¹Division of Pulmonary and Critical Care, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA

²Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA

Correspondence to: Dr B Afessa, Pulmonary and Critical Care Division, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

Pulmonary complications develop in 30-60% of hematopoietic stem cell transplants (HSCT). The main, late onset, non-infectious complications include Bronchiolitis obliterans (BO), Bronchiolitis obliterans organizing pneumonia (BOOP), and idiopathic pneumonia syndrome (IPS). BO and BOOP occur almost exclusively in allogeneic HSCT, and have 61% and 21% mortality rates, respectively. BOOP responds favorably to corticosteroids. IPS has less than 15% 1-year survival. Bone Marrow Transplantation (2001) 28, 425-434.

pulmonary complications; Bronchiolitis obliterans; Bronchiolitis obliterans organizing pneumonia; interstitial pneumonia; hematopoietic stem cell transplantation

Despite the success in treating otherwise fatal diseases, HSCT is associated with multiple complications. Pulmonary complications develop in 30-60% of HSCT recipients.^1,2 Factors that influence the development of pulmonary complications in HSCT include previous infections, pre-transplant conditioning regimen, current or prior immunosuppressant and radiation treatment, type of stem cell transplant (autologous vs allogeneic), use of prophylactic antibiotics, and time elapsed since transplant. With the use of prophylactic antibiotics, the spectrum of pulmonary complications following HSCT has changed increasingly from infectious to non-infectious etiologies. The times of onset and distinguishing features of the main non-infectious pulmonary complications are shown in Figure 1 and Table 1. This review will focus on the late-onset, non-infectious pulmonary complications in HSCT recipients. An algorithmic approach is outlined in Figure 2. Since most of the treatable pulmonary complications in HSCT recipients are diagnosed non-invasively and by bronchoscopy, we rarely subject our patients to surgical lung biopsy. However, in patients with suspected BOOP and when bronchoscopy is contraindicated or non-diagnostic, we occasionally resort to video-assisted thoracoscopic surgical lung biopsy.

Abnormal lung function

Restrictive and obstructive ventilatory defects, and gas transfer abnormalities occur frequently in HSCT recipients.^3,4 In a study of 52 young, asymptomatic HSCT recipients, 38% had abnormalities in pulmonary function tests (PFT): 23% restrictive defect with or without impaired gas transfer and 15% isolated impaired gas transfer.³ An abnormal pulmonary function test is a risk factor for pulmonary complications.^5,6,7,8,9 However, the role of PFT in identifying HSCT recipients at risk for pulmonary complications needs further investigation. The PFT findings in BO, BOOP, and delayed pulmonary toxicity syndrome are listed in Table 2.

Bronchiolitis obliterans (BO)

GVHD is a frequent complication of allogeneic HSCT.¹⁰ The pulmonary morphological manifestations of GVHD include diffuse alveolar damage, lymphocytic bronchitis/ bronchiolitis with interstitial pneumonitis, BOOP, and BO.¹¹ BO is a nonspecific inflammatory injury affecting primarily the small airways.¹² It is recognized by the presence of airflow limitation clinically and intraluminal fibrosis histologically. BO can be idiopathic or associated with connective tissue disease, inhaled toxins, infections, drugs, and chronic GVHD.¹² Although almost non-existent, two cases of fatal BO have been reported in autologous HSCT recipients.¹³

Epidemiology

The lack of precise definition and uniform diagnostic criteria has led to variations in the reported incidence of BO in different studies. Most reported cases of BO are diagnosed by the presence of airflow limitation in the appropriate clinical setting without histological confirmation. The incidence of BO was 8.3% among 2152 allogeneic HSCT recipients reported in nine studies.^{14,15,16,17,18,19,20,21,22} The incidence varies between 6% and 20% in long-term survivors with GVHD.^17,22,23,24

Chronic GVHD, methotrexate use, and serum immunoglobulin deficiency are risk factors for BO.^14,17,21,24 In one study of allogeneic HSCT recipients, 6% of those with chronic GVHD developed BO compared with none of those without chronic GVHD.¹⁷ Although pulmonary infections are common in BO, it is not clear whether they are causally related or result from the patients' immunodeficiency.

