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The use of the flow-volume loop to screen for lung rejection.

Lung rejection in lung or heart-lung transplant patients takes the form of obliterative bronchiolitis and, in fact, obliterative bronchiolitis is the major complication in survivors of heart-lung transplantation. The lung, whether transplanted or not, is constantly exposed to the outside environment which includes particulates, viruses, and bacteria. In comparison to the heart the lung is structurally more fragile and susceptible to auto-immune attacks.

The use of the flow-volume loop in the pulmonary function laboratory or in the clinic serves as an effective and accurate screen for the detection of lung rejection. Although the FEV1 is the traditionally accepted parameter, we at Stanford University Hospital have done a study, which has been repeated, showing that the FEF25-75 is actually much more effective in the early detection of bronchiolitis obliterans.


Obliterative bronchiolitis, also known as bronchiolitis obliterans or OB, is a direct manifestation of chronic or acute allograft rejection. It can be caused by other factors such as exposure to toxic fumes or mineral dust. It can also be the result of infection by mycoplasma pneumonia, legionella or certain viral respiratory infections. Rheumatologic conditions have been implicated in OB such as rheumatoid arthritis, system lupus erythematosus and polymyositis. It is often an associated condition with hypersensitivity pneumonia and as the result of medications such as penicillamine.

OB is very rare, but unfortunately it is a now familiar result of lung rejection in the transplantation of lungs from one human to another. It eventually develops in nearly half of all patients who receive a lung transplant from an unrelated donor.

The rejection process involves an inflammatory response resulting in a large number of lymphocytes (a specific kind of white blood cell for fighting infection) migrating to the graft tissue (transplanted tissue), resulting in significant fibrosis (increase in fibrous tissue) and progressive permanent closing off or narrowing of the airway. The airway is narrowed until complete closure is affected. This occurs in the medium to smaller airways.

Because this auto-immune process results in airway narrowing and closure it is detected as increasing degrees of airway obstruction which can be observed through a flow volume loop as a decrease in expiratory flow or as coving in the expiratory limb of the flow volume loop. This process of rejection is a major cause of death in patients after receiving lung transplantation.

OB is one of the major obstacles for prolonged survival following lung transplantation. Survival after the transplant of the lung is significantly poorer when compared to the transplantation of any other organ. Both the lung's delicate structure and its exposure to the outside environment introduce various factors which can damage the lung when under any auto-immune stress.

OB within the first year after transplantation is not common, but its incidence increases. When present, many patients live the remaining years of their lives with chronic rejection if the process is finally arrested. It occurs to a total of 50 percent to 80 percent of patients in a period of five years following lung transplantation. Lung transplant patients encountering acute allograft rejection (rejection caused by a foreign organ immediately after transplantation), especially patients with severe or multiple episodes, are at a greatly increased risk of developing OB.

Besides lung rejection, there are risk factors, which include mismatching of HLA (the major histocompatibility complex in humans), and pneumonias caused by cytomegalovirus. Injury from repeated respiratory infection of the airways can trigger OB.

As a matter of interest, besides allograft rejection there are other factors that can cause OB. About three years ago, studies were done showing that exposure to a chemical called diacetyl, a component of artificial butter flavoring, can be harmful to the nose and airways of mice. Scientists at the National Institute of Environmental Health Sciences, part of the National Institutes of Health, conducted the study because diacetyl had been implicated in causing OB in humans.

OB has been detected recently in workers who inhale significant or daily concentrations of the flavoring in plants manufacturing microwave popcorn. The lung condition caused by diacetyl has been labeled "popcorn lung." There has to be significant exposure over an extended time period for the specific disease process to develop. Lung function is not threatened by casual exposure as a consumer might encounter. When laboratory mice inhaled diacetyl vapors for three months, they developed lymphocytic bronchiolitis, a potential precursor of OB but none of the mice were diagnosed with full OB.

The OB diagnosis is established through bronchoscopy, which includes bronchoalveolar lavage (lung washings) and culture. The flow-volume loop, which is performed either in the pulmonary function laboratory or in clinic, offers a quick and easy screen for the very beginning of lung rejection expressed as OB. The flow-volume loop should be performed using a device which meets all American Thoracic Society/European Respiratory Society standards for sensitivity and accuracy.

