Diffuse Lung Disease

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					Diffuse Lung Disease
David Turner, M.D.

I. Clinical Evaluation of the Chest Radiograph                                     It is important to recognize that when we are faced with a patient with diffuse lung
                                                                                   disease there are several radiographic patterns. It is often useful to separate out 3 types
                                                                                   of radiographic patterns. First of all an interstitial pattern, often called reticulonodular.
   A. Radiographic patterns                                                        Secondly there is an alveolar pattern, and thirdly there is a nodular pattern.

       1. Interstitial - reticulonodular                                           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
          a. Known cause - inorganic dust (pneumoconiosis), organic dust           pattern. That makes it very difficult to create a realistic sort of differential diagnosis. I
                                                                                   think when approached with this type of radiograph the best thing is to try to break
             (hypersensitivity pneumonitis), iatrogenic (drugs, radiation
                                                                                   down the long differential diagnosis. I find it is easiest to break it down into 3
             therapy)                                                              categories. First of all, diseases of known cause, second of all, diseases of unknown
                                                                                   cause, and third, mimicking causes, or causes that look like interstitial lung disease but
          b. Unknown cause - sarcoidosis, idiopathic pulmonary fibrosis,           in fact really fall out of the diagnostic category of what we usually consider in this broad
             pulmonary fibrosis with connective tissue disease                     group 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. The
       2. Alveolar - fluffy, often with air bronchograms                           drugs include cancer chemotherapeutic agents. Disease of unknown cause is sarcoidosis,
                                                                                   idiopathic pulmonary fibrosis, and pulmonary fibrosis associated with connective tissue
          a. Acute - cardiogenic pulmonary edema, non-cardiogenic                  disease. The mimicking causes are congestive heart failure, malignancy, and infections,
             pulmonary edema (ARDS), diffuse alveolar pneumonia, alveolar          and of the infections, particularly viral pneumonia and Pneumocystis carinii pneumonia.
             hemorrhage                                                            When faced with a patient that has this type of interstitial pattern, it is actually
                                                                                   worthwhile to go first to the 3rd cause, the mimicking causes and make sure that your
                                                                                   not dealing with someone who might have heart failure, tumor, or infection.
          b. Subacute or chronic - sarcoidosis, bronchioloalveolar cell
             carcinoma, lymphoma, pulmonary alveolar proteinosis,                  The second category is an alveolar pattern, and, unlike the interstitial pattern, this is a
             desquamative interstitial pneumonitis                                 pattern that is more fluffy, cloudlike, or cottony and represents filling of alveolar spaces
                                                                                   with fluid or an inflammatory infiltrate often. With the alveolar lung diseases I think it
       3. Nodular - often suggests hematogenous origin                             is actually best to separate out 2 types of presentation either an acute presentation or a
                                                                                   subacute or chronic presentation. With an acute presentation the easiest way to
                                                                                   categorize of characterize alveolar lung disease is by thinking about the types of the
          a. Disseminated malignancy, tuberculosis, fungal disease,                things that can fill alveolar spaces. For example, we can have a relatively low protein or
             pneumoconiosis, sarcoidosis, eosinophilic granuloma                   transudative type of fluid as we might see in a patient with cardiogenic pulmonary
                                                                                   edema. We can see more of a relatively high protein fluid due to abnormal permeability
   B. Distribution of disease                                                      of 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 blood
                                                                                   with diffuse alveolar hemorrhage. The subacute or chronic disorders that can fill
       1. Lower lobe - idiopathic pulmonary fibrosis, pulmonary fibrosis           alveolar spaces. Those include sarcoidosis, bronchioloalveolar cell carcinoma,
          associated with connective tissue disease, asbestosis                    lymphoma, alveolar proteinosis, and DIP or desquamative interstitial pneumonitis.

       2. Upper lobe - silicosis, sarcoidosis, eosinophilic granuloma              The 3rd radiographic pattern is a pattern of nodular lung disease and these discrete
                                                                                   nodules. This is actually from a patient with disseminated cancer. I should mention that
                                                                                   the interstitial pattern was from scleredema interstitial lung disease. The diffuse alveolar
       3. Non-anatomic margins - radiation-induced pulmonary disease               pattern was from acute respiratory distress syndrome. This one though is from a patient
                                                                                   who has disseminated carcinoma. For nodular lung disease, often what we are thinking
       4. Peripheral distribution - chronic eosinophilic pneumonia;                about are disorders that spread to the lung by hematogenous spread. For example,
          occasionally bronchiolitis obliterans with organizing pneumonia          disseminated malignancy or some of the granulomatous diseases when there has been
                                                                                   spread of the organism to the lung that has resulted from hematogenous spread.
                                                                                   Disseminated malignancy, tuberculosis, and fungal disease are examples of this.
   C. With hilar adenopathy - sarcoidosis, silicosis, berylliosis, malignancy      However, there are some disorders that actually can produce a nodular pattern because
                                                                                   of airway access to the lung such as the pneumoconiosis, the inhaled dust disorders.
   D. With pleural disease - asbestosis, RA, lupus, occasionally sarcoidosis. In   Then there are a couple of idiopathic disorders, like sarcoidosis and eosinophilic
      AIDS, suggestive of KS.                                                      granuloma, that can produce nodular lung disease. One point to keep in mind is that
                                                                                   sarcoidosis falls into all 3 categories, so sarcoid can produce an interstitial pattern, an
                                                                                   alveolar pattern, and a nodular pattern.