Pathogenesis

The pathogenesis of BO in HSCT recipients is poorly defined. The association between BO and chronic GVHD suggests that host bronchiolar epithelial cells serve as a target for donor cytotoxic T-lymphocytes.²⁵ Alternative explanations include recurrent aspiration due to GVHD- associated esophagitis, abnormal local immunoglobulin secretory function in the lungs, or unrecognized infection.^17,25 The variations in histopathologies, bronchoalveolar lavage (BAL) cell differential, and clinical course suggest a multifactorial pathogenesis.^13,25,26

Clinical findings

Airway obstruction develops between 80 and 700 days following HSCT in BO.^14,21,22,27 The respiratory symptoms include dry cough, dyspnea, and wheezing.^14,21,22 Dry cough is present in 60-100% and dyspnea in 50-70%.^14,22 Antecedent 'cold' symptoms develop in 20%, and another 20% are asymptomatic at the time of abnormal PFT.¹⁴ Wheezing is detected in about 40%.¹⁴ Unlike BOOP, fever is absent in BO. Since these symptoms are nonspecific, a complete history and physical examination focusing on signs of chronic GVHD should be obtained.

Diagnostic evaluation

Since early diagnosis may improve outcome, HSCT recipients with suspected BO should undergo spirometry, lung volumes, diffusing capacity for carbon monoxide (DLCO), and arterial blood gas measurements.²⁸ Although normal airflow has been reported in histologically proven BO,¹³ airflow obstruction is its hallmark. Based on forced expiratory volume in 1 s (FEV1) expressed as percent of baseline, BO is classified into three stages: mild (FEV1 66-80%), moderate (FEV1 51-65%), and severe (FEV1 50%).²⁹

In suspected BO, laboratory evaluation should be undertaken to exclude infection and other complications of GVHD. Complete blood count with differential, blood urea nitrogen, creatinine, total bilirubin, hepatic transaminases, gammaglobulin levels, and urinalysis are recommended.²⁵

Chest radiograph is usually normal or may show hyperinflation.^14,15,16 High resolution computed tomography (HRCT) of the chest may show hypoattenuation, bronchial dilatation, bronchiolectasis, and expiratory air trapping (Figure 3).^15,16,18

Since there is a high prevalence of sinusitis in these patients, radiographic assessment of the paranasal sinuses is recommended.^23,25,30,31 If gastrointestinal GVHD is suspected, endoscopy should be performed.^25,32

BAL shows neutrophilic and/or lymphocytic inflammation.²⁶ Transbronchial lung biopsy is unlikely to add to the diagnostic yield in BO and is contraindicated if there is severe airway obstruction or thrombocytopenia. Because BO involves the respiratory and membranous bronchioles, transbronchial lung biopsy is usually nondiagnostic. Video-assisted thoracoscopic lung biopsy is required to make a definitive histological diagnosis. Lung biopsies show small airway involvement with fibrinous obliteration of the lumen (Figure 4).^{15,22,33,34,35} Necrotizing bronchitis and bronchiolitis have been reported.³³ Peribronchiolar inflammatory cellular infiltrates consisting of neutrophils and lymphocytes may be present.¹⁹

Although obstructive airways disease and BO exist as distinct clinical entities in HSCT recipients, the diagnostic criteria of BO have not been clearly defined. Airway obstruction may exist without bronchiolitis and bronchiolitis without airway obstruction.²⁵ BO should be defined by the presence of obstructive airways with suspected bronchiolitis due to chronic GVHD or the demonstration of new onset airflow obstruction in a HSCT recipient without pulmonary symptoms.²⁵ Bronchiolitis is suspected by the presence of cough, wheezing, dyspnea, or hypoxemia in a HSCT recipient with a normal chest radiograph.²⁵ Pulmonary veno-occlusive and interstitial pulmonary diseases can have similar presentation. However, pulmonary veno-occlusive disease is unlikely to show airways obstruction.³⁶ Interstitial pulmonary diseases show restrictive defects on PFT and parenchymal abnormalities on HRCT scan of the chest.

Treatment

No prospective clinical trial has addressed the management of BO. Based on anecdotal reports, corticosteroids and augmented immunosuppression are used for treatment. However, only a minority improve.^{4,13,14,15,16,18} Prednisone 1-1.5 mg/kg/day, not to exceed 100 mg/day, is given for 4 to 6 weeks.²⁵ If the respiratory status remains stable, corticosteroid therapy is tapered and discontinued in 6 to 12 months. If no improvement is noted within 1 month, immunosuppression with cyclosporine or azathioprine is initiated.²⁵ The dose of azathioprine is 2-3 mg/kg/day, not to exceed 200 mg a day. Cyclosporine dose is adjusted according to the serum level.

