Noninfectious Lung Disease After Organ Transplantation
Special Feature
Noninfectious Lung Disease After Organ Transplantation
By Stephen W. Crawford, MD
Patients with compromised immune function suffer a wide variety of lung insults. Organ transplantation is associated with specific lung injuries. Infections are the most common causes of both acute and chronic lung diseases, but many noninfectious conditions affect the lungs. The clinical presentations of these noninfectious conditions often mimic infections, thus causing diagnostic dilemmas. Lung injury after lung or marrow transplantation is associated with a diversity of etiologies: sepsis, irradiation, graft rejection, reperfusion injury, graft-vs.-host disease, and chemotherapeutic agents and other drug reactions. Establishing a specific diagnosis and etiology for the injury often is problematic. From a pragmatic standpoint, excluding the possibility of infection is the principal aim of diagnostic testing.
Pulmonary complications after transplantation may be either acute or chronic in nature, and either may be encountered in the ICU. Inciting causes may be associated with either or both presentations (see Figure). The constellation of symptoms and signs accompanying these infiltrates may vary from minimal to profound respiratory failure. Unfortunately, the presentation is rarely of clinical use in pinpointing a specific cause. Confirmation of the diagnosis may not be as relevant as is the exclusion of opportunistic infection or cardiac pulmonary edema as causes of the process. With the possible exception of cardiac pulmonary edema, most causes of diffuse noninfectious pulmonary injury are associated with a poor prognosis. Specific treatments rarely have been proven to be effective.
Idiopathic Pneumonia After Blood and Marrow Transplantation
Idiopathic pneumonia is characterized as a syndrome of hypoxemia and radiographic nonlobar infiltrates in the absence of congestive heart failure and without evidence of infectious etiology after bone marrow transplantation.1 Most noninfectious causes of lung injury are attributed to treatment-related toxicities. While both infectious and noninfectious pneumonia are associated with the presence of graft-vs.-host disease (GVHD), it is unproven whether GVHD causes a direct lung injury (i.e., an alloreactive process directed against the lung). Other conditions associated with diffuse noninfectious pulmonary infiltrates are alveolar hemorrhage, pulmonary edema, obliterative bronchiolitis, and bronchiolitis obliterans with organizing pneumonia (BOOP). The incidence of idiopathic pneumonia is largely unchanged by measures that have decreased the incidence of pneumonia caused by cytomegalovirus (CMV).2
The overall mortality of idiopathic pneumonia after allogeneic marrow transplantation is high (71%) but less than one-third of patients die of progressive respiratory failure, and infection is commonly associated with death despite a previous negative lung biopsy.
Idiopathic Pneumonia Syndrome
In 1992, the spectrum of idiopathic lung injury was recognized as a syndrome (idiopathic pneumonia syndrome [IPS]) by an NIH-sponsored workshop on idiopathic lung injury after marrow transplantation. This terminology acknowledged the probability of multiple etiologies and varied clinical presentation for diffuse non-infectious lung injury.3 The diagnosis of IPS is made by a bronchoalveolar lavage (BAL) that does not reveal an infection, in the presence of nonlobar radiographic infiltrates and physiological changes consistent with pneumonia. Evidence of alveolar hemorrhage is consistent with IPS. The entity commonly called "diffuse alveolar hemorrhage" is included within the syndrome.4
The incidence of IPS appears lower (6-8%) and the onset earlier (mean about 2-3 weeks after transplantation) than previously reported for idiopathic pneumonia.5 The major risks appear to be regimen-related toxicity and multiorgan dysfunction associated with alloreactive processes.
The diagnosis of idiopathic lung injury rests largely on the results of BAL. Lung biopsy (transbronchial or open) appears to add little to the diagnostic sensitivity of BAL for infection in the presence of diffuse parenchymal infiltrates. At present, histopathology does not help to direct therapy in idiopathic lung injury after hematopoietic stem cell transplantation. Lung biopsy should be considered in cases with patchy or multifocal infiltrates because of the higher incidence of infection and concern for false-negative results from BAL.
