Diffuse Lung Disease
David Turner, M.D.
I.Clinical Evaluation of the Chest RadiographA.Radiographic patterns1.Interstitial - reticulonodulara.Known cause - inorganic dust (pneumoconiosis), organic dust(hypersensitivity pneumonitis), iatrogenic (drugs, radiationtherapy)b.Unknown cause - sarcoidosis, idiopathic pulmonary fibrosis,pulmonary fibrosis with connective tissue disease2.Alveolar - fluffy, often with air bronchogramsa.Acute - cardiogenic pulmonary edema, non-cardiogenicpulmonary edema (ARDS), diffuse alveolar pneumonia, alveolarhemorrhageb.Subacute or chronic - sarcoidosis, bronchioloalveolar cellcarcinoma, lymphoma, pulmonary alveolar proteinosis,desquamative interstitial pneumonitis3.Nodular - often suggests hematogenous origina.Disseminated malignancy, tuberculosis, fungal disease,pneumoconiosis, sarcoidosis, eosinophilic granulomaB.Distribution of disease1.Lower lobe - idiopathic pulmonary fibrosis, pulmonary fibrosisassociated with connective tissue disease, asbestosis2.Upper lobe - silicosis, sarcoidosis, eosinophilic granuloma3.Non-anatomic margins - radiation-induced pulmonary disease4.Peripheral distribution - chronic eosinophilic pneumonia;occasionally bronchiolitis obliterans with organizing pneumoniaC.With hilar adenopathy - sarcoidosis, silicosis, berylliosis, malignancyD.With pleural disease - asbestosis, RA, lupus, occasionally sarcoidosis. InAIDS, suggestive of KS.
It is important to recognize that when we are faced with a patient with diffuse lungdisease there are several radiographic patterns. It is often useful to separate out 3 typesof radiographic patterns. First of all an interstitial pattern, often called reticulonodular.Secondly there is an alveolar pattern, and thirdly there is a nodular pattern.The interstitial pattern or reticulonodular pattern is characterized by a lot of lines, dots,and streaks. There are about 150 different disorders that can produce this type of pattern. That makes it very difficult to create a realistic sort of differential diagnosis. Ithink when approached with this type of radiograph the best thing is to try to break down the long differential diagnosis. I find it is easiest to break it down into 3categories. First of all, diseases of known cause, second of all, diseases of unknowncause, and third, mimicking causes, or causes that look like interstitial lung disease butin fact really fall out of the diagnostic category of what we usually consider in this broadgroup of disease. Under each of these 3 categories there are 3 separate sub-categories.For example, disease of known cause is inorganic dust, organic dust, and iatrogenic.Within the iatrogenic ones would be things such as drugs and radiation therapy. Thedrugs include cancer chemotherapeutic agents. Disease of unknown cause is sarcoidosis,idiopathic pulmonary fibrosis, and pulmonary fibrosis associated with connective tissuedisease. The mimicking causes are congestive heart failure, malignancy, and infections,and of the infections, particularly viral pneumonia and Pneumocystis carinii pneumonia.When faced with a patient that has this type of interstitial pattern, it is actuallyworthwhile to go first to the 3
rd
cause, the mimicking causes and make sure that yournot dealing with someone who might have heart failure, tumor, or infection.The second category is an alveolar pattern, and, unlike the interstitial pattern, this is apattern that is more fluffy, cloudlike, or cottony and represents filling of alveolar spaceswith fluid or an inflammatory infiltrate often. With the alveolar lung diseases I think itis actually best to separate out 2 types of presentation either an acute presentation or asubacute or chronic presentation. With an acute presentation the easiest way tocategorize of characterize alveolar lung disease is by thinking about the types of thethings that can fill alveolar spaces. For example, we can have a relatively low protein ortransudative type of fluid as we might see in a patient with cardiogenic pulmonaryedema. We can see more of a relatively high protein fluid due to abnormal permeabilityof the alveolar epithelium as we might see in the acute respiratory distress syndrome.Inflammatory fluid can occur in diffuse alveolar pneumonia, and we can have bloodwith diffuse alveolar hemorrhage. The subacute or chronic disorders that can fillalveolar spaces. Those include sarcoidosis, bronchioloalveolar cell carcinoma,lymphoma, alveolar proteinosis, and DIP or desquamative interstitial pneumonitis.The 3
rd
radiographic pattern is a pattern of nodular lung disease and these discretenodules. This is actually from a patient with disseminated cancer. I should mention thatthe interstitial pattern was from scleredema interstitial lung disease. The diffuse alveolarpattern was from acute respiratory distress syndrome. This one though is from a patientwho has disseminated carcinoma. For nodular lung disease, often what we are thinkingabout are disorders that spread to the lung by hematogenous spread. For example,disseminated malignancy or some of the granulomatous diseases when there has beenspread of the organism to the lung that has resulted from hematogenous spread.Disseminated malignancy, tuberculosis, and fungal disease are examples of this.However, there are some disorders that actually can produce a nodular pattern becauseof airway access to the