In addition to immunosuppression, prophylaxis for Pneumocystis carinii and Streptococcus pneumoniae should be maintained. Although only a minority of patients respond to bronchodilators, a trial is warranted.^14,23,33 In selected patients, lung transplant is an option.^11,37

Macrolides have been shown to improve outcome in panbronchiolitis.^38,39 Their beneficial effects are considered to be due to their anti-inflammatory rather than anti-bacterial activities.^40,41,42 Although there has been no report of macrolide use in BO, their mechanisms of action and relatively minor adverse effects warrant a clinical trial. Despite one case report of BO responding to thalidomide,⁴³ a recent study has shown no benefit in pulmonary chronic GVHD.⁴⁴ Intravenous immunoglobulin has not been shown to prevent the development of BO.⁴⁵ Cyclosporine may prevent the development of BO.⁴⁶

Prognosis

The FEV1 decline rate is widely variable in BO.¹⁴ Rapid deterioration in FEV1 is associated with increased mortality.¹⁴ Despite treatment with bronchodilators, corticosteroids and immunosuppression, improvement in lung function is noted in only 8% to 20%.^16,22,25,28 The reported case fatality rates vary widely, ranging from 14% to 100% with a mean of 61%.^{4,11,13,14,15,17,19,21,22,27,28,47} In one study of allogeneic HSCT recipients with GVHD, the 3-year mortality rate of those with BO was 65% compared to 44% of those without BO.¹⁴

Future direction

With expanding use of allogeneic HSCT, the incidence of BO is likely to increase. BO was first recognized in allogeneic HSCT recipients about 20 years ago. However, its pathogenesis is unknown, the diagnostic criteria have not been clearly defined, and prospective clinical trials of treatment are non-existent. Although serial PFTs may identify patients earlier during their clinical course, their impact on outcome is yet to be determined. Lung biopsy may broaden our knowledge about BO with therapeutic and prognostic implications for the future. However, due to the lack of effective treatment, routine lung biopsy is not recommended at this time unless another disease is suspected. Because of the associated high mortality rate, prospective studies are needed to determine the appropriate management of BO in the HSCT recipient.

Bronchiolitis obliterans organizing pneumonia (BOOP)

The first cases of BOOP in HSCT recipients were reported in the early 1990s.^48,49 BOOP is less common than BO. BOOP is characterized by the presence of granulation tissue within the alveolar ducts and alveoli. It presents more like pneumonia than airways disease.

Incidence

Among 296 patients with BOOP reported in 63 publications, four (1.4%) were HSCT recipients.⁵⁰ In our institution, the incidence of BOOP was 1.7% in allogeneic HSCT recipients who survived for 3 months or longer.¹⁶ The publications on BOOP in HSCT recipients are limited to case reports with a maximum number of five patients.^{11,16,48,49,50,51,52,53}

Pathogenesis/pathophysiology

The occurrence of BOOP almost exclusively in allogeneic HSCT recipients with GVHD suggests that it may represent rejection of the lung by the transplanted stem cell.

Clinical presentation

Although BOOP has been reported in the absence of GVHD,^49,54 most HSCT recipients with BOOP have GVHD.^16,50,51 The presenting symptoms include dry cough, dyspnea, and fever,^48,49,50 with onset between 1 and 13 months following transplant.^{16,48,49,50,51,52,53,54,55}

Diagnostic evaluation

BOOP should be included in the differential diagnosis of bilateral airspace disease in HSCT recipients, especially if they do not respond to antibiotics for presumed pneumonia. PFTs show a restrictive defect, decreased DLCO, and normal expiratory flow.^48,50,56 Arterial blood gas analysis shows hypoxemia.⁵⁰ Chest radiographs and computed tomographies (CT) show peripherally distributed patchy air space consolidation, ground-glass attenuation and nodular opacities.^{48,49,50,57,58,59}