There are no randomized studies of treatment of idiopathic lung injury after marrow transplantation. High-dose corticosteroids (ranging from 1-16 mg/kg/d of methylprednisolone) are commonly used, and anecdotal reports suggest successful outcomes. A recent study noted that increased immunosuppression resulted in a durable improvement in three of eight patients with diffuse idiopathic pneumonia that occurred more than three months after transplantation.6 Corticosteroid administration has been reported effective in diffuse lung injury in BCNU-containing treatment protocols.7
| Table-Criteria for Diagnosis of Idiopathic Pneumonia Syndrome |
| 1. Evidence of widespread alveolar injury: |
| a. Multilobar infiltrates on chest radiograph or computed tomography |
| b. Symptoms and signs of pneumonia |
| c. Evidence of abnormal physiology |
| 2. Absence of active lower respiratory tract infection documented by negative bronchoalveolar lavage, lung biopsy or autopsy, with examination of stains and cultures for bacteria, fungi and viruses, including: |
| a. Cytomegalovirus (CMV) centrifugation culture |
| b. Cytology for viral inclusions and Pneumocystis carinii |
| c. Immunofluorescence monoclonal antibody staining for |
| — CMV |
| — Respiratory syncytial virus |
| — Influenza virus |
| — Parainfluenza virus |
| — Adenovirus |
Alveolar Hemorrhage
Alveolar flooding due to interstitial or endobronchial bleeding is probably a common occurrence among patients who have concomitant thrombocytopenia. Review of patients at risk revealed that 60% of leukemia patients had pulmonary hemorrhage evident at autopsy, that more than 30% of infiltrates represented hemorrhage, and that this was uncommon unless the platelet count was less than 20,000/mL.8
Pulmonary hemorrhage presents radiographically as either focal or diffuse alveolar opacification. Clinically patients tend to appear less compromised physiologically than would be predicted from the extent of the radiographic infiltration. The symptoms and signs that the patients demonstrate most often relate to the process that is responsible for the hemorrhage. Normal alveolar lining and endobronchial mucosa do not spontaneously bleed without provocation. Such bleeding should be assumed to be secondary to an inflammatory process until proven otherwise. Hemoptysis is present in no more than half of the cases.
Confirmation of pulmonary hemorrhage can be elusive without a lung biopsy. Bronchoalveolar lavage demonstration of grossly bloody alveolar fluid and hemosiderin-laden macrophages without evidence of airway bleeding may support the clinical suspicion but is not diagnostic. There is poor correlation between the bronchoscopic detection of alveolar hemorrhage and histologic confirmation at autopsy.9 The presence of alveolar hemorrhage is not predictive of etiology of lung injury or clinical outcome.10 Diagnostic procedures should be undertaken primarily to evaluate for potential infectious etiologies.
Rarely, hemorrhage may be of sufficient severity to result in asphyxiation. These cases are often found to represent acute respiratory distress syndrome (ARDS) or hemorrhagic infections, such as invasive Aspergillus infection. Therapy should be directed at correcting thrombocytopenia, clotting deficits, and azotemia. The prognosis is most related to the process causing the bleeding than to the bleeding itself.
Lung Transplantation
Overall, survival after lung (or heart-lung) transplantation approaches 50% at three years.11 Infection accounts for 29% of deaths in the first three months, whereas rejection is the single most frequent cause later (29%). Several noninfectious pulmonary complications occur after lung transplantation. These include conditions that diffusely involve the lungs, such as acute and chronic rejection, and early graft dysfunction (also called "reperfusion edema" or "reimplantation response"), and localized disorders, such as airway dehiscence or stricture.
Early Graft Dysfunction
Graft dysfunction of some degree is common in the first days after implantation. Depending on definitions, clinically relevant infiltrates and hypoxemia develops in 15-35%. Physiologically, pulmonary edema is present, presumably due to ischemia-reperfusion responses in the preserved donor lung. Histologically, either diffuse alveolar damage or organizing pneumonia is seen.12 Acute lung rejection is uncommon within five days of transplantation and CMV pneumonia is rare within two weeks. Therefore, the diagnosis of graft dysfunction can be established in many cases on clinical presentation. Treatment is supportive, as for ARDS. The hospital case-fatality rate is 16%.13
Acute Rejection
Acute rejection is mediated primarily by helper T lymphocytes that recognize donor major histocompatibility complexes and secrete cytokines that cause proliferation of cytotoxic T lymphocytes.14 Most recipients experience at least one episode regardless of immunosuppressive regimen, usually within the first year. Clinical presentation is nonspecific. Cough, low-grade fever, dyspnea, and crackles are common. Most patients demonstrate abnormal radiographs with perihilar haziness, septal lines, and/or pleural effusions. Since the clinical presentation mimics infection, bronchoscopy is frequently indicated. Transbronchial biopsy has a high diagnostic yield and may be used to stage the extent of acute rejection.15 Standard treatment is high-dose corticosteroids.