lung such as the pneumoconiosis, the inhaled dust disorders.Then there are a couple of idiopathic disorders, like sarcoidosis and eosinophilicgranuloma, that can produce nodular lung disease. One point to keep in mind is thatsarcoidosis falls into all 3 categories, so sarcoid can produce an interstitial pattern, analveolar pattern, and a nodular pattern.The distribution of disease, and by this I mean radiographic distribution of diseasewhere it is in the lungs, can actually be very helpful as one try’s to put together thedifferential diagnosis. For example, lower lobe disease is relatively common inidiopathic pulmonary fibrosis, pulmonary fibrosis associated with connective tissuedisease, or asbestosis related. In contrast, upper lobe disease is seen with silicosis,sarcoidosis, and eosinophilic granuloma. If we see margins that are non-anatomic andby that I mean relatively sharp margins that do not follow the distribution of lobar
II.Diagnosis and Treatment of Diffuse Lung DiseaseA.Idiopathic pulmonary fibrosis (IPF)1.Original description of Hamman-Rich syndrome was an acuteinterstitial pneumonia with rapid progression and death withinmonths; this is different from chronic idiopathic pulmonary fibrosis2.Desquamative interstitial pneumonia (DIP) - not clear if a subtype of IPF, a cellular variant of IPF, or a different disease. Desquamatedcells are primarily alveolar macrophagesa.Respiratory bronchiolitis in smokers may be associated withinterstitial lung disease resembling DIP; ? part of a spectrum,since large majority of patients with DIP are also smokers3.Therapya.Standard therapy is still prednisoneb.Increasing interest in cyclophosphamide or azathioprineused instead of, or in conjunction with steroids, but relativerole of steroids and other immunosuppressives is not yetclearB.Sarcoidosis1.Despite common finding of depressed cell-mediated immunity withcutaneous anergy, cell-mediated immune processes are enhancedlocally in the lunga.Bronchoalveolar lavage - increased lymphocytes withincreased CD4/CD
8
ratio2.Pattern of parenchymal infiltrates on chest X-ray can bereticulonodular, nodular, or alveolar3.Endobronchial involvement can cause chronic cough and/or airflowobstruction4.Angiotensin converting enzyme levels - generally not useful fordiagnosis or for following disease activity5.Standard treatment is still corticosteroids; results with cyclosporinehave been disappointing. ? role for methotrexate.C.Hypersensitivity pneumonitis1.Examples - farmer's lung; air conditioner or humidifier lung2.Pathology shows mononuclear cell infiltrate with poorly formedgranulomas3.Distinction between acute hypersensitivity pneumonitis (fever,cough, dyspnea, pulmonary infiltrates hours after exposure) andchronic hypersensitivity pneumonitis (mimics other forms of chronic interstitial lung disease)
boundaries or fissures then we will often think about something like radiationpneumonitis or radiation fibrosis, which often tends to follow the ports of the radiationtherapy. Finally a peripheral pattern and I will show you an example of this later wherethe infiltrates are primarily along the periphery of the lung is seen in chroniceosinophilic pneumonia and sometimes in bronchiolitis obliterans with organizingpneumonia.Associated features on the radiograph may be helpful if there is hilar adenopathy wetend o think of sarcoid, silicosis, berylliosis, and malignancy. Silicosis and berylliosisare the 2 inhaled disorders for pneumoconiosis that can be associated hilar adenopathy.If we see associated pleural disease then obviously asbestosis, a couple of the connectivetissue diseases particularly rheumatoid arthritis and lupus and occasionally with sarcoid,although less than 10% of patients with sarcoid will have involvement of the pleural. Ina patient who has AIDS and has pleural disease then we often think about coexistingKaposi sarcoma or Kaposi sarcoma really is the cause of the pleural disease particularlypleural effusion.A few points about the pulmonary function features in a patient who has diffuseparenchyma lung disease we generally will see a restrictive pattern of lung volumescharacterized by a relatively symmetric decrease in lung volumes, total lung capacity,functional residual capacity, vital capacity, and residual volume. If we had to chooseone of them that is most important I would have to say it is the total lung capacity andthe low total lung capacity is really what defines the presence of a restrictive physiologicpattern. We generally do not see airflow obstruction and that means that the FEV1/ forced vital capacity ratio is normal or actually may even be increased. However, if welook at the FEV1 in isolation or if we look at the forced vital capacity in isolation theymay be down, but they are down in proportion to the other lung volumes. The key thingis they may be decreased but the ratio between them the FEV1/forced vital capacityratio is normal. If we do see coexisting airflow obstruction based on a low FEV1 toforced vital capacity ration then that may clue us in to a few disorders such ashistiocytosis X, which is the same as eosinophilic granuloma,lymphangioleiomyomatosis a rare disorder that I will mention later, sarcoid, and cysticfibrosis. All of those can have coexisting airflow obstruction. Typically the diffuse andcapacity is decreased in the diffuse parenchyma