Although PFT and CT scan findings, in conjunction with the clinical features, suggest the diagnosis, definite confirmation requires surgical or transbronchial lung biopsy. Histologic confirmation of the diagnosis is particularly warranted, as long-term corticosteroid therapy is usually needed. Surgical lung biopsy is considered the gold standard for diagnosis. The histologic hallmark of BOOP is the presence of patchy intraluminal fibrosis, consisting of polypoid plugs of immature fibroblasts, resembling granulation tissue (Figure 5).⁶⁰ Intraluminal fibrosis is present in the distal airways, alveolar ducts, and peribronchial alveolar spaces.⁶⁰

Treatment

About 80% of HSCT recipients with BOOP respond favorably to treatment.^{16,48,49,50,51,52,53,55} The duration and dosage of corticosteroid therapy have not been clearly defined.

Radiographic abnormalities usually clear within 1 to 3 months of initiating corticosteroid therapy.^49,50,52 Based on the experience from non-HSCT recipients with BOOP, the initial dose of corticosteroid therapy is prednisone 0.75-1.5 mg/kg/day up to 100 mg, for 1-3 months, and this is followed with lower doses for a total duration of 6-12 months.⁶¹ We provide prophylaxis for Pneumocystis carinii pneumonia with trimethoprim/sulfamethoxazole during corticosteroid therapy. Erythromycin 10 mg/kg/day for 14 months was used in conjunction with corticosteroids in one patient.⁵³

Prognosis

BOOP following HSCT has a worse prognosis than idiopathic BOOP.⁵⁰ Among 19 reported HSCT recipients with BOOP, the overall case fatality was 21%.^{11,16,48,49,50,51,52,53,54,55}

Future direction

Although BOOP responds to corticosteroid therapy, the dose and duration of therapy need to be clarified in future studies. The role of macrolides in the treatment of BOOP requires further evaluation.

Idiopathic pneumonia syndrome (IPS)

Despite aggressive diagnostic work-up, no infectious etiology is identified in many HSCT recipients with suspected pneumonia. IPS is defined by the presence of widespread alveolar injury in the absence of lower respiratory tract infection.⁶²

Epidemiology

In a 1985 review of 4500 HSCT recipients, Krowka et al²⁷ reported a 35% incidence rate of IPS. In 12 recent studies of 4496 HSCT recipients, the overall incidence was 10%, range between 2% and 17%.^{4,63,64,65,66,67,68,69,70,71,72,73} Differences in the patient study populations, lack of uniform definition and diagnostic criteria, reliance on lung biopsy in the earlier studies, changes in the intensity of cytoreduction and immune suppression, new developments in infection prophylaxis, and improved infection detection using newer techniques are likely to have contributed to variations in the reported incidence rates.

Factors which predispose the HSCT recipient to IPS are listed in Table 3. Although Kantrow et al⁶⁷ did not find that allogeneic transplantation predisposes to IPS, our analysis of data from selected studies shows 36 of 617 autologous HSCT recipients (5.8%) developed IPS compared to 380 of 3569 allogeneic HSCT recipients (10.6%), a significant difference.^{4,63,64,65,67,68,69,70,72,73} The probability of developing IPS increases with the number of risk factors.⁶⁵ Patients transplanted for aplastic anemia are at low risk for IPS.⁶⁴

Pathogenesis/pathophysiology

IPS represents a heterogeneous group of conditions that result in interstitial pneumonitis or diffuse alveolar damage.⁶⁷ Its pathogenesis has not been well defined. The potential mechanism of IPS is parenchymal damage from previous chemoradiation therapy and/or the conditioning regimen, GVHD, undiagnosed infection, and excessive recruitment and activation of inflammatory cells.

Clinical course

Patients with IPS present with dyspnea, dry cough, hypoxemia, and radiographic infiltrates.⁶² The clinical spectrum is broad, ranging from acute respiratory failure to incidental radiographic abnormalities.⁶² Because IPS mimics infectious pneumonia, most patients are on antibiotics at the time of diagnosis.⁶⁷ The median time of onset of IPS is 21 to 65 days, range 0 to 1653 days, after transplant.^64,67,68,74

The pneumonia resolves in about 31% of patients with IPS.^67,74 However, the patients' clinical courses are usually complicated by infections, predominantly viral and fungal, pneumothorax, pneumomediastinum, subcutaneous emphysema, pulmonary fibrosis, and auto-immune polyserositis involving the pleura and pericardium.^4,67,74,75

