Professor Lu Bingbing: Diagnosis and treatment of patients with hematopoietic stem cell transplantation complicated with bronchiolitis obliterans syndrome (BOS)

On March 27, 2021, the "Symposium on Diagnosis and Treatment of Hematological Diseases and Pulmonary Complications after Hematopoietic Stem Cell Transplantation" was grandly held.
The meeting invited respiratory infections, inspections, pathogenic microorganisms, radiation, and hematological tumors through online and offline channels.
Many experts talk about the diagnosis and treatment of blood diseases and pulmonary complications after hematopoietic stem cell transplantation.

At the meeting, Professor Lu Bingbing from the Department of Respiratory and Critical Care Medicine, Peking University People's Hospital, gave a wonderful sharing on "Diagnosis and Treatment of Bronchiolitis Obliterans Syndrome (BOS) in Patients with Hematopoietic Stem Cell Transplantation".

To understand the occurrence of chronic graft-versus-host disease (cGVHD) after BOS hematopoietic stem cell transplantation (HSCT), which seriously affects the prognosis of patients, how to prevent and treat cGVHD is the current direction of exploration.

The manifestations of cGVHD in the lungs include two forms, namely obstructive lung disease (OLD) caused by involvement of the small airways and restrictive lung disease (RLD) caused by involvement of the interstitium of the lung.
Its histopathological feature is the surrounding small airways (OLD).
Or pulmonary interstitial (RLD) collagen deposition and progressive fibrosis, which can cause severe damage to the patient’s lung function.

At present, bronchiolitis obliterans (BO) is the main manifestation of chronic GVHD in the lungs, and this view has been widely accepted by the academic community.

On the other hand, the pathophysiology and clinical features of cGVHD-related interstitial lung disease (ILD) are currently lacking sufficient research.

At this conference, Professor Lu discussed the diagnosis and treatment of bronchiolitis obliterans syndrome (BOS) caused by cGVHD involving small airways.

Lymphocytic bronchiolitis (LB) and bronchiolitis obliterans (BO) are both histopathological diagnoses.

The histological feature of LB is that a large number of donor-derived lymphocytes infiltrate the wall of the bronchioles, leading to bronchiolitis.

The main clinical symptoms of LB patients include severe cough and sputum, which can be accompanied by wheezing or airway hyperresponsiveness, which is easy to be misdiagnosed as asthma.

Bronchiolitis at this stage is more sensitive to hormone and immunosuppressive therapy, and the course of the disease is reversible.

The histological features of bronchiolitis obliterans (BO) are fibrosis of the bronchiole submucosa and around the bronchiole, and the lumen of the bronchiole is concentrically narrowed or completely occluded in the late stage.

The main symptoms of BO patients are progressively worsening active shortness of breath, insidious onset, and irreversible course.

HRCT of his chest showed hyperventilation or "mosaic" sign, and central bronchiectasis was seen in the late stage.

Lung function is characterized by restricted expiratory flow rate and obstructive ventilatory dysfunction.

LB is the early stage of BO's development, and it is also a high-risk factor for the occurrence of BO.

BO and BOS need to be distinguished.
As mentioned earlier, the diagnosis of BO requires surgical lung biopsy.
This invasive examination is not easy to achieve for most HSCT patients.
Therefore, obstructive airflow is defined as clinically obstructive bronchiolitis syndrome (BOS) CGVHD-pulmonary disease with restricted characteristics.

Diagnostic criteria for BOS: 1) HSCT patients have been diagnosed with cGVHD in any other organ; 2) Exclude lower respiratory tract infection; 3) Lung function: FEV1/FVC＜70%, FEV1＜75% pred and FEV1 decreased by more than 10% within 2 years .

The severity of BOS is determined by the symptomology score and the lung function (FEV1%pred) score.
When the symptomology score and the lung function score are inconsistent, the lung function score (FEV1%pred) shall prevail.

As long as the lung function score reaches 2 or 3 points, the patient's overall cGVHD is severe.

In view of the insidious onset of BO, the lung function of patients is often severely impaired during treatment, so early diagnosis is particularly important.

It is recommended that all patients with cGVHD be followed up regularly for their lung function.

 The severity of BOS is graded differently.
BOS patients have different treatment responses.
BOS is a clinical diagnosis based on pulmonary function tests and cannot be equal to BO. The small airway pathology of BOS patients may be either donor lymphocyte infiltration (LB), airway wall fibrosis (BO), or a mixture of the two.
Only after treatment can the outcome be clear.

As mentioned earlier, LB patients are more sensitive to treatment, while BO patients have a poor prognosis.