lung diseases. However, the diffuse andcapacity if it is increased we should think about alveolar hemorrhage because of redcells in the alveolar spaces taking up carbon monoxide, or because of coexisting highleft atrial pressures because of increased blood volume within the lungs capable of taking up carbon monoxide. That would be the case obviously with heart failure ormitral valve disease.Next I would like to go through a number of the specific disorders. I’ll try to focus on afew of the interesting clinical features and treatment aspects of some of the diffuseparenchyma lung diseases. I’ll start by talking about idiopathic pulmonary fibrosis orIPF. If I gave this talk in England I would be talking about cryptogenic fibrosingalveolitis. That is synonymous with idiopathic pulmonary fibrosis. Many people haveheard and think about the term Hamman-Rich syndrome, which was the term that wascoined in the 1940’s down at Hopkins for a disorder that was subsequently thoughtperhaps to be idiopathic pulmonary fibrosis. If one goes back and looks at the originalcases of Hamman-Rich syndrome it turns out that these cases were actually quite a bitdifferent from what we think of as idiopathic pulmonary fibrosis now. The Hamman-Rich cases were much more rapidly progressive and often lead to death within 6 months.In contrast idiopathic pulmonary fibrosis is really a slowly progressive disease and onethat progresses with fibrosis that occurs over the course of years rather than months.Although it can and certainly often does lead to respiratory failure and death as I saidthe issue is that it progresses over years rather than months. The term DIP ordesquamative interstitial pneumonitis is in some ways similar to idiopathic pulmonaryfibrosis, but in some ways different. The pathology is slightly different in the sense thatthere are cells within the alveolar spaces that actually represent macrophages. They arenot desquamative alveolar cells, but rather are intra-alveolar inflammatory cells. Thequestion that has come up is whether DIP represents a sub-type of idiopathic pulmonaryfibrosis with a fair amount of inflammation, or whether it represents a different diseaseand that is really not clear. It has been however, suggested that maybe there is actuallymore of an association with some small airways disease. Many of the patients who havedesquamated interstitial pneumonitis actually are smokers and they also often will havean inflammatory process in the small airways and one of the questions that comes up isthis more of a smoking related disease as opposed to a non-smoking related disease suchas idiopathic pulmonary fibrosis. The treatment of IPF has really not improved muchover the past decade or even a couple of decades. We tend to just try to suppress theinflammatory response with prednisone generally. There are many people who favorusing an immunosuppressive agent other than prednisone like cyclophosphamide hasbeen used. There has not been really good head to head studies comparing those and I
4.Bronchoalveolar lavage (BAL) fluid shows lymphocytosis withlowCD4/CD8 ratioD.Eosinophilic granuloma (histiocytosis X)1.Atypical histiocytes (Langerhans' cells) in infiltrate; variety of celltypes in infiltrate with scattered eosinophils2.May have airflow obstruction; may have surprisingly normal lungvolumes for degree of interstitial disease seen on radiograph3.Chest X-ray and CT scan may show numerous small cysts andnodules; eventual progression to fibrosis and honeycombing4.Presence of cysts explains possible clinical presentation withspontaneous pneumothorax5.Very high association with smoking6.Quite variable natural history ranging from spontaneous resolutionto marked progression with honeycombing and endstage lung7.No clear response to any form of therapy, thoughsteroids/immunosuppressives often usedE.Lymphangioleiomyomatosis1.Exclusively in women, almost all of childbearing age2.Atypical smooth muscle proliferation around lymphatics,bronchioles, small pulmonary vessels3.Clinical presentation with any of the following: pleural effusion(chylothorax), interstitial lung disease (with cysts, similar toeosinophilic granuloma), spontaneous pneumothorax, hemoptysis4.Like eosinophilic granuloma, may have airflow obstruction, normallung volumes despite interstitial pattern on chest radiograph5.Treatment - alteration of hormonal milieu, e.g., progesterone,oophorectomyF.Chronic eosinophilic pneumonia1.Often in patients with underlying asthma2.Term refers to eosinophils in the pulmonary, infiltrate, which isinterstitial and intra-alveolara.Peripheral blood eosinophilia common but not present in allpatients3.Often subacute presentation with dyspnea, cough, fever, otherconstitutional symptoms4.Typical peripheral distribution of infiltrates - photographic negativeof pulmonary, edema5.Often dramatic response to steroids - can be used for diagnostic trial