The flow-volume loop test includes measuring the FEV1, which is the volume of air that can be forced out in one second after taking a deep breath. The FEF[logical not]25-75 is the forced expiratory flow rate between 25 and 75 percent of the forced vital capacity. This test is not officially recognized as a marker for the onset or progression of OB since the test is considered to be too dependent upon technologist experience and skill and the patient's maximum effort. I feel that the FEF25-75, when administered by an experienced and credentialed pulmonary function technologist, is a very precise intra-laboratory measurement.

Of course, the precision of the test also depends on the use of a testing device adhering to ATS/ERS standards. Compared to the FEV1, the FEF 25-75 has the advantage of being more reflective of smaller airway patency. As the airways become occluded or completely obstructed through the organizing scar tissue, the flow rates decrease proportionally showing coving in the expiratory limb of the flow volume loop. Internet-based home monitoring of pulmonary function tests to show progression of airway obstruction at home after lung transplantation is a program that has been adopted by some lung transplant centers.

The progression or the time frame from lung transplantation to the start of symptoms of OB is variable, ranging from three months to more than nine years after transplantation. Once OB develops, the lung function typically declines progressively unless aggressive treatment is initiated within days of the start of the disease process, which is why testing with the flow volume loop is very important as an easy and quick diagnostic tool.

Generally, progressive obstruction to airflow results in decreased lung function with exercise limitation, repetitive lung infections and, eventually, death. The course of OB, however, varies greatly between individuals. Some patients experience rapid loss of lung function and die within a few months. Others progress slowly, followed by prolonged stability, which may last 10 years or longer.

OB has been graded into five categories based on FEV1. The five categories for OB are BOS 0, BOS 0-p, BOS 1, BOS 2 and BOS 3 with declining lung function indicated as the grade goes higher. The BOS stages have been defined as a 10- to 15-percent decrease in FEV1 from a previous baseline. Additionally, evidence suggests that the forced expiratory flow (FEF25-75) decreases before the FEV1 in most bilateral and heart-lung transplant recipients with OB. Therefore a reduction of FEF25-75 by [greater than or equal to] 25 percent may also be an indicator of early OB. However, after having performed and monitored flow-volume loops for lung transplant patients for 25 years, I have observed that even a 5 percent change in FEF25-75 can indicate beginning OB with associated lung transplant rejection.

Probable outcomes for lung transplantation are significantly behind those for heart transplants. The death rate at three years after the start of OB is more than 50 percent. The survival rate at five years after the start of the disease is only 30 to 50 percent. Patients who develop OB within the first three years after transplantation have a poorer outcome. A majority of these patients have a greater decline in lung function, greater need for oxygen and a higher rate of transplant failure requiring re-transplantation if qualified.

OB is sometimes treated with bronchodilators to relieve symptoms of airway obstruction, but pure OB does not respond to bronchodilators because the airway obstruction is due to organizing scar tissue, and there is no smooth muscle involvement. Oxygen supplementation is necessary with advanced levels of OB.

In order to treat or prevent episodes of mild or acute rejection, the following treatment options may be considered: increased immunosuppression such as methylprednisolone (to suppress the inflammatory response), drugs like tacrolimus, mycophenolate mofetil (MMF), and cytolytic and clarithromycin therapy. A second transplantation of the lung may be considered in some cases, if there are no complicating factors such as tumor or general organ failure.

A recent study demonstrated in experimental mice that inhalation of safe and controlled doses of carbon monoxide for several weeks after transplant surgery prevented the development of OB. This might be a useful treatment option in the future, but further research is still needed. Because carbon monoxide is a poisonous gas, care must be taken in terms of dosage in any future therapy to prevent toxicity.

The flow-volume loop measuring both FEV1 and FEF25-75 has been shown to be a reliable and simple test to document the very beginning of lung rejection in lung transplant patients. The FEF25-75 has been found to be more specific to small airway measurement than the FEV1, and when used by competent technologists in well-run laboratories or clinics, it should be relied on to signal the beginning of OB as a complication of lung rejection.

Jim Harvey MS, RPFT, RCP works in the Pulmonary Function Laboratory at Stanford Hospital and Clinics in Palo Alto, and teaches Pulmonary Function at Skyline College in San Bruno, California.

by Jim Harvey MS, RPFT, RCP
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Author:Harvey, Jim
Publication:FOCUS: Journal for Respiratory Care & Sleep Medicine
Date:May 1, 2010
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