%, Hz 8, Dp 70, and later transitioned to airway pressure release ventilation or APRV. The patient was also started on inhaled tranexamic acid or TXA and high-dose pulse steroids. The patient initially continued to have some blood coming out from the ETT with suctioning but secretions became clear in ~24 hours.

The mother reported that the patient has never had hematemesis/hemoptysis before, or bleeding from any site in the past. Denied history of frequent respiratory infections or recent URI symptoms. The patient has been vaccinated/boosted x3 vs covid. Her COVID PCR is negative. The mother states that she does not engage in tobacco products or alcohol.

A physical exam revealed a well-developed teenage girl laying supine in bed deeply sedated and mechanically ventilated. There was decreased AE at lung bases and coarse breath sounds throughout. There was no hepatosplenomegaly and exams of the heart, abdomen and other systems were normal. There was no skin rash and extremities were well perfused with no clubbing in the fingers. The pulmonary team was consulted and a workup was started for pulmonary hemorrhage.

To summarize key elements from this case, this patient has:

• Autoimmune disease: Systemic lupus erythematosus
• Respiratory Failure warranting MV 2/2 Pulmonary hemorrhage
• Her presentation and deterioration bring up a concern for diffuse alveolar hemorrhage our topic of discussion for today.
• This episode will be organized…
• Definition
• Etiology
• Pathophysiology
• Diagnosis
• Management
• Rahul: How do we define pulmonary hemorrhage (PH):
• PH is defined as the extravasation of blood into airways and/or lung parenchyma. Blood in the airways produces a diffusion barrier resulting in hypoxemia. Due to the reduction of airway diameter from accumulated blood, there is increased airway resistance and even airway obstruction. Subsequently, ventilation can be impaired leading to increased WOB as well as myocardial work required for O2 delivery. Repeated episodes of PH can result in interstitial fibrosis thus changing lung compliance. Hemoptysis by definition is any bleeding from below the vocal cords. PH can be classified as focal or diffuse. Diffuse is further classified as diffuse immune or diffuse nonimmune.

Loss of 10% of a patient’s circulating blood volume into the lungs, regardless of age, causes a significant alteration in cardiorespiratory function and should be considered massive. In adults, massive pulmonary hemorrhage is defined as blood loss of 600mL or more in 24 hours. In infants, the involvement of at least two pulmonary lobes by confluent foci of extravasated RBCs constitutes as massive PH. “Enough bleeding to make one nervous is probably massive.”

Let's pivot and talk about etiologies.

• Pradip, What are some of the causes of pulmonary hemorrhage in the PICU?
• Non-immune diffuse PH is usually seen in patients with congenital heart disease (TAPVR, pulmonary atresia, mitral stenosis, hypoplastic left heart syndrome to name a few) neonates (secondary to sepsis, HIE, BW < 1500 gms, persistent pulmonary hypertension) and due to coagulopathy. bronchiectasis, infections such as TB, mycetomas are also important causes of PH. Cocaineas and vaping (typically adulterated with other substances) are also important toxic causes of DAH.
• Diffuse PH due to immune causes includes pulmonary-renal syndromes (good pastures, Wegener granulomatosis, SLE, anti-phospholipid syndrome PAN, HSP), drug-induced vasculitis (PTU, methimazole, hydralazine, and minocycline) and infections such as hantavirus, CMV, legionella, etc. Lupus and PAN account for the majority of the vasculitis resulting in PH.
• Focal PH: FB aspiration with chronic retention, pulmonary sequestration, AV fistula, thrombus or embolus, and neoplasms.
• Idiopathic pulmonary hemosiderosis a diagnosis of exclusion presents with the triad of hemoptysis, microcytic hypochromic anemia, and diffuse alveolar-filling opacities. Nonspecific lung injury not attributed to vasculitis or immune deposits is noted on microscopic examination.

Alright to summarize diffuse pulmonary hemorrhage — think about non-immune causes secondary to heart disease and immune causes secondary to rheumatologic conditions. Our patient in our case likely had immune-mediated PH.

Let's conclude our episode by going through diagnostics and management.

• If you had to work up this patient with PH, what would be your diagnostic approach?
• We can start with a chest radiograph. Typically in PH, you can see ground-glass diffuse opacities or consolidations; sometimes a mosaic-type perfusion pattern can indicate a true arteriolar vasculitis. In some patients, the chest radiograph can be normal. High Resolution Computed tomography(HRCT) has higher sensitivity and the classic features include ground-glass opacities in a random distribution.
• Bronchoscopy and bronchoalveolar lavage (BAL) are other diagnostic tools. In bronchoalveolar lavage, the pathologist must search for hemosiderin-laden macrophages, which usually appear 24–48 h after the DAH has started. The presence of >5% of hemosiderin-laden macrophages highly suggests the presence of blood from DAH.
• Echocardiogram
• Labs: Blood gas, CMP, CBC, Coagulation panel, ESR, CRP, specific auto-antibodies (consult with renal or rheumatology colleagues). Urine analysis, In some rare cases a biopsy (skin, lung, or kidney) may be needed in pulmonary-renal syndromes.