would say that if you’d look across the country as far as what pulmonologist do I wouldsay maybe 60% will start with prednisone and about 40% will start with an agent suchas cyclophosphamide. There really is no good data for head to head comparison.Sarcoidosis is my favorite of the interstitial lung diseases. It also I think it is fair to saythe most common of the interstitial lung diseases. We still to this day do not what causessarcoidosis. The presumption is that sarcoid reflects a response to some agent, animmunologic response to some agent, whether or not it is an exogenous agent or perhapseven an indigenous agent isn’t really clear. It is also though that it may occur in anygenetically susceptible host, although that has also not been well worked out. At themoment the National Institutes of Health has a multi-center study to try to sort out theideology of the sarcoid. We have medical center and one of the 10 centers and the hopeis by applying newer molecular biologic techniques we’ll be able to try to figure outwhat the ideology of sarcoid is. However, we can state a few points about sarcoid interms of describing what happens. One of the interesting immunologic features is thatthere seems to be a hyperactive T cell mediated immunologic response in the lungs thatseems to result in the formation of granulomas. If we look in the lungs to do abronchoalveolar lavage for example, we can find an increased number of lymphocytes inthe lungs and also a high helper to suppressor cell ratio, high CD
4
to CD
8
ratio. Incontrast, if we look in the peripheral blood for example, we find a depression of T cellmediated responses as we think about things such as impaired delayed hypersensitivitypatients are often anergic on skin testing. However, unlike patients with HIV infectionthis cutaneous anergy and sarcoid is not associated with an increased risk of opportunistic infections. As I mentioned earlier radiographic patterns can be anything.It can be reticulonodular, nodular, or alveolar. We often will see endobronchialinvolvement. If we look with a bronchoscope we will see that there are often little bumpssometimes called cobble stoning in the airway surface that is often responsible for asignificant problem with cough. In general angiotensin converting enzyme levels, whichhad been proposed in the past to be useful in the diagnosis of follow-up of patients withthe disease. I would have to say, in general, most people felt that they are not useful.There are a number of diseases that have been associated to high elevated levelsincluding other granulomas diseases and the correlation is not necessarily all that greatwith activity of the disease. Corticosteroids remain the mainstay of therapy, but wereally do not have any good evidence that corticosteroids alter the overall natural historyof the disease even though they will acutely suppress many of the manifestations of thedisease. One might think because of the presumed pathogenic role of T cellsparticularly T helper cells in this disease that cyclosporine might be useful, but actuallywhen it has been looked at the results have been quite disappointing so far. The otheragent that there is a lot of interest in is methotrexate used primarily as a steroid sparingagent in this disease, but also potentially as a steroid alternative. There are some trialsthat are going on right now, but I don’t think that we really have any definitiveinformation about the role of methotrexate versus steroids for sarcoid.Another disorder in the lung that will often have some granulomas on pathology,although they are not as well formed as the granulomas of sarcoid. This ishypersensitivity pneumonitis. Examples are being farmer’s lung, air conditioner orhumidifier lung. For all of these basically the underlying pathogenesis is animmunologic response to an inhaled organic antigen. In the case of farmer’s lung andall of these what we are dealing with is a response to thermophilic Actinomyces, a moldthat can grow either in hay or can grow in a forced air system. The other common typeof organic antigen would be an antigen from animals such as antigens form birds ascould be seen in bird breeders. The pathology is poorly formed granulomas. The diseasecan present either in an acute form or in a more chronic form. The acute form oftenpresents as fever, constitutional symptoms, shortness of breath, and pulmonary infiltratesoccurring 4 to 6 hours after exposure. The chronic form presents more as a diffuseinterstitial lung disease often in those patients where the underlying exposure is notbeing recognized and they have repeated exposure. Interestingly enough if you look inthe lungs by doing a bronchoalveolar lavage and recover cells you’ll find that there is aincreased number of lymphocytes very similar to what we see in sarcoid, but they aredifferent lymphocytes. In sarcoid we have a high CD
4
to CD
8
ration where as inhypersensitivity pneumonitis the converse is true where the CD
4
to CD
8
ratio is actuallylow.A few less common disorders and one is eosinophilic granuloma, which is also calledhistiocytosis X. It turns out that the name of this is somewhat of a misnomer in the sensethat they really are not a huge number of eosinophils and we do not see well formedgranulomas in this disease. Rather what we see is an accumulation of a type of histiocytic cell called the Langerhans’ cell, which is normally found in the dermis, butthere are also Langerhans’ cells that appear to be important in the antigen processing inthe lungs. These cells accumulate and they seem to proliferate in the lungs. It is not aneoplastic disorder of these cells. What we see often is that airflow obstruction is
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Diffuse Lung Disease
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