Diagnostic evaluation

The clinical presentation and radiographic findings do not differentiate between infectious and idiopathic pneumonia. PFT and CT of the chest are nonspecific. More than 90% of patients with IPS have diffuse infiltrates on chest radiograph.⁷⁴ The criteria for diagnosing IPS are listed in Table 4.⁶²

Infection needs to be excluded by BAL or lung biopsy. In earlier studies, IPS was diagnosed histologically when biopsy or autopsy of lung tissue showed inflammation without infection.^63,64,68,74 In one recent study, 80% of IPS cases were diagnosed by BAL, 4% required lung biopsy, and 16% were diagnosed at autopsy.⁶⁷ The limitation of BAL in providing information about the histopathological structure, interstitial fungi and neoplasms, vascular damage, and other abnormalities of potential therapeutic or prognostic importance is well recognized. In our diagnostic approach to patients with suspected IPS, we perform BAL and transbronchial lung biopsy if there are no contraindications.

Lung biopsies in IPS show diffuse alveolar damage, organizing or acute pneumonia, and interstitial lymphocytic inflammation.^4,67

Treatment

Studies addressing the treatment of IPS in the HSCT recipient are non-existent. Griese et al⁴ reported three cases of IPS that responded to treatment, including corticosteroids. Studies with larger sample sizes have not shown any outcome benefit with corticosteroid treatment.^67,74 Currently, the only accepted treatment regimen is supportive care combined with prevention and treatment of infection.

Prognosis

In our review of six selected studies, the overall mortality of 388 HSCT recipients with IPS was 74%, range between 60 and 86%.^{63,64,65,67,68,74} The 1-year survival is less than 15%.^67,76 Infectious complications and non-pulmonary organ failure contribute to the high mortality.^67,76 For those who require mechanical ventilation, mortality exceeds 95%.⁶⁷

Future direction

IPS is a heterogenous entity of diseases of unknown etiology and pathogenesis. It has a high mortality rate and no effective therapy. We need new studies to determine the etiology, pathogenesis, and effective therapy of IPS.

Diffuse alveolar hemorrhage

Since DAH occurs early after transplant, we will discuss it only briefly. DAH develops in 10% to 21% of HSCT recipients.^77,78 Despite the presence of thrombocytopenia in most, DAH is not corrected with platelet transfusions.⁷⁷ The pathophysiology of DAH is not clearly understood. The presence of neutrophils in the BAL of some patients with DAH⁷⁷ suggests an inflammatory mechanism. Patients with DAH present with progressive dyspnea, hypoxemia, and cough.⁷⁷ Hemoptysis is rare.⁷⁷ Chest radiograph and CT show diffuse infiltrates that start centrally.^58,77,79,80 BAL shows progressively bloodier aliquots of lavage return.⁷⁷ Lung biopsies show histologic features consistent with the proliferative phase of diffuse alveolar damage.⁷⁷ Based on anecdotal experiences and retrospective studies, we use corticosteroids to treat DAH.^78,81,82,83 The reported mortality of DAH is 70-100%.^77,79,84,85 However, in our experience of 18 HSCT recipients admitted to the intensive care unit and treated with corticosteroids in the last 4 years, the mortality was 33%.

Peri-engraftment respiratory distress syndrome

A study from our institution has described a peri-engraftment respiratory distress syndrome, defined by onset of symptoms within 5 days of engraftment, temperature >38.3°C, radiographic pulmonary infiltrates, absence of cardiac dysfunction, arterial oxygen saturation less than 90%, and negative blood culture.⁸⁶ There may be overlap between this syndrome and DAH. Since peri-engraftment respiratory distress syndrome occurs early in the post- transplant period, it will not be discussed here.

