Clinical summary continued: Biopsy was followed by a bronchopleural fistula (BPF) that was slow to resolve. Antibiotics for bacteria, fungi, and virus were continued. The BPF was repaired surgically on 7/12. Fever up to 38° developed, and cough became productive of blood-tinged sputum. He required nasal oxygen (4 L/min) and appeared chronically ill, dyspneic, and wasted. Bronchial breath sounds and crackles were heard bilaterally, and there were multiple opacities on the chest film. WBC was 6.7 k/µl, hct 31%, plt 162 k/µl, BUN 19 mg/dl, and creatinine 1.6 mg/dl. On 7/15, steroids were begun and increased to high dose over one week. Ten days later cyclosporine was added, and his symptoms and chest film gradually improved. Steroids were tapered and appetite returned. Pulmonary function tests were performed 7/29: TLC 3.1 L (62% pred.), RV 0.9 L (60% pred.), FVC 2.4 L and FEV1 2.1 L with FEV1/FVC 87%. FEF 25-75 was 3.1 L/sec (84% pred.), and DLCO 12.9 ml/min/mmHg (77% pred). Blood gases were pH 7.42, pCO2 35, and pO2 57. Oxygen saturation was 90%. The decreased DLCO and restriction were interpreted as being consistent with a cryptogenic organizing pneumonia-like pattern. He was discharged improved in mid-August.

Diagnosis: Pulmonary graft versus host disease displaying cellular, organizing, and fibrosing interstitial pneumonia; a COP-like (BOOP-like) pattern; lymphocytic bronchiolitis; and cicatricial, constrictive bronchiolitis.

Comment: This patient's PFTs showed restrictive lung disease, but both parenchymal and airway disease were present in the biopsy. Both probably resolved to some degree with increased immunosuppression because neither showed dense, endstage scar. The presence of constrictive bronchiolitis, which is not a feature of chemotherapeutic drug toxicity, helps to confirm a diagnosis of GVHD. There was no evidence of a necrotizing pneumonia or viral inclusions in the biopsy, and an immunoperoxidase stain for CMV was negative. The presence of GVHD in the lung helps to confirm the clinical suspicion of GVHD in the bowel and liver although histologic confirmation was lacking.

Pulmonary Complications of Bone Marrow Transplantation

Introduction: Although infection must be considered in all patients with respiratory complaints following BMT, several noninfectious syndromes occur. The syndromes may be classified as parenchymal or airway, but combinations occur. Parenchymal disease may be subdivided into diffuse alveolar hemorrhage, and early and late idiopathic pneumonia syndromes. Patients are sometimes managed on the basis of the clinical, radiographic, and physiologic changes, but when a biopsy is performed, an understanding of the histologic changes is important in guiding therapy.

1. Idiopathic pneumonia syndrome (IPS): This syndrome has an incidence of 12% after allogeneic transplants and is responsible for 20% of deaths. Symptoms vary from mild to severe and radiographs from incidental opacities to an ARDS-like picture. Median time to onset is 7-8 weeks after transplant, but IPS may occur late (after 100 days). IPS is believed to be a manifestation of GVHD. Death can result from IPS or superimposed infection. Criteria for diagnosis are listed in the Table [1].

Table. Diagnostic criteria for idiopathic pneumonia syndrome [1]

Diagnosis requires excluding infection by:

  1. No improvement on broad-spectrum antibiotics
  2. No organisms identified (BAL negative for routine bacteria, viruses, fungi; shell vial for CMV negative; cytologic preparations negative)
  3. Transbronchial biopsy
  4. Repeat of 1 & 2 after 2 to 14 days

In a review of 41 patients with severe IPS of early onset, 24 (59%) died. Unexpectedly, patients with acute GVHD or those who received >1,200 cGy of TBI were more likely to recover than others [3]. In a series of 143 patients who survived more than 6 months after BMT, 29 (20%) developed IPS. All 29 had reduction in lung volume, but only 18 (62%) had evidence of airway obstruction. Stratification of patients according to the FEV1 predicted response to immunosuppressive therapy (mostly steroids). Those with FEV1 >65% of pretransplant baseline did well, and those with FEV1 <45% did poorly [2].

