Case 39-2004 — A 52-Year-Old Woman with Recurrent Episodes of Atypical Pneumonia
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《新英格兰医药杂志》
A 52-year-old woman was admitted to the hospital because of cough and dyspnea.
She had smoked two to three packs of cigarettes daily for 35 years. During the two decades before admission, she had been treated for many episodes of pneumonia, often designated as "atypical." Her treatment over the years had included antibiotics as well as adrenocorticosteroids for bronchospasm. The earliest chest radiographs showed a slight increase of the interstitial markings bilaterally, but no focal parenchymal disease; the heart size was normal.
Nine years before the current admission, the patient had been admitted to this hospital for the first time with a nonproductive cough. The results of laboratory tests at that time were normal, except for a lactate dehydrogenase level of 422 U per liter. Chest radiographs had revealed bilateral ground-glass opacification and consolidation, predominantly in the middle and lower lung zones. The heart was enlarged. Treatment with antibiotics was given, and her condition improved.
Two years later, the patient returned to this hospital because of dyspnea and dry cough, and a diagnosis of chronic obstructive pulmonary disease with superimposed pneumonia was made. A chest radiograph again showed diffuse ground-glass opacification and patches of consolidation. Hypersensitivity screening for pneumonitis revealed a normal IgE level, and tests for antibodies to a standard panel of inhaled aeroallergens were negative. An examination of fluid from bronchoalveolar lavage revealed bronchial epithelial cells, neutrophils, and lymphocytes and no eosinophils or malignant cells; tests for influenza A antigen, respiratory syncytial virus antigen, and viral cultures were negative. A transbronchial biopsy specimen revealed a few pigment-laden alveolar histiocytes. There was no evidence of infection, and the results of special stains for microorganisms were negative. Tests for the presence of rheumatoid factor, antinuclear antibodies, antiglomerular basement-membrane antibodies, and antineutrophil cytoplasmic autoantibodies were negative. Cytologic examination of sputum was negative. Multiple antibiotics and a beclomethasone inhaler were given, and she improved.
Five years later, two years before the current admission, dyspnea and dry cough recurred, and the patient was readmitted to this hospital. The oxygen saturation was 85 percent while she was breathing ambient air and 91 percent while she was receiving oxygen at 1 liter per minute. Chest radiographs revealed diffuse consolidation with sparing of the upper lobes. The trachea was intubated; methylprednisolone and nebulizers were given. A computed tomographic (CT) study of the thorax after the intravenous injection of contrast material showed extensive bilateral patchy ground-glass opacities with interlobular septal thickening and more focal consolidation in the lower lobes. The heart was enlarged. The results of a bronchoscopic examination were negative; an evaluation of bronchoalveolar-lavage fluid disclosed neutrophils and lymphocytes without eosinophils, and cultures were negative for bacteria. Cytologic examination disclosed chronic and acute inflammation and abundant foamy macrophages, without malignant cells. A planned open-lung biopsy was canceled because there was evidence of improvement on chest radiography. The patient was discharged with instructions to continue with prednisone treatment (40 mg daily for two weeks), and then to slowly taper off the medication.
At home, for the next two years, the patient used inhalers, but no prednisone or oxygen, and she was in a reasonably good state of health. Two days before the current admission, a cough productive of yellow sputum developed, with reported fevers and chilliness. Worsening dyspnea prompted her return to the hospital, where she was admitted.
The patient had a 20-year history of schizoaffective disorder, with multiple depressive episodes that led to drug overdoses in attempts at suicide. She had received nine courses of electroconvulsive therapy eight years before the current admission and took multiple psychotropic medications. She had been married for nine years and was divorced. She resided in a group home for patients with psychiatric illnesses. She smoked two packs of cigarettes daily and did not drink alcohol or use illicit drugs. Her medications included fluticasone nasal spray, paroxetine, benztropine, buspirone, loxapine, risperidone, gabapentin, omeprazole, tramadol, calcium carbonate, an antacid, and ipratropium, fluticasone, and albuterol inhalers.