                                                                                   The distribution of disease, and by this I mean radiographic distribution of disease
                                                                                   where it is in the lungs, can actually be very helpful as one try’s to put together the
                                                                                   differential diagnosis. For example, lower lobe disease is relatively common in
                                                                                   idiopathic pulmonary fibrosis, pulmonary fibrosis associated with connective tissue
                                                                                   disease, or asbestosis related. In contrast, upper lobe disease is seen with silicosis,
                                                                                   sarcoidosis, and eosinophilic granuloma. If we see margins that are non-anatomic and
                                                                                   by that I mean relatively sharp margins that do not follow the distribution of lobar
                                                                                  boundaries or fissures then we will often think about something like radiation
                                                                                  pneumonitis or radiation fibrosis, which often tends to follow the ports of the radiation
                                                                                  therapy. Finally a peripheral pattern and I will show you an example of this later where
II. Diagnosis and Treatment of Diffuse Lung Disease                               the infiltrates are primarily along the periphery of the lung is seen in chronic
                                                                                  eosinophilic pneumonia and sometimes in bronchiolitis obliterans with organizing
   A. Idiopathic pulmonary fibrosis (IPF)                                         pneumonia.

      1. Original description of Hamman-Rich syndrome was an acute                Associated features on the radiograph may be helpful if there is hilar adenopathy we
                                                                                  tend o think of sarcoid, silicosis, berylliosis, and malignancy. Silicosis and berylliosis
         interstitial pneumonia with rapid progression and death within
                                                                                  are the 2 inhaled disorders for pneumoconiosis that can be associated hilar adenopathy.
         months; this is different from chronic idiopathic pulmonary fibrosis     If we see associated pleural disease then obviously asbestosis, a couple of the connective
                                                                                  tissue diseases particularly rheumatoid arthritis and lupus and occasionally with sarcoid,
      2. Desquamative interstitial pneumonia (DIP) - not clear if a subtype of    although less than 10% of patients with sarcoid will have involvement of the pleural. In
         IPF, a cellular variant of IPF, or a different disease. Desquamated      a patient who has AIDS and has pleural disease then we often think about coexisting
         cells are primarily alveolar macrophages                                 Kaposi sarcoma or Kaposi sarcoma really is the cause of the pleural disease particularly
                                                                                  pleural effusion.
          a. Respiratory bronchiolitis in smokers may be associated with          A few points about the pulmonary function features in a patient who has diffuse
             interstitial lung disease resembling DIP; ? part of a spectrum,      parenchyma lung disease we generally will see a restrictive pattern of lung volumes
             since large majority of patients with DIP are also smokers           characterized by a relatively symmetric decrease in lung volumes, total lung capacity,
                                                                                  functional residual capacity, vital capacity, and residual volume. If we had to choose
                                                                                  one of them that is most important I would have to say it is the total lung capacity and
   3. Therapy
                                                                                  the low total lung capacity is really what defines the presence of a restrictive physiologic
                                                                                  pattern. We generally do not see airflow obstruction and that means that the FEV1/
      a. Standard therapy is still prednisone                                     forced vital capacity ratio is normal or actually may even be increased. However, if we
                                                                                  look at the FEV1 in isolation or if we look at the forced vital capacity in isolation they
      b. Increasing interest in cyclophosphamide or azathioprine                  may be down, but they are down in proportion to the other lung volumes. The key thing
         used instead of, or in conjunction with steroids, but relative           is they may be decreased but the ratio between them the FEV1/forced vital capacity
                                                                                  ratio is normal. If we do see coexisting airflow obstruction based on a low FEV1 to
         role of steroids and other immunosuppressives is not yet                 forced vital capacity ration then that may clue us in to a few disorders such as
         clear                                                                    histiocytosis X, which is the same as eosinophilic granuloma,
                                                                                  lymphangioleiomyomatosis a rare disorder that I will mention later, sarcoid, and cystic
   B. Sarcoidosis                                                                 fibrosis. All of those can have coexisting airflow obstruction. Typically the diffuse and
                                                                                  capacity is decreased in the diffuse parenchyma lung diseases. However, the diffuse and
                                                                                  capacity if it is increased we should think about alveolar hemorrhage because of red
      1. Despite common finding of depressed cell-mediated immunity with
                                                                                  cells in the alveolar spaces taking up carbon monoxide, or because of coexisting high
      cutaneous anergy, cell-mediated immune processes are enhanced               left atrial pressures because of increased blood volume within the lungs capable of
      locally in the lung                                                         taking up carbon monoxide. That would be the case obviously with heart failure or
                                                                                  mitral valve disease.
          a. Bronchoalveolar lavage - increased lymphocytes with
          increased CD4/CD8 ratio                                                 Next I would like to go through a number of the specific disorders. I’ll try to focus on a