Diffuse alveolar hemorrhage (DAH): DAH is another type of idiopathic pneumonia syndrome. Although it usually affects patients undergoing autologous BMT [4], DAH also occurs, but less frequently, in patients with allogeneic transplants [5, 6]. In one series, patients with DAH (21% of 141 cases [4]), who had undergone autologous BMT, presented with progressive dyspnea, hypoxemia, fever, and/or mucositis, but usually no hemoptysis, up to 40 d after transplantation. Plain films showed diffuse alveolar opacities in most [7]. Diagnosis was by lavage, which showed increasingly bloody fluid in serial returns, and exclusion of infection. Risk factors included age over 40, transplant for solid malignancies, severe mucositis, and renal insufficiency [4]. Pretransplant chemotherapy and radiation were thought to be causative. The disorder coincides with marrow recovery and return of PMNs [8]. Another study found that airway inflammation (PMNs >20% ± any eosinophils) in the first lavage sample (bronchial sample) predicted DAH in patients undergoing autologous BMT for Hodgkin disease [9]. Histologic changes include alveolar damage and bleeding. Although high dose corticosteroids increase in-hospital survival, survival after 100 days is only about 10% [4,8,10].

2. Airway disease: Bronchitis/bronchiolitis, with an incidence of about 10% after allogeneic BMTs, usually occurs in patients with pre-existing GVHD and is considered to be a component of it. Suspected risk factors include older age, methotrexate for immunosuppression of GVHD, and possibly low serum immunoglobulin levels [11]. Onset is before 150 days in 40% and after in 60%. Symptoms include cough, dyspnea, or wheeze in 80%; 20% are asymptomatic. Wheezes or crackles may be heard on auscultation in about half of patients. The chest radiograph is normal in 80%. Chronic GVHD is present in about 3/4 of patients [11]. Diagnosis may be made clinically based on symptoms, radiographs, PFTs, and BAL, the last to exclude infection. Because IPS may coexist with airway disease, pulmonary function tests may show a decrease in both FEV1 and FVC of IPS in addition to an increased residual volume suggesting airflow insufficiency [11]. Survival of patients with chronic GVHD without airflow insufficiency was 50% at 5 years whereas in those with airflow insufficiency, it was 25% [11]. A faster rate of progression of airflow insufficiency signifies a worse prognosis than a slow rate, and early treatment is advocated [11]. Although airway disease is considered to be a manifestation of GVHD, there is no direct evidence for it, and aspiration or infection, especially viral infection, may be required for its development [11]. In a recent experimental model, CMV was found to potentiate tracheal obliterans in a tracheal allograft [12]. Some patients with airway disease have been treated with lung transplantation [13].

Histologic findings: There are no studies of the correlation of histologic changes with radiographic and functional studies. A report of findings in biopsies of 17 patients with non-infectious disease post-BMT indicates a wide spectrum of acute and chronic changes. The author proposes that early airway lesions may coincide with late parenchymal ones and vice versa. Biopsy findings include the following [13].

1. Diffuse alveolar damage with interstitial edema, hyaline membranes, and type II cell hyperplasia, often atypical, is found either early or late after BMT. PMNs may be present focally in the interstitium. Alveolar hemorrhage accompanies the alveolar damage in some cases. The clinical correlate is IPS or DAH.

2. A lymphocytic bronchitis/bronchiolitis accompanied by interstitial pneumonia may be found. Airway disease consists of a lymphoid infiltrate that invades the airway wall and the epithelium. The epithelium often shows hyperplasia with focal erosions and goblet cell metaplasia. The hyperplasia and erosions produce an "up-down" pattern. The lumen may have a fibrinopurulent exudate. The interstitial pneumonia, which varies in extent, shows widening of the alveolar walls by a lymphoid infiltrate that occasionally suggests a diagnosis of lymphocytic interstitial pneumonia. There is type II cell hyperplasia, and the cells are often atypical. There may be focal hyaline membranes. Clinical correlates include IPS ± airway disease.