The temperature was 36.2°C, the pulse 86 beats per minute, and the respiratory rate 18 breaths per minute. The blood pressure was 100/70 mm Hg. The oxygen saturation was 91 percent while the patient was breathing oxygen by way of a nasal cannula at 4 liters per minute. On physical examination, the patient appeared well. There were diffuse crackles and rhonchi throughout the lungs, with intermittent wheezes. The heart sounds were normal, as were the results of examination of the abdomen and extremities.
The results of urinalysis, a complete blood count, and the levels of urea nitrogen, creatinine, calcium, phosphorus, magnesium, electrolytes, alpha1-antitrypsin, total complement, C3, C4, C1-inhibitor protein, and thyrotropin were normal, and a test for thyroid autoantibodies was negative. The level of lactate dehydrogenase was elevated, at 275 U per liter. A blood culture was sterile, and tests for antibodies to the human immunodeficiency virus (HIV), types 1 and 2, were negative. A test for antinuclear antibodies was positive at a titer of 1:80 and negative at 1:160, and a test for antineutrophil cytoplasmic autoantibodies was negative. A chest radiograph disclosed peribronchial thickening and diffuse ground-glass opacification throughout the lungs that had worsened since a study performed six months earlier.
A course of treatment with ceftriaxone and azithromycin was begun, and the patient continued with her usual nebulizers. She was afebrile at all times. A CT scan of the thorax performed after the administration of contrast material showed considerable improvement in the diffuse parenchymal disease observed on the previous CT scan two years earlier, with residual patchy diffuse ground-glass opacities and septal thickening. The patient repeatedly left the floor to smoke cigarettes, and a nicotine patch was placed.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Walter J. O'Donnell: May we review the radiologic studies?
Dr. Conrad Wittram: The chest radiograph taken nine years before this admission shows mild cardiac enlargement; there is diffuse ground-glass opacification and more confluent opacities indicating air-space consolidation (Figure 1A). The films from an admission two years later also showed diffuse ground-glass opacification with more confluent patches of consolidation located centrally and peripherally in the right lung and in the left lower lobe.
Figure 1. Chest Imaging Studies.
A chest radiograph obtained with a portable device nine years before the patient's current admission (Panel A) shows diffuse ground-glass opacification and patches of consolidation. Another chest radiograph, obtained two years before the current admission (Panel B), shows diffuse consolidation and mild cardiac enlargement, which is worse than shown in the previous chest radiograph. A high-resolution CT image obtained at the time the second radiograph was obtained (Panel C) shows extensive bilateral ground-glass opacities with interlobular septal thickening; the combination of these radiographic signs has been described as "crazy paving." More focal consolidation is also evident.
The films from an admission two years ago show mild cardiac enlargement. The pulmonary consolidation has worsened (Figure 1B). A high-resolution CT scan obtained during that admission shows a mosaic pattern of ground-glass opacification with interlobular septal thickening (Figure 1C). Some lobules are spared, and in dependent areas of the lung there are regions of consolidation. The combination of ground-glass opacification and septal thickening, which creates a mosaic appearance, is called the "crazy-paving pattern."
A radiograph taken during the current admission showed diffuse ground-glass opacification. A high-resolution CT scan again demonstrated ground-glass opacification and interlobular septal thickening. As compared with the study obtained two years earlier, there was improvement in the ground-glass opacification and consolidation.
Dr. O'Donnell: This 52-year-old woman with a schizoaffective disorder who was a heavy smoker had a long history of respiratory illnesses requiring hospital admission. These illnesses were characterized by mild hypoxemia, an absence of fever and systemic symptoms, negative cultures, and responsiveness to corticosteroid treatment. During the episodes, chest-imaging studies showed air-space opacification and septal fibrosis — a pattern on CT known as crazy paving; between episodes, the air-space opacification resolved but the increase in interstitial markings remained. On physical examination, she appeared well and had diffuse crackles and rhonchi throughout the lungs, but no physical signs of emphysema, and no clubbing of the fingers was reported, which would indicate chronic hypoxemia. The only laboratory abnormality had been a persistently elevated level of lactate dehydrogenase.
This patient had an atypical pneumonia syndrome. This clinical syndrome is characterized by findings that are atypical for the usual bacterial pneumonia: a lack of fever or systemic symptoms, negative cultures, unusual radiographic features, or a combination of these. In this case, the atypical pneumonia syndrome was recurrent. The causes of recurrent atypical pneumonia are listed in Table 1.