                                                                                  few of the interesting clinical features and treatment aspects of some of the diffuse
                                                                                  parenchyma lung diseases. I’ll start by talking about idiopathic pulmonary fibrosis or
      2. Pattern of parenchymal infiltrates on chest X-ray can be                 IPF. If I gave this talk in England I would be talking about cryptogenic fibrosing
         reticulonodular, nodular, or alveolar                                    alveolitis. That is synonymous with idiopathic pulmonary fibrosis. Many people have
                                                                                  heard and think about the term Hamman-Rich syndrome, which was the term that was
      3. Endobronchial involvement can cause chronic cough and/or airflow         coined in the 1940’s down at Hopkins for a disorder that was subsequently thought
                                                                                  perhaps to be idiopathic pulmonary fibrosis. If one goes back and looks at the original
         obstruction                                                              cases of Hamman-Rich syndrome it turns out that these cases were actually quite a bit
                                                                                  different from what we think of as idiopathic pulmonary fibrosis now. The Hamman-
      4. Angiotensin converting enzyme levels - generally not useful for          Rich cases were much more rapidly progressive and often lead to death within 6 months.
         diagnosis or for following disease activity                              In contrast idiopathic pulmonary fibrosis is really a slowly progressive disease and one
                                                                                  that 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 said
      5. Standard treatment is still corticosteroids; results with cyclosporine
                                                                                  the issue is that it progresses over years rather than months. The term DIP or
         have been disappointing. ? role for methotrexate.                        desquamative interstitial pneumonitis is in some ways similar to idiopathic pulmonary
                                                                                  fibrosis, but in some ways different. The pathology is slightly different in the sense that
   C. Hypersensitivity pneumonitis                                                there are cells within the alveolar spaces that actually represent macrophages. They are
                                                                                  not desquamative alveolar cells, but rather are intra-alveolar inflammatory cells. The
          1. Examples - farmer's lung; air conditioner or humidifier lung         question that has come up is whether DIP represents a sub-type of idiopathic pulmonary
                                                                                  fibrosis with a fair amount of inflammation, or whether it represents a different disease
                                                                                  and that is really not clear. It has been however, suggested that maybe there is actually
          2. Pathology shows mononuclear cell infiltrate with poorly formed       more of an association with some small airways disease. Many of the patients who have
             granulomas                                                           desquamated interstitial pneumonitis actually are smokers and they also often will have
                                                                                  an inflammatory process in the small airways and one of the questions that comes up is
          3. Distinction between acute hypersensitivity pneumonitis (fever,       this more of a smoking related disease as opposed to a non-smoking related disease such
                                                                                  as idiopathic pulmonary fibrosis. The treatment of IPF has really not improved much
             cough, dyspnea, pulmonary infiltrates hours after exposure) and
                                                                                  over the past decade or even a couple of decades. We tend to just try to suppress the
             chronic hypersensitivity pneumonitis (mimics other forms of          inflammatory response with prednisone generally. There are many people who favor
             chronic interstitial lung disease)                                   using an immunosuppressive agent other than prednisone like cyclophosphamide has
                                                                                  been used. There has not been really good head to head studies comparing those and I
        4. Bronchoalveolar lavage (BAL) fluid shows lymphocytosis with            would say that if you’d look across the country as far as what pulmonologist do I would
        low                                                                       say maybe 60% will start with prednisone and about 40% will start with an agent such
                                                                                  as cyclophosphamide. There really is no good data for head to head comparison.
            CD4/CD8 ratio
                                                                                  Sarcoidosis is my favorite of the interstitial lung diseases. It also I think it is fair to say
D.      Eosinophilic granuloma (histiocytosis X)                                  the most common of the interstitial lung diseases. We still to this day do not what causes
                                                                                  sarcoidosis. The presumption is that sarcoid reflects a response to some agent, an
     1. Atypical histiocytes (Langerhans' cells) in infiltrate; variety of cell   immunologic response to some agent, whether or not it is an exogenous agent or perhaps
                                                                                  even an indigenous agent isn’t really clear. It is also though that it may occur in any
        types in infiltrate with scattered eosinophils
                                                                                  genetically susceptible host, although that has also not been well worked out. At the
                                                                                  moment the National Institutes of Health has a multi-center study to try to sort out the
     2. May have airflow obstruction; may have surprisingly normal lung           ideology of the sarcoid. We have medical center and one of the 10 centers and the hope
        volumes for degree of interstitial disease seen on radiograph             is by applying newer molecular biologic techniques we’ll be able to try to figure out
                                                                                  what the ideology of sarcoid is. However, we can state a few points about sarcoid in
     3. Chest X-ray and CT scan may show numerous small cysts and                 terms of describing what happens. One of the interesting immunologic features is that