Delayed pulmonary toxicity syndrome

A 'delayed pulmonary toxicity syndrome', characterized by interstitial pneumonitis and fibrosis, delayed for months to years, develops in autologous BMT recipients with breast cancer who have received high-dose chemotherapy pre-transplant.^87,88 The high-dose chemotherapy with cyclophosphamide, cisplatin, and bischloroethylinitrosurea (BCNU), high incidence, low mortality, and good response to corticosteroid treatment distinguish this syndrome from IPS.⁸⁷ It develops in about 72% of autologous HSCT recipients who have received high-dose chemotherapy for breast cancer.⁸⁸ It presents with dry cough, dyspnea and fever. It has a better prognosis than IPS.^87,88 The DLCO declines to a nadir level in 15-18 weeks following the chemotherapy/ transplant.⁸⁷ Lung function improves with corticosteroid treatment.⁸⁸ No deaths attributable to this syndrome have been reported, and the published studies are limited to a single institution.^87,88

Pulmonary cytolytic thrombi

Pulmonary cytolytic thrombi is a non-infectious pulmonary complication of HSCT.⁸⁹ It occurs almost exclusively in children with GVHD and is characterized by fever and pulmonary nodules. Biopsy of the nodules shows necrotic, basophilic thromboemboli with amorphous material suggestive of cellular breakdown products.⁹⁰ Its time of onset ranges between 8 and 343 days (median 72) after transplant.⁸⁹ Most patients improve clinically within 1-2 weeks and radiographically over weeks to months.⁸⁹ In the only published study, nine of the 13 HSCT recipients with pulmonary cytolytic thrombi were alive at a median follow-up of 1.5 years.⁸⁹ All received antibiotics, and nine were treated with systemic corticosteroids.⁸⁹ The published reports on pulmonary cytolytic thrombi are limited to one institution.

Others

Other uncommon noninfectious pulmonary complications of HSCT include progressive pulmonary fibrosis,⁴ pulmonary hypertension,⁹¹ pulmonary veno-occlusive disease,³⁶ hepatopulmonary syndrome,⁹² alveolar proteinosis⁹³ and eosinophilic pneumonia.⁹⁴

Conclusions

Non-infectious pulmonary complications are common following HSCT. The pathogeneses and diagnostic criteria of most of these complications have not been clearly defined. Current treatment modalities, although effective in some cases, are not based on scientific evidence. Future studies are needed to better define the pathogeneses and clarify the diagnostic criteria of, and determine effective therapeutic approaches to non-infectious pulmonary complications in the HSCT recipient.

With the wider application of peripheral blood stem cell transplantation, neutrophil recovery time has shortened.⁹⁵ This may lead to a decrease in the incidence of early infectious complications and increase in the relative frequency of non-infectious pulmonary complications. However, since the exact impact of peripheral blood stem cell transplantation on pulmonary complications has not been clearly defined, we need to monitor and report the changes in future studies.

Acknowledgements

We thank Dr Jeffrey L Myers for providing us with the pathology slides and legends.

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Figure 1 Approximate time of onset of non-infectious pulmonary complications following hematopoietic stem cell transplant. BO = Bronchiolitis obliterans; BOOP = Bronchiolitis obliterans organizing pneumonia; DAH = diffuse alveolar hemorrhage; DPTS = delayed pulmonary toxicity syndrome; IPS = idiopathic pneumonia syndrome; PERDS = peri-engraftment respiratory distress syndrome; PCT = pulmonary cytolytic thrombi.

Figure 2 An algorithmic approach to non-infectious pulmonary complications in HSCT.

Figure 3 A computed tomography of the chest in a patient with Bronchiolitis obliterans showing diffuse areas of parenchymal hypoattenuation, proximal bronchiectasis, and subsegmental bronchial dilatation.

Figure 4 Lung pathology in Bronchiolitis obliterans showing bronchiolar inflammation and luminal obliteration associated with excess fibrous connective tissue. Alveoli and their ducts are spared. (Hematoxylin & eosin and Verhoeff-Van Gieson elastic tissue stain.)

Figure 5 Lung pathology in Bronchiolitis obliterans organizing pneumonia showing the presence of intraluminal granulation tissue in bronchioli, alveolar ducts, and alveoli. There is also interstitial infiltration with mononuclear cells and foamy macrophages. (Hematoxylin & eosin stain.)

Table 1 The distinguishing features of the main non-infectious pulmonary complications in hematopoietic stem cell transplant recipients

Table 2 Pulmonary function test findings in late-onset, non-infectious pulmonary complications of HSCT patients

Table 3 Risk factors for idiopathic pneumonia syndrome

Table 4 Criteria for the diagnosis of idiopathic pneumonia syndrome in the hematopoietic stem cell transplant recipient⁶²