I would also highly recommend a collaborative approach with pulmonary specialists, rheumatologists, intensivists, and hematology.

• If our history, physical, and diagnostic investigation led us to PH as our diagnosis what would be your general management framework?
• Initially, we must focus on basic PICU care with maintenance of airway and oxygenation/ventilation as well as hemodynamic stability. O2 supplementation EVEN mechanical ventilation may be required; Prior to intubation placement of the patient in Trendelenburg position (which helps clots exit the airway) may be helpful. PEEP should be increased on conventional ventilation for tamponade effect as well as help with hypoxemia. We typically use HFOV with deep sedation +/- chemical paralysis or APRV mode on a conventional ventilator. It is important to correct any coagulation factor deficiency as well as transfuse platelets or pRBCs as needed.
• Increased PEEP, HFOV, and APRV all create increased mean airway pressure which not only has a local tamponade but increases intrathoracic pressure to decrease preload and downstream pulmonary hydrostatic pressure.

What are some other modalities used in DAH?

• Endobronchial tamponade (Fogarty catheter, cuffed endotracheal tube) can be tried if bleeding is restricted to a segment of a particular lung. Right upper lobe bleeding is best managed by intubating the left main stem bronchus with a cuffed endotracheal tube and inflating the cuff of the tube. Utilization of a double-lumen or Carlens-type endotracheal tube may also be helpful in isolating the bleeding segment. Consult with anesthesia colleagues may be helpful in the management of such patients.
• There may be a role for rigid bronchoscopy to identify the source and type of bleeding. Rigid Bronchoscopy can also be used for large volume lavage as well as suctioning of blood and even control the source of bleeding. The help of general or cardiothoracic surgery colleagues is invaluable in such patients. For focal PH- surgical resection of the involved segment or selective embolization of bronchial vessels may be needed.
• What about medical management?
• Specific pulmonary-renal syndromes can be treated using corticosteroids and other immunosuppressive agents. Plasmapheresis is an option for Good Pastures syndrome. High-dose methylprednisolone (30mg/kg or 1gm daily X 3 days followed by slow taper) is typically used in diffuse immune-mediated PH. Cyclophosphamide is the drug of choice for the treatment of patients with Wegener granulomatosis
• Are there any therapeutics on the horizon?
• One study by O’Neil et al in Crit Care Explor 2020 reported the use of Inhaled Tranexamic Acid As a Novel Treatment for Pulmonary Hemorrhage in Critically Ill Pediatric Patients-Cessation of pulmonary hemorrhage was achieved in 18 of 19 patients (95%) with inhaled tranexamic acid with no major adverse events recorded. The study also reported that other variables such as oxygenation and coagulation were not affected by the use of inhaled TXA in our study. Additionally, they reported that the patients received significantly less blood product after receiving inhaled TXA.
• How does TXA work and what are the applications clinically?
• Tranexamic acid (TXA) is a lysine analog that blocks the conversion of plasminogen to plasmin and inhibits binding of plasmin to fibrin which stabilizes the fibrin matrix, thereby reducing bleeding. Systemic TXA, however, may be associated with serious complications including venous thromboembolism, neurotoxicity, and seizures. In our patients, we use inhaled or endotracheally instilled TXA (250-500mg of 100mg/ml solution) every 6 hours. Nebulization is done over 15-20minutes and can be delivered in line during mechanical ventilation. Dosing frequency was subsequently decreased based on patients’ responses.

Rahul, can you summarize today's episode on DAH:

Diffuse alveolar hemorrhage is a medical emergency. 33% can present without hemoptysis. Along with clinical findings of cough, hemoptysis, and dyspnea the presence of hemosiderin-laden macrophages confirms the diagnosis of pulmonary hemorrhage. Protecting the airway and optimizing oxygenation/ventilation is the most important part of management. Then identify and stop the offending agent if possible and administer treatments accordingly.

This concludes our episode on a pulmonary hemorrhage. We hope you found value in our short, case-based podcast. We welcome you to share your feedback, subscribe & place a review on our podcast! Please visit our website picudoconcall.org which showcases our episodes as well as our Doc on Call management cards. PICU Doc on Call is co-hosted by myself Dr. Pradip Kamat and Dr. Rahul Damania. Stay tuned for our next episode! Thank you!

References

• Fuhrman & Zimmerman - Textbook of Pediatric Critical Care 6th edition. Chapter 52: Pneumonitis and interstitial Disease. Parakininkas D. Pages 603-607
• Reference 1: Martínez-Martínez MU, Oostdam DAH, Abud-Mendoza C. Diffuse Alveolar Hemorrhage in Autoimmune Diseases. Curr Rheumatol Rep. 2017 May;19(5):27. doi: 10.1007/s11926-017-0651-y. PMID: 28397125.
• Reference 2: States LJ, Fields JM. Pulmonary hemorrhage in children. Semin Roentgenol. 1998 Apr;33(2):174-86. doi: 10.1016/s0037-198x(98)80021-7. PMID: 9583112.