                                                                                  there seems to be a hyperactive T cell mediated immunologic response in the lungs that
        nodules; eventual progression to fibrosis and honeycombing                seems to result in the formation of granulomas. If we look in the lungs to do a
                                                                                  bronchoalveolar lavage for example, we can find an increased number of lymphocytes in
     4. Presence of cysts explains possible clinical presentation with            the lungs and also a high helper to suppressor cell ratio, high CD4 to CD8 ratio. In
        spontaneous pneumothorax                                                  contrast, if we look in the peripheral blood for example, we find a depression of T cell
                                                                                  mediated responses as we think about things such as impaired delayed hypersensitivity
                                                                                  patients are often anergic on skin testing. However, unlike patients with HIV infection
     5. Very high association with smoking
                                                                                  this cutaneous anergy and sarcoid is not associated with an increased risk of
                                                                                  opportunistic infections. As I mentioned earlier radiographic patterns can be anything.
     6. Quite variable natural history ranging from spontaneous resolution        It can be reticulonodular, nodular, or alveolar. We often will see endobronchial
        to marked progression with honeycombing and endstage lung                 involvement. If we look with a bronchoscope we will see that there are often little bumps
                                                                                  sometimes called cobble stoning in the airway surface that is often responsible for a
     7. No clear response to any form of therapy, though                          significant problem with cough. In general angiotensin converting enzyme levels, which
                                                                                  had been proposed in the past to be useful in the diagnosis of follow-up of patients with
        steroids/immunosuppressives often used                                    the 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 levels
E. Lymphangioleiomyomatosis                                                       including other granulomas diseases and the correlation is not necessarily all that great
                                                                                  with activity of the disease. Corticosteroids remain the mainstay of therapy, but we
     1. Exclusively in women, almost all of childbearing age                      really do not have any good evidence that corticosteroids alter the overall natural history
                                                                                  of the disease even though they will acutely suppress many of the manifestations of the
                                                                                  disease. One might think because of the presumed pathogenic role of T cells
     2. Atypical smooth muscle proliferation around lymphatics,                   particularly T helper cells in this disease that cyclosporine might be useful, but actually
        bronchioles, small pulmonary vessels                                      when it has been looked at the results have been quite disappointing so far. The other
                                                                                  agent that there is a lot of interest in is methotrexate used primarily as a steroid sparing
     3. Clinical presentation with any of the following: pleural effusion         agent in this disease, but also potentially as a steroid alternative. There are some trials
        (chylothorax), interstitial lung disease (with cysts, similar to          that are going on right now, but I don’t think that we really have any definitive
                                                                                  information about the role of methotrexate versus steroids for sarcoid.
        eosinophilic granuloma), spontaneous pneumothorax, hemoptysis
                                                                                  Another disorder in the lung that will often have some granulomas on pathology,
     4. Like eosinophilic granuloma, may have airflow obstruction, normal         although they are not as well formed as the granulomas of sarcoid. This is
        lung volumes despite interstitial pattern on chest radiograph             hypersensitivity pneumonitis. Examples are being farmer’s lung, air conditioner or
                                                                                  humidifier lung. For all of these basically the underlying pathogenesis is an
                                                                                  immunologic response to an inhaled organic antigen. In the case of farmer’s lung and
     5. Treatment - alteration of hormonal milieu, e.g., progesterone,            all of these what we are dealing with is a response to thermophilic Actinomyces, a mold
        oophorectomy                                                              that can grow either in hay or can grow in a forced air system. The other common type
                                                                                  of organic antigen would be an antigen from animals such as antigens form birds as
F. Chronic eosinophilic pneumonia                                                 could be seen in bird breeders. The pathology is poorly formed granulomas. The disease
                                                                                  can present either in an acute form or in a more chronic form. The acute form often
                                                                                  presents as fever, constitutional symptoms, shortness of breath, and pulmonary infiltrates
     1. Often in patients with underlying asthma
                                                                                  occurring 4 to 6 hours after exposure. The chronic form presents more as a diffuse
                                                                                  interstitial lung disease often in those patients where the underlying exposure is not
     2. Term refers to eosinophils in the pulmonary, infiltrate, which is         being recognized and they have repeated exposure. Interestingly enough if you look in
        interstitial and intra-alveolar                                           the lungs by doing a bronchoalveolar lavage and recover cells you’ll find that there is a
                                                                                  increased number of lymphocytes very similar to what we see in sarcoid, but they are
     a. Peripheral blood eosinophilia common but not present in all               different lymphocytes. In sarcoid we have a high CD4 to CD8 ration where as in
                                                                                  hypersensitivity pneumonitis the converse is true where the CD4 to CD8 ratio is actually
        patients                                                                  low.

