Noninfectious Pulmonary Complications

Introduction

Pulmonary complications, both infectious and non-infectious, are common in bone marrow transplantation and hematopoietic cell transplantation (HCT). These complications are influenced by underlying disease, treatment effects, graft-versus-host disease (GVHD), and conditioning regimens. They are classified as early or late, depending on whether they occur before or after 100 days post-transplant.

Early non-infectious complications include pulmonary edema, upper airway issues, alveolar hemorrhage, thrombi, and pleural effusion. Late complications comprise bronchiolitis obliterans, veno-occlusive disease, and secondary malignancies. Idiopathic pneumonia syndrome, GVHD, and radiation-induced lung injury may occur early or late post-BMT. While uncommon, noninfectious lung complications post-HCT pose significant morbidity and mortality risks, often affecting lung tissue, airways, or vascular structures, excluding extrapulmonary, renal, or cardiac causes.

What Are Noninfectious Pulmonary Complications?

Lung injury is common after HCT and plays a significant role in morbidity and mortality shortly after the transplant and during subsequent months and years. In the past, about half of all pulmonary issues post-HCT were due to infections, but careful use of broad-spectrum antimicrobial drugs has shifted the focus towards noninfectious causes. Noninfectious lung injury post-HCT can result from immune or non-immune mechanisms and may account for up to half of noninfectious mortality following allo-HCT.

What Are the Noninfectious Complications of the Lungs?

Noninfectious pulmonary complications are as follows:

1. Idiopathic Pneumonia Syndrome (IPS):

It is defined as a pneumopathy of unknown cause following HCT. Diagnosis involves identifying widespread alveolar injury, evidenced by multilobular infiltration on imaging, pneumonia symptoms, an increased A-a gradient, or a restrictive pattern on PFTs (pulmonary function tests), while ruling out infection, fluid overload, or cardiac or renal dysfunction.

IPS affects allogenic and autologous HCT recipients and is categorized based on presumed tissue injury sites. Its incidence after myeloablative preparative regimens ranges from three to fifteen percent, with risk factors including full-intensity conditioning, total body irradiation, GVHD, and certain underlying diagnoses. Bronchoscopy is crucial to rule out infection. The etiology of IPS is unclear but likely involves cellular injury from various lung insults, including HCT conditioning regimens and immunologic reactions. Treatment options include Etanercept and steroids. Early lung injuries that comprise IPS are capillary leak syndrome, diffuse alveolar hemorrhage, peri-engraftment respiratory distress syndrome (PERDS), acute interstitial pneumonitis, or toxic pneumonitis.

2. Peri-Engraftment Respiratory Distress Syndrome (PERDS):

PERDS is a lung injury that occurs around neutrophil engraftment post-HCT, often accompanying engraftment syndrome (ES). It presents with hypoxemic respiratory failure and bilateral pulmonary infiltrates, which are not fully explained by other factors. Risk factors include rapid immune system recovery, HCT sources, and GM-CSF (granulocyte macrophage colony-stimulating factor) use.

Diagnosis is challenging due to nonspecific symptoms that overlap with other post-transplant conditions. Treatment involves high-dose corticosteroids with rapid tapering, which usually leads to quick improvement. Short-term prognosis is generally good if promptly recognized and treated.

3. Diffuse Alveolar Hemorrhage (DAH):

DAH is a subset of IPS marked by bloodier bronchoalveolar lavage (BAL) return or the presence of haemosiderin-laden macrophages. It rapidly progresses to respiratory failure and is seen as a sign of an underlying lung injury influenced by various risk factors. Factors like graft sources, high doses of total body irradiation, and delayed engraftment contribute to DAH. Its onset, typically within two weeks of neutrophil engraftment, may involve a sudden neutrophil influx and bronchial inflammation preceding alveolar inflammation.

The exact pathogenesis remains unclear but involves multiple factors beyond immune-mediated injury, including direct lung injury and cytokine-mediated effects. Clinical representation includes dyspnea, cough, and hypoxemia, with radiographic findings showing diffuse infiltrates. Systemic corticosteroids are commonly used, but outcomes are poor. Supportive care may involve platelet transfusions, procoagulant therapies, and cytokine antagonists, but their efficacy varies.