Bronchiolitis (Chronic Rejection)
Chronic lung transplant rejection is a clinicopathologic syndrome of graft dysfunction characterized by airflow obstruction and bronchiolitis.16 Because it is difficult to establish with certainty the cause of new-onset airflow limitation after lung transplantation, the term "bronchiolitis obliterans syndrome" (BOS) is used. The incidence of BOS increases with the number of episodes of acute rejection. Onset is usually insidious with cough and dyspnea. Spirometry should be performed routinely to detect subtle decreases in airflow. Severity of BOS is defined by declines in the FEV1 from baseline. The diagnosis is difficult to confirm with transbronchial biopsy and is usually based on spirometric and clinical information.17 Despite intensive immunosuppressive regimens, the clinical course is usually inexorable decline.18 Mean survival at three years after diagnosis is 50%.
Obstructive Airway Disease After Marrow Transplantation
New onset of obstructive airway disease after marrow transplantation is similar in many clinical respects to the bronchiolitis obliterans syndrome after lung transplantation. The most important distinction is that it is predominantly associated with clinical evidence of chronic GVHD after allogeneic marrow transplantation. The estimated incidence of airflow obstruction is 10-11% of long-term survivors of bone marrow transplantation with chronic GVHD.19,20 The incidence after autolo-gous marrow transplantation appears to be much lower, but not zero.21
Patients tend to present with cough, wheeze, or dyspnea within 1.5 to 10 months after marrow transplantation. Lung function tests reveal airflow obstruction, as demonstrated by diminished FEV1/FVC. Chest radiographs only occasionally reveal infiltrates. The case-fatality rate is more than 50% despite aggressive treatments with corticosteroids, bronchodilators, and, in many cases, azathio-prine. Less than 10% demonstrate slowly improved lung function, usually over six to 24 months.22
Airflow obstruction in allogeneic recipients with GVHD may be a heterogeneous group of disorders arising from distinctly different causes. Bronchiolitis is the predominant, but not invariable, pathological finding. Evidence of parenchymal lung injury also may be present.
Pulmonary infection has been identified in half of the cases examined histopathologically. Infectious agents included bacteria, fungus, Pneumocystis carinii, and viruses. Although some of these infections may have been causally related to the bronchiolitis, more likely they were the consequence of the immune deficiency associated with chronic GVHD and represent coincident or terminal events.
There are no direct data to support that obstructive airway disease after marrow transplantation is a pulmonary GVHD reaction. Although it is an attractive theory for the pathogenesis of bronchiolitis, evidence of bronchiolar epithelial-directed cytotoxic response by donor lymphocytes has not been established. Alternatively, inflammatory cytokines could play a role in the bronchiolar injury; however, data to support this concept are currently lacking. Other explanations for small airway inflammation after marrow transplantation include recurrent aspiration of oral material due to esophagitis associated with GVHD, or unrecognized viral infection. The varied histopathologies, BAL cell differentials and apparent clinical courses, the frequency of associated pulmonary infection, and the occurrence after autologous marrow transplantation together suggest that new onset obstructive airways disease after marrow transplantation is not a single entity but rather a response to multiple inciting events.23
Conclusions
Noninfectious pulmonary complications of transplantation are most often related to complications of the underlying disorder, immunologically mediated or acute lung injury secondary to systemic infection. Diagnostic testing rarely leads to specific treatment. The rationale behind evaluation of suspected noninfectious lung disease is exclusion of infection.
References
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18. Valentine VG, et al. Actuarial survival of heart-lung and bilateral sequential lung transplant recipients with obliterative bronchiolitis. J Heart Lung Transplant 1996;15:371-383.
19. Chan CK, et al. Small-airways disease in recipients of allogeneic bone marrow transplants. An analysis of 11 cases and a review of the literature. Medicine 1987;66: 327-340.
20. Clark JG, et al. Risk factors for airflow obstruction in recipients of bone marrow transplants. Ann Intern Med 1987;107:648-656.
21. Paz HL, et al. Bronchiolitis obliterans after autologous bone marrow transplantation. Chest 1992;101:775-778.
22. St. John RC, et al. Analysis of airflow obstruction by bronchoalveolar lavage following bone marrow transplantation: Implications for pathogenesis and treatment. Chest 1990;98:600-607.
23. Crawford SW, Clark JG. Bronchiolitis associated with bone marrow transplantation. In: King TE, ed. Clinics in Chest Medicine 1993:741-749.
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