     3. Often subacute presentation with dyspnea, cough, fever, other             A few less common disorders and one is eosinophilic granuloma, which is also called
        constitutional symptoms                                                   histiocytosis X. It turns out that the name of this is somewhat of a misnomer in the sense
                                                                                  that they really are not a huge number of eosinophils and we do not see well formed
                                                                                  granulomas in this disease. Rather what we see is an accumulation of a type of
     4. Typical peripheral distribution of infiltrates - photographic negative
                                                                                  histiocytic cell called the Langerhans’ cell, which is normally found in the dermis, but
        of pulmonary, edema                                                       there are also Langerhans’ cells that appear to be important in the antigen processing in
                                                                                  the lungs. These cells accumulate and they seem to proliferate in the lungs. It is not a
     5. Often dramatic response to steroids - can be used for diagnostic trial    neoplastic disorder of these cells. What we see often is that airflow obstruction is
      in setting of typical chest X-ray. Prolonged therapy (at least 6        relatively common in eosinophilic granuloma largely because there are cysts that form.
      months) usually necessary.                                              I will show you this later. If one sees a combination of interstitial disease plus large
                                                                              lung volumes, or associated obstructive disease then eosinophilic granuloma is one of
                                                                              the disorders to consider. Chest x-rays and CT scans will often show nodular disease as
   6. Distinguish from acute eosinophilic pneumonia, an acute febrile         well as cysts. Because of the cysts patients may develop spontaneous pneumothorax if a
      illness with hypoxemic respiratory, failure, diffuse pulmonary.         subpleural cyst ruptures. Interestingly enough there is an epidemiologic association of
      infiltrates, BAL eosinophilia, and a dramatic response to steroids      this disorder with smoking that has never really been well worked out. We don’t
      without recurrence after withdrawal                                     exactly know what it is, but the overwhelming majority of patients who have this disease
                                                                              our smokers. The natural history is variable. In some cases the disease will resolve on
                                                                              its own and in other cases the disease goes on to progressive respiratory insufficiency
G. Bronchiolitis obliterans with organizing pneumonia (BOOP)                  and may require transplantation or it may lead to death. There is no proven treatment.
                                                                              Often people will use things like corticosteroids, but in fact they have never been shown
   1. Pathology - fibrous plugs in small airways; organizing inflammatory.    to work. This is an example of a high resolution CT scan of a patient who has
      infiltrate in pulmonary, parenchyma                                     eosinophilic granuloma and what you can see first of all is that there are some nodular
                                                                              changes here. At the same time there are impressive cystic changes as well and these are
                                                                              responsible to some extent for the airflow obstruction and also for the spontaneous
   2. Can be idiopathic (often called cryptogenic organizing                  pneumothoraces that can develop. It is pretty is easy to see that if this thing adjacent to
      pneumonitis), related to infection, associated with connective tissue   the visceral pleural will rupture one will end with a spontaneous pneumothorax.
                                                                              Another disease that in some respects looks a little bit similar, but also is different from
   3. Subacute illness with dyspnea, cough, constitutional symptoms           eosinophilic granuloma is the one that has the longest name of all the interstitial lung
                                                                              diseases, which is, lymphangioleiomyomatosis often called LAM. It is an interesting
                                                                              disorder and it occurs exclusively in women. Almost all of who are of childbearing age
   4. Chest radiograph often with patchy or localized alveolar infiltrates;   and that certainly raises the issue if whether or not there may be a hormonal influence in
      can mimic bacterial pneumonia                                           the production of the disease. The disease is characterized by atypical smooth muscle
                                                                              cell proliferation. The smooth muscle cells will proliferate around lymphatics,
   5. Responds well to steroids; generally treated for months                 bronchioles, and small vessels. Involvement of each of these can lead to clinical
                                                                              manifestations. For example, one can see pleural effusion as a result of lymphatic
                                                                              blockage. You can see interstitial lung disease just as a result of the increased number of
                                                                              smooth muscle cells. Pneumothorax can develop as a result of involvement of
                                                                              bronchioles and airflow obstruction and cyst formation. Hemoptysis can occur as a
                                                                              result of vessel involvement. Like eosinophilic granuloma airflow obstruction is
                                                                              common, so one can see relatively normal lung volumes despite the presence of
                                                                              interstitial lung disease on chest x-ray. The treatment of the disease is felt to be
                                                                              hormonal manipulation and often what that may mean is progesterone therapy or
                                                                              actually going ahead to oophorectomy. This is an example of a chest radiograph of
                                                                              women with LAM. You can see that the lung volumes are actually very large here. The
                                                                              diaphragms are down. If you could see the lateral you’d actually see that the
                                                                              diaphragms are relatively flat. There is also sort of a hazy appearance over here. This is
                                                                              not just breast shadow, but there is a very subtle interstitial pattern there as well.
                                                                              Perhaps most dramatic though is the CT scan in someone like that. This is near the top
                                                                              of the lungs in the patient with LAM and what you see in this case is a very severe
                                                                              disease essentially all of the parenchyma is replaced with these cysts. It is really quite
                                                                              striking. You really don’t see anything that looks like gas exchanging area of the lungs.
                                                                              In fact, recognizing that this on a gross scale of a CT scan and this is more of what you
                                                                              would expect to see microscopically histologically of what alveolar septi look like. It is
                                                                              really quite striking.