3. COP-like changes may occur with a proliferative bronchiolitis and organizing pneumonia in adjacent alveoli. The residual airway epithelium shows the "up-down" appearance noted above. The clinical correlate is IPS.

4. Mural bronchiolar scar produces a cicatricial, constrictive bronchiolitis that may be accompanied by a fibrosing interstitial pneumonia. Clinical correlates include IPS and airway disease.

Other changes in biopsies include perivenular infiltrates of lymphocytes and plasma cells ± transmural and subendothelial lymphoid cells and reactive endothelial cells. Mild bronchiectasis has been described by CT.

In summary, airway lesions include: lymphocytic bronchitis/bronchiolitis, proliferative bronchitis/bronchiolitis, and cicatricial, constrictive bronchiolitis. Parenchymal lesions include cellular interstitial pneumonia, organizing alveolar/interstitial pneumonia, and interstitial fibrosis. Lesions may occur alone or in any combination. Only the cicatricial, constrictive bronchiolitis and interstitial fibrosis are irreversible. In any case, the process is patchy, and treatment may delay or halt progression, even when some scarring is present in the biopsy. Exclusion of infection is an important part of handling the open lung biopsy.


1. Clark J, Hansen J, Hertz M, Parkman R, Jensen L, Peavy H. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis 1993; 147:1601-1606.

2. Schwarer A, Hughes J, Trotman-Dickenson B, Krausz T, Goldman J. A chronic pulmonary syndrome associated with graft-versus-host disease after allogeneic marrow transplantation. Transplantation 1992; 54:1002-1008.

3. Crawford S, Hackman R. Clinical course of idiopathic pneumonia after bone marrow transplantation. Am Rev Respir Dis 1993; 147:1393-1400.

4. Robbins R, Linder J, Stahl M, Thompson III A, Haire W, Kessinger A, Armitage J, et al. Diffuse alveolar hemorrhage in autologous bone marrow transplant recipients. Am J Med 1989; 87:511-518.

5. Cordonnier C, Bernaudin J-F, Bierling P, Huet Y, Vernant J-P. Pulmonary complications occurring after allogeneic bone marrow transplantation. A study of 130 consecutive transplanted patients. Cancer 1986; 58:1047-1054.

6. Agustí C, Ramirez J, Picado C, Xaubet A, Carreras E, Ballester E, Torres A, et al. Diffuse alveolar hemorrhage in allogeneic bone marrow transplantation. A postmortem study. Am J Respir Crit Care Med 1995; 151:1006-1010.

7. Witte R, Gurney J, Robbins R, Linder J, Rennard S, Arneson M, Vaughan W, et al. Diffuse pulmonary alveolar hemorrhage after bone marrow transplantation: radiographic findings in 39 patients. AJR 1991; 157:461-464.

8. Metcalf J, Rennard S, Reed E, Haire W, Sisson J, Walter T, Robbins R, et al. Corticosteroids as adjunctive therapy for diffuse alveolar hemorrhage associated with bone marrow transplantation. Am J Med 1994; 96:327-334.

9. Sisson J, Thompson A, Anderson J, Robbins R, Spurzem J, Spence P, Reed E, et al. Airway inflammation predicts diffuse alveolar hemorrhage during bone marrow transplantation in patients with Hodgkin disease. Am Rev Respir Dis 1992; 146:439-443.

10. Robbins R, Floreani A, Buchalter S, Spurzem J, Sisson J, Rennard S. Pulmonary complications of transplantation. Annu Rev Med 1992; 43:425-435.

11. Crawford S, Clark J. Bronchiolitis associated with bone marrow transplantation. Clin Chest Med 1993; 14:741-749.

12. Koskinen P, Kallio E, Bruggeman C, Lemström K. Cytomegalovirus infection enhances experimental obliterative bronchiolitis in rat tracheal allografts. Am J Respir Crit Care Med 1997; 155:2078-2088.

13. Yousem S. The histological spectrum of pulmonary graft-versus-host disease in bone marrow transplant recipients. Hum Pathol 1995; 26:668-675.

Clinical summary

Copyright 1997 by Martha L. Warnock. All rights reserved.

Last revised 10/4/97

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