Table 1. Causes of Recurrent Atypical Pneumonia.
Recurrent episodes of infection can occur with bronchiectasis, but it is unlikely that this condition would be missed on repeated CT scans. The organisms commonly responsible for causing atypical pneumonia, such as tuberculosis or legionella, do not tend to recur in an immunologically intact person. Atypical pneumonia due to pneumocystis may recur in patients who are HIV-positive, and it is responsive to steroids, as this patient's condition was, but she was HIV-negative. Aspiration pneumonia can be recurrent and produce an atypical pneumonia syndrome. This patient had a psychiatric disorder and could be having episodes of aspiration pneumonia associated with altered consciousness as a result of her primary condition, the drugs used to treat it, or the drug overdoses during her suicide attempts. Recurrent episodes of pulmonary edema are unlikely in this patient, who had no history of coronary artery disease, but the mild cardiac enlargement shown on chest radiographs raises the possibility of cardiac failure. The negative serologic studies and the absence of involvement of other organs tend to rule out the rheumatologic diseases as likely diagnoses.
The differential diagnosis can be narrowed further by the finding of a crazy-paving pattern on the chest CT scan. Crazy paving was first described in a report that characterized the CT appearance of pulmonary alveolar proteinosis, in which the feature was seen in all of six patients.1 Pulmonary alveolar proteinosis, described by Dr. Benjamin Castleman and colleagues in 1958,2 is characterized by periodic acid–Schiff–positive proteinaceous alveolar deposits, without inflammatory cells or septal fibrosis. Its estimated incidence is 0.3 to 1.0 per 1 million people. The median age at onset is 39 years; 72 percent of the patients with this condition are smokers.3 It is associated with immunologic defects and hematologic cancers. The presentation of pulmonary alveolar proteinosis is subacute, with dyspnea and cough; about one third of the patients are asymptomatic, but have signs that are detected on chest radiographs. The chest is often clear to auscultation, and clubbing is uncommon, but hypoxemia is common. An elevated level of lactate dehydrogenase, present in this case, is found in 82 percent of patients. Pulmonary alveolar proteinosis is usually a slowly progressive disease, and the treatment is whole-lung lavage; steroids are not known to be effective.
What is the specificity of the crazy-paving pattern for pulmonary alveolar proteinosis? A study of more than 5000 CT scans revealed 46 with this pattern.4 All five cases of pulmonary alveolar proteinosis had the crazy-paving pattern, but images of the lungs from patients with 14 other diseases also showed this pattern, although with decreased frequency. Since most of these disorders — acute respiratory distress syndrome, bacterial pneumonia, acute interstitial pneumonitis, and drug-induced pneumonitis — are more common than pulmonary alveolar proteinosis, they made up the majority of the cases. Thus, the positive predictive value of crazy paving for pulmonary alveolar proteinosis is low. Whereas several features of this case suggest pulmonary alveolar proteinosis — the patient's age and history of smoking, the relatively mild symptoms, and the crazy-paving pattern on CT scanning — other features are not typical of this rare disease, and this is unlikely to be the diagnosis.
Idiopathic pulmonary hemosiderosis usually is manifested before the patient reaches 10 years of age, but it can affect adults, in whom the presentation is usually subacute, with dyspnea, iron-deficiency anemia, and hemoptysis. Acute respiratory failure and pulmonary fibrosis may occur. Imaging studies show ground-glass opacities with interstitial fibrosis. Bronchoalveolar lavage shows alveolar macrophages with hemosiderin. Steroids are effective, especially acutely. However, in this patient, the bronchoalveolar lavage did not show hemosiderin or hemorrhage, there was no hemoptysis, and she was not anemic.