                                                                              Another disorder is one that I think is very important to recognize for clinicians because
                                                                              it is really quite treatable and that is the disorder called chronic eosinophilic pneumonia.
                                                                              This is a disorder that is characterized by eosinophils in a parenchymal infiltrate within
                                                                              the lungs. The name eosinophilic pneumonia does not necessarily refer to peripheral
                                                                              eosinophils. It refers to eosinophils in the infiltrate. It turns out that these patients often
                                                                              will have peripheral eosinophilia, but they so not have to. The patients often will have
                                                                              underlying asthma, but again they do not have to have that either. When they present
                                                                              they present often over the course of weeks to even a month or two, so the presentation
                                                                              is more subacute. They will often have respiratory symptoms and they may have
                                                                              constitutional symptoms as well. By constitutional symptoms here I mean basically
                                                                              they may have fever, fatigue, etc. One often makes attentive diagnosis or one thinks
                                                                              through the diagnosis because of the finding of peripheral infiltrates, a so-called
                                                                              photographic negative of pulmonary edema. Many people feel that this radiographic
                                                                              pattern is typical enough so that one does not actually need to do a biopsy and one can
                                                                              treat the patient with corticosteroids and use that as an empiric diagnostic and
                                                                              therapeutic trial. The patients respond exquisitely to steroids so that often very dramatic
                                                                              radiographic infiltrates will melt over the course of a few days. This is an example of a
                                                                              patient who has chronic eosinophilic pneumonia and let me just point out toward the
                                                                              periphery of the lung here, these whitish areas, this doesn’t represent scapula. It does not
                                                                              represent pleural disease. It is actually parenchymal disease. On the other side as well
                                                                              you can see that there is this extra white stuff here and some up in the upper lung zones
                                                                              where as the more central areas are spared. Unlike what we think of with relatively
                                                                              central pulmonary edema, often a butterfly pattern, this is the opposite of that and that is
                                                                                 why this is called the photographic negative of pulmonary edema. We see this chronic
                                                                                 eosinophilic pneumonia and we also will see it in another slide after this. We may see it
                                                                                 in bronchiolitis obliterans with organizing pneumonia. In contrast to eosinophilic
III. Important diagnostic methods                                                pneumonia I do want to mention a disorder that is called acute eosinophilic pneumonia,
                                                                                 which does not develop over weeks to months, but rather often develops over days as an
   A. High resolution CT scanning                                                acute febrile illness that is associated with hypoxemic respiratory failure. The patients
                                                                                 will have diffuse pulmonary infiltrates rather than the peripheral pulmonary infiltrates.
       1. Width of cuts decreased from 10 mm to 1.0 or 1.5 ram, and special      Like the patients with chronic eosinophilic pneumonia they will have lots of eosinophils
                                                                                 in the lung parenchyma. If you do a bronchoalveolar lavage on either of the disorders
          algorithm used for spatial reconstruction
                                                                                 you’ll find lots of eosinophils. These patients like the chronic eosinophilic pneumonia
                                                                                 patients will respond dramatically to steroids, but what is different and what is
       2. Can detect subtle disease not apparent on chest X-ray                  interesting is that in the acute eosinophilic pneumonia patients once they are treated the
                                                                                 infiltrates melt and you taper them off steroids. They do not get a recurrence of their
       3. Certain patterns suggestive of specific diagnoses                      disease. In contrast, patients with chronic eosinophilic pneumonia often need to be
                                                                                 treated over a number of months and if you withdrawal the steroids prematurely then the
                                                                                 disease will recrudesce.
          a. Lymphangitic carcinoma - polygonal pattern
                                                                                 The next disorder is bronchiolitis obliterans with organizing pneumonia or BOOP is
          b. Eosinophilic granuloma and lymphangioleiomyomatosis -               really characterized by the pathology, which reflects the title. The pathology will show
             multiple small cysts                                                bronchiolitis obliterans, which in practice means that there are fibrous plugs in small
                                                                                 airways. The organizing pneumonia component means that one often sees in adjacent
                                                                                 alveolar spaces is what looks like a chronic or resolving inflammatory infiltrate often
          c. Sarcoidosis - bronchovascular pattern
                                                                                 with mononuclear cells. The ideology is there are a number of disorders that can be
                                                                                 associated with bronchiolitis obliterans with organizing pneumonia and therefore, rather
          d. Idiopathic pulmonary fibrosis - heterogeneous pattern with          than being a specific disease that actually may be a syndrome that has several
             prominent subpleural disease and cyst formation                     underlying ideologies. The probably most common is idiopathic. It can also be
                                                                                 associated with infection as a post-infectious probably in the stage of resolution. It can
   B. Bronchoalveolar lavage                                                     also be associated with some underlying connective tissue diseases. Like chronic
                                                                                 eosinophilic pneumonia the presentation is often subacute with respiratory and often
                                                                                 with constitutional symptoms. The chest x-ray shows patchy or localized infiltrates and
       1. Most useful for recovery of organisms, e.g., Pneumocystis in AIDS      the treatment is generally with corticosteroids. These patchy or localized infiltrates may
                                                                                 be very non-specific. They may look just like pneumonia and sometimes may have a
       2. Typical patterns in some diseases, but generally not specific enough   peripheral distribution mimicking chronic eosinophilic pneumonia. This is an example
          to replace biopsy                                                      of a patient with BOOP. You should ignore the fact that there is an enlarged heart here.
                                                                                 This patient also had an underlying cardiomyopathy that was really not related. What
                                                                                 the patient did have were these infiltrates. Here is one that is actually very much an
          a. Lavage lymphocytosis in sarcoidosis and hypersensitivity            alveolar filling pattern on the left side as well as another patchy infiltrate on the right.
             pneumonitis; CD4/CD8 >2 in sarcoidosis and <1 in                    This patient was found by biopsy to have BOOP and was treated with steroids and the
             hypersensitivity pneumonitis                                        infiltrates melted.

          b. Profile variable in idiopathic pulmonary fibrosis - some with       Diagnostic methods and some of the newer diagnostic methods that are used in patients
                                                                                 that have diffuse parenchymal lung disease. First of all, high resolution CT scan is now
             increased PMNs, some with increased lymphocytes                     very important in the diagnostic evaluation of these patients for 3 reasons. First of all,
                                                                                 there are some patients where we can detect very subtle disease where the chest x-ray is
       3. Histiocytosis X cells (with S-100 antigen) in eosinophilic granuloma   actually normal, but the CT scan will show subtle abnormalities that just were not
                                                                                 detected. Secondly, there are some disease specific patterns and I’ll show you some of
   C. Thoracoscopic lung biopsy - has generally replaced open lung biopsy        these things such as lymphangitic spread of carcinoma, eosinophilic granuloma, and
                                                                                 lymphangioleiomyomatosis. All of those have relatively typical patterns on CT scans
      because of better patient tolerance and shorter hospitalization            that can suggest the diagnosis. Finally there is interest in whether or not the pattern of
                                                                                 abnormality on CT scan reflects the activity of the disease with a ground-glass pattern
                                                                                 suggesting more active and more inflammatory disease. This is an example of a CT
                                                                                 scan in a patient who was short of breath, had restrictive disease on pulmonary function
                                                                                 tests, and had a normal chest x-ray. The high resolution CT scan shows a patchy pattern
                                                                                 of a sort of ground-glass increase in density and in between the areas of increased
                                                                                 density are relatively normal areas that look sort of hypodense here. It turns out that the
                                                                                 blacker areas are not the abnormal areas. It is not like these are cysts or areas of
                                                                                 emphysema. If you could see the original you’d see that there are actually lung
                                                                                 markings going through these areas, rather it is the ground-glass or somewhat whitish
                                                                                 areas that are the abnormal areas. This patient on biopsy turned out to have a
                                                                                 hypersensitivity pneumonitis and actually this particular pattern is often seen in patients
                                                                                 who have a hypersensitivity pneumonitis. In contrast, this is sort of a linear pattern and
                                                                                 actually is affecting a lot of interlobular septi and this is a pattern that we commonly
                                                                                 will see in the spread of tumor throughout the lungs. Sometimes it is described as a
                                                                                 polygonal pattern and may have geometric shapes. This is a high resolution CT scan of
                                                                                 the patient with idiopathic pulmonary fibrosis, which often has a pattern of distribution
                                                                                 of a fair amount of fibrosis out toward the periphery of the lungs. You can see several
                                                                                 areas here often patchy and are often associated with some cyst formation. This is a
                                                                                 pattern that is quite typical.

                                                                                 Another technique that is used and is relatively new is one called bronchoalveolar
                                                                                 lavage. It is used primarily for recovery of organisms certainly in patients who have
                                                                                HIV infection, but in addition it can be used for cell characterization more actually on a
                                                                                research basis then for differential diagnosis of patients with interstitial lung disease.
                                                                                However, as I mentioned earlier one does find an increased number of lymphocytes in
References                                                                      sarcoid and in hypersensitivity pneumonitis, but the CD4/CD8 ratios are different. The
                                                                                CD4 to CD8 is high in sarcoid and it is actually low in hypersensitivity pneumonitis.
1. DePaso WJ, Winterbauer RH. Interstitial lung disease. Dis Mon 37:61-133,     Idiopathic pulmonary fibrosis will have high numbers of either polys or lymphocytes, so
   1991. Excellent recent review of the interstitial lung diseases.             that is not particularly useful diagnostically. In histiocytosis X or eosinophilic
                                                                                granuloma one can actually find certain changes in the cells. One can detect what’s
                                                                                called the S-100 antigen, which identifies those Langerhans’ cells and one can
2. Silver RM, Miller KS, Kinsella MB, Smith EA, Schabel SI. Evaluation and
                                                                                potentially even make a diagnosis of EG just on the basis of lavage. Finally,
   management of scleroderma lung disease using bronchoalveolar lavage. Am      thoracoscopic lung biopsy is where the surgeon will go in with what is the equivalent of
   J Med 88:470-476, 1990. 49% of patients with scleroderma had BAL             the chest version of laparoscopy where a scope is used to get into the pleural space and
   evidence of an active alveolitis; these patients appeared to have some       get lung biopsy specimens. That now has really essentially in many cases replaced open
   improvement following                                                        lung biopsy for obtaining a diagnosis in some of these patients, so when we are thinking
   treatment with cyclophosphamide and prednisone.                              of getting diagnostic tissue are main options these days are either transbronchial biopsy
                                                                                or a thoracoscopic lung biopsy.
3. Panos RJ, Mortenson RL, Niccoli SA, King TE Jr. Clinical deterioration in
   patients with idiopathic pulmonary fibrosis. Am J Med 88:396-404, 1990.
   Besides progression of disease, patients may have disease-related
   complications, e.g., lung cancer (10%), pneumothorax, corticosteroid side
   effects, including immunosuppression.

4. Lower EE, Baughman RP. Prolonged use of methotrexate for sarcoidosis.
   Arch Intern Med 155:846-851, 1995. The authors present their generally
   positive (but uncontrolled) experience with methotrexate in sarcoidosis.

5. Muller NL, Miller RR. Computed tomography of chronic diffuse infiltrative
   lung disease. Am Rev Respir Dis 142:1206-1215, 1440-1448, 1990.
   Excellent review of CT scanning, including high resolution CT scanning, in
   the evaluation of diffuse infiltrative lung disease.

6. Kalassian KG, Doyle R, Kao P, Ruoss S, Raffin TA.
   Lymphangioleiomyomatosis: new insights. Am J Respir Crit Care Med
   155:1183-1186, 1997. A recent short review of LAM.

7. Muller NL, Ostrow DN. High-resolution computed tomography of chronic
   interstitial lung disease. Clin Chest Med 12:97-114, 1991. Excellent
   overview of high-resolution CT scanning in interstitial lung disease.

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