4. Cryptogenic Organizing Pneumonia (COP):

COP, or bronchiolitis obliterans organizing pneumonia, presents nonspecific respiratory symptoms, patchy lung consolidation on imaging, and a restrictive ventilatory defect on PFTs. It occurs more commonly after allogeneic HCT, with symptoms typically rising between two and fifteen months post-transplantation. COP results from alveolar epithelial injury, leading to inflammatory cell infiltration and granulation tissue formation. Diagnosis is confirmed by PFT, CT (computed tomography) imaging, BAL cytology, and transbronchial lung biopsy. Treatment involves prolonged corticosteroid therapy, with relapses being common during steroid tapering.

Delayed pulmonary toxicity syndrome (DPTS) primarily affects autologous stem cell transplant recipients and is associated with conditioning regimens containing certain agents. It presents with nonspecific respiratory symptoms and patchy, diffuse lung infiltrates on imaging. Treatment with high-dose steroids usually leads to resolution. Various pneumotoxic agents used before transplantation can worsen overall survival and may cause interstitial pneumonitis or idiopathic pulmonary fibrosis.

5. Bronchiolitis Obliterans Syndrome (BOS):

BOS presents with airflow limitation after allogeneic HCT and occasionally in other contexts, such as lung transplantation. Risk factors include specific conditioning regimens, GVHD, and certain infections. Diagnosis relies on spirometric and radiographic criteria, with a surgical lung biopsy rarely performed. Treatment options are limited, with prolonged corticosteroid use no longer recommended due to side effects. Azithromycin, Montelukast, and inhaled Budesonide or Formoterol have shown some promise in improving lung function. Supportive measures include infection prevention, GERD (gastroesophageal reflux disease) treatment, and pulmonary rehabilitation.

6. Interstitial Lung Disease (ILD):

ILD is a rare but serious complication of HCT. It typically occurs around eleven months post-transplant, often following peripheral stem cell transplantation and extrathoracic GVHD. High-resolution computed tomography imaging commonly reveals alveolar consolidation or ground-class opacities, while PFTs show a restrictive ventilator defect in most cases. Treatment usually involves steroids, and ILD may be associated with autoimmune diseases that develop as a part of GVHD, such as scleroderma or vasculitis.

7. Pulmonary Hypertension (PH):

PH is a rare but serious complication of HCT, mainly observed in the pediatric population. It is characterized by elevated mean pulmonary arterial pressure and can be classified into different subtypes based on hemodynamic criteria. PH can occur after both myeloablative and reduced-intensity regimens, with mortality rates as high as 86 percent in some cases. Diagnosis may be challenging due to nonspecific symptoms.

Pulmonary veno-occlusive disease (PVOD), a rare variant of PH, has been reported in HCT patients and is thought to result from pulmonary vascular endothelial damage due to cytotoxic medications and radiation therapy. Some experts are considering screening for PH, especially in patients with bronchiolitis obliterans syndrome (BOS) after HCT, using transthoracic echocardiography due to its high prevalence in the post-transplant population.

What Are the Diagnostic Considerations for Noninfectious Pulmonary Complications?

• Diagnostic considerations for noninfectious pulmonary complications are crucial for effective management.

• Pre-transplant evaluation should include a comprehensive assessment of medical history, physical examination, PFTs, and chest radiography.

• Chest CT scans may be warranted, particularly in high-risk patients such as older individuals or smokers, to establish a baseline for post-transplant changes.

• During the early post-transplant period, respiratory symptoms should be evaluated considering symptoms acuity and the patient's immune status, including neutrophil count, immunosuppressive medications, acute GVHD, and antimicrobial prophylaxis.

• Infectious etiologies should be the primary consideration during this phase.

• High-resolution CT of the chest is more sensitive to detecting pulmonary abnormalities and can provide valuable diagnostic information.

• BAL may yield a diagnosis in approximately half of the patients.

• However, noninvasive diagnostic methods such as viral PCR studies and serological tests are increasingly being utilized, reducing the need for invasive procedures like lung biopsies.

• In the late post-HCT period, chronic noninfectious pulmonary complications like BOS, ILD, or mixed changes become more significant.

• Since treatment options are limited once damage is established, close monitoring through regular outpatient visits and respiratory symptom review is recommended.

Conclusion

Noninfectious pulmonary complications pose significant challenges in diagnosis and management. These complications include BOS, ILD, pulmonary hypertension, IPS, and others that significantly impact patient outcomes and quality of life. Early recognition, evaluation, and close monitoring are essential for timely intervention and optimizing patient care.