A clinical study in 2013 confirmed the above view.

A total of 33 BOS patients were included in the study.
The results of all patients receiving lung biopsy showed that: 33 BOS patients included 10 cases of BO, 9 cases of LB, 4 cases of BO co-infection, 2 cases of LB co-infection, and 8 cases of other pathological diagnosis.
.

All patients received triple therapy including tacrolimus (FK)/cyclosporine (CsA) + mycophenolate mofetil (MMF) + hormones, and regular follow-up of lung function.

The results showed that the lung function of BO patients gradually stabilized, with a small decrease in the later period; while the lung function of LB patients was significantly improved and remained stable in the later period.

In addition, during the follow-up period, the mortality rate of the BO group was 50% (7/14) and that of the LB group was 9% (1/11).

In summary, the prognosis of patients in the LB group was significantly better than that of BO.

The main treatment plan of BOS, Professor Lu combined with his own diagnosis and treatment experience, gave a detailed introduction to the current treatment status and precautions of BOS.

 First-line treatment of glucocorticoids: first-line treatment drugs.

Long-term use of hormones has greater side effects (opportunistic infections, osteoporosis, muscle weakness, diabetes, etc.
).
Therefore, intravenous hormones only need short-term use.
Long-term use of high-dose hormones (>30mg prednisone) is not recommended.

Professor Lu personally suggested that the maintenance dose should be controlled at ≤10mg prednisone.

Second-line treatment of calcineurin inhibitors-cyclosporine/tacrolimus: second-line treatment drugs.

If the patient's condition is still progressing while using cyclosporine, it is recommended to switch to tacrolimus.

Tacrolimus is significantly stronger than cyclosporine, and it is well tolerated by patients.

Azathioprine (AZA): a second-line treatment drug.

Professor Lu said that the drug has a definite clinical effect, but it has a slower onset and is more suitable for maintenance therapy, and should not be used for rapidly progressing BOS.

In some patients, the lack of thiopurine methyltransferase (TPMT) leads to the enhanced cytotoxicity of AZA, which is likely to cause bone marrow suppression.

In addition, AZA should be avoided in combination with methotrexate (MTX), MMF, etc.
, otherwise the cytotoxic effect will be significantly enhanced.

Mycophenolate mofetil: second-line therapy.

The effect of single application is weak, and it is often used in combination with hormones, cyclosporine/tacrolimus.

The drug should not be combined with azathioprine, otherwise it will excessively inhibit the metabolism of purine.

Azithromycin: A small dose of Azithromycin has anti-inflammatory effects.
It is recommended that patients with BOS take long-term medication for at least 3 months.

Third-line treatment of imatinib and similar tyrosine kinase inhibitors (TKI): empirical medication, there is no evidence-based evidence at present, it is generally believed that imatinib is suitable for mild BOS, but has little effect on moderate to severe BOS .

Rucotinib: It is suitable for refractory or hormone-resistant acute and chronic GVHD.
There is no evidence-based evidence.

Adjuvant supportive treatment of BOS-inhalation therapy Inhalation therapy, including inhaled hormones and inhaled bronchodilators, can be used as an adjuvant therapy for BOS.

Due to the low quality of research evidence, the recommendation level of such drugs in the treatment of cGVHD-BOS is weak.

Summary BOS is a cGVHD-pulmonary disease characterized by obstructive airflow limitation based on pulmonary function tests.

The main symptoms of the patient are shortness of breath and decreased activity endurance after progressively aggravated activities.

BOS is not the same as BO, so there is room for treatment, and active treatment and follow-up are advocated.

The treatment is based on a combination of drugs with different mechanisms of action.

Treatment goals include: 1) delay the decline of lung function; 2) maintain stable lung function; 3) limited improvement of lung function.

Professor Lu Bingbing, deputy chief physician of the Department of Respiratory and Critical Care Medicine, Peking University People's Hospital, studied at the Institute of Respiratory Diseases of the Cleveland Medical Center in the United States in 2012.
The main research directions include respiratory critical illness, interstitial lung disease and lung transplantation.

 For many years, he has been working in the clinical frontline, and he is proficient in the basic theories in the field of respiratory critical medicine and various advanced life support technologies.
He is good at treating respiratory critical illnesses.

Focus on the research progress in the cross-field between respiratory medicine and other medical professions, in diffuse interstitial lung disease, solid organs and hematopoietic stem cell transplantation-related pulmonary complications, pulmonary comorbidities of systemic diseases, pulmonary vascular diseases, etc.
In terms of standardized diagnosis and treatment, he has a solid theoretical foundation and rich clinical experience.

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