Bronchiolitis obliterans with organizing pneumonia, which has been renamed cryptogenic organizing pneumonia, should also be considered. Patients have an atypical pneumonia syndrome, often with constitutional symptoms. Bronchoalveolar lavage may show features similar to those in this case, including foamy macrophages, and fulminant presentations can occur. However, spontaneous remission is rare; rapid relapse occurs in about one third of patients when steroids are discontinued,5 and nonsmokers outnumber smokers by two to one. Hypersensitivity pneumonitis may be chronic, subacute, or acute. Elevated levels of lactate dehydrogenase are common. A CT scan will show a patchy, ground-glass pattern, and it recurs on reexposure to the inciting agent. However, smokers appear to be at much lower risk for hypersensitivity pneumonitis than those who have never smoked.
We do have an important clue to the diagnosis in this case. The patient is a long-term heavy smoker. Smoking-related interstitial lung diseases are listed in Table 2. The disease that most closely fits this patient's clinical picture is the entity now known as respiratory bronchiolitis with interstitial lung disease–desquamative interstitial pneumonitis, or, as it is sometimes called, smoking-related interstitial lung disease. The American Thoracic Society and the European Respiratory Society have concluded that desquamative interstitial pneumonia and respiratory bronchiolitis with interstitial lung disease represent points on a continuum, with desquamative interstitial pneumonia the result of more extensive filling of alveoli with macrophages.6,7
Table 2. Smoking-Related Interstitial Lung Diseases.
Respiratory bronchiolitis, with the characteristic features of increased peribronchial and interstitial markings on radiographs and peribronchial clusters of pigmented histiocytes on pathological examination, is found in virtually all smokers, regardless of age.8,9 Desquamative interstitial pneumonia is more likely to develop in older persons with a longer smoking history than in younger persons; in this disease, both interstitial thickening and ground-glass opacities are found, and the alveoli are filled with pigmented histiocytes.10 Respiratory bronchiolitis with interstitial lung disease appears to be an intermediate stage. Patients with desquamative interstitial pneumonia may show a restrictive pattern of abnormality on pulmonary-function tests, and digital clubbing may develop. Such patients may present with acute hypoxemic respiratory failure, and when treated with high-dose corticosteroids may have striking immediate improvement. Spontaneous resolution may occur. Both disorders respond to smoking cessation, with the addition of steroids in desquamative interstitial pneumonia. The prognosis is good in respiratory bronchiolitis with interstitial lung disease, with virtually all patients responding to cessation of smoking; in about one third of patients, desquamative interstitial pneumonia may continue to progress despite treatment.11
I suspect that the diagnostic test in this case was a thoracoscopic lung biopsy. The biopsy probably showed changes on the spectrum of respiratory bronchiolitis with interstitial lung disease and desquamative interstitial pneumonia and showed, in particular, features of desquamative interstitial pneumonia. The treatment should be smoking cessation and, if necessary, steroids.
Dr. Nancy Lee Harris (Pathology): Dr. Barker, you took care of this patient on some of her admissions; would you comment on your thinking before the diagnostic procedure?
Dr. George F. Barker (Pulmonary Medicine): I believed that she had an interstitial lung disease that was responsive to smoking cessation, environmental change, or steroid therapy, all of which took place each time she was admitted. I suspected either desquamative interstitial pneumonia or hypersensitivity pneumonitis but could not rule out bronchiolitis obliterans with organizing pneumonia.
Clinical Diagnosis
Respiratory bronchiolitis with interstitial lung disease–desquamative interstitial pneumonitis.
Dr. Walter J. O'Donnell's Diagnosis
Respiratory bronchiolitis with interstitial lung disease–desquamative interstitial pneumonitis.
Pathological Discussion
Dr. Harris: Dr. Richard Kradin will describe the diagnostic procedure and the pathological findings.
Dr. Richard L. Kradin: The procedure was a video-assisted thoracoscopic lung biopsy. The right middle lobe and the superior segment of the right lower lobe were sampled. The findings in the two biopsy specimens were similar. There was patchy consolidation centered on small airways (Figure 2A). Respiratory bronchioles were distorted by mural fibrosis and showed intraluminal filling by pigmented macrophages (Figure 2B). Many alveolar spaces were filled with pigmented macrophages (Figure 2C). The pulmonary macrophages did not react to staining for CD1a, a marker of Langerhans' cells. A trichrome stain showed mild interstitial fibrosis of the alveolar septa. The findings are consistent with smoking-associated interstitial lung disorder, with overlapping features of respiratory bronchiolitis with interstitial lung disease and of desquamative interstitial pneumonitis.
Figure 2. Lung-Biopsy Specimen (Hematoxylin and Eosin).
At low magnification, there is consolidation centered on a small airway, a feature of respiratory bronchiolitis (Panel A). The periphery of the field is relatively uninvolved. At higher magnification, the bronchiole (Panel B) contains a small amount of mucin and numerous pigmented macrophages, features of respiratory bronchiolitis. Numerous alveoli (Panel C) also contain pigmented macrophages, features of desquamative interstitial pneumonitis.
Respiratory bronchiolitis was first described in the lungs of young smokers at autopsy.12 In 1987, Myers and coworkers13 described six smokers with respiratory bronchiolitis who had radiographic and physiological evidence of interstitial lung disease. This disorder, termed respiratory bronchiolitis with interstitial lung disease, is one of several interstitial pulmonary diseases linked to cigarette smoking (Table 2).14 All include the intraalveolar accumulation of macrophages and interstitial fibrosis, which appear to be cardinal features of smoking-associated interstitial lung disorders. In one study,15 all current smokers and 49 percent of former smokers had the histologic features of respiratory bronchiolitis, which in some cases had persisted for many years after smoking cessation. The number of pack-years of smoking correlated with the degree of macrophage pigmentation and peribronchiolar fibrosis. The authors concluded that distinguishing respiratory bronchiolitis from respiratory bronchiolitis with interstitial lung disease on purely histologic grounds was not possible.
In a review of respiratory bronchiolitis with interstitial lung disease,16 4 of 10 patients had overlapping histologic features associated with desquamative interstitial pneumonia. The authors suggested that the term "smoking-associated interstitial lung disorder" be adopted, because it can be difficult to distinguish the histologic findings of respiratory bronchiolitis with interstitial lung disease from those of desquamative interstitial pneumonia.
Dr. Harris: I have asked Dr. Eden Evins to discuss smoking and schizophrenia and the problems with getting patients such as the one we are discussing to quit smoking.
Dr. A. Eden Evins: This case illustrates an important problem in the care of patients with schizophrenia. Seventy-five to 85 percent of people with schizophrenia in the United States smoke cigarettes, as compared with 23 percent in the general population17,18; 20 to 40 percent smoke more than 30 cigarettes per day, as did the patient in this case,17 and smokers with schizophrenia acquire more nicotine per cigarette than do control smokers, presumably through deeper inhalation.19 Age-adjusted rates of death due to pulmonary disease are as much as 130 percent higher among people with schizophrenia than in the general population.20 Thus, there is an important opportunity to prevent tobacco-related morbidity and mortality in a vulnerable population, yet patients with schizophrenia seldom receive advice or treatment for smoking cessation. In one analysis of outpatient visits, physicians identified the smoking status at 78 percent of visits with schizophrenic patients but provided advice to quit smoking at only 11 percent of visits and offered nicotine replacement therapy at only 0.4 percent of visits.21
In advocating smoking cessation for a patient with schizophrenia, it is important to recognize that nicotine may provide specific therapeutic benefits. Patients with schizophrenia have abnormal neuronal nicotine-receptor expression and function22; nicotine transiently normalizes a sensory-gating deficit that is associated with schizophrenia.23,24 Nicotine is associated with improvement in attention, concentration, and extrapyramidal symptoms.25,26,27
Clinical trials have shown that patients with schizophrenia remain clinically stable during attempts at smoking cessation when they use nicotine-replacement therapies or bupropion.28,29,30 Bupropion treatment also appears to reduce negative and depressive symptoms during and after an attempt at smoking cessation and should have been considered for this patient, who had a history of depression. Six-month rates of successful smoking cessation that range from 11 to 19 percent have been reported among patients with schizophrenia when bupropion or nicotine-replacement therapy plus behavioral treatment was added to the usual antipsychotic-medication regimen, as compared with 0 to 6 percent with placebo and behavioral therapy.28,29,30,31,32,33 Patients may be more likely to quit smoking when treated with clozapine or other atypical antipsychotic medications.30
Smokers with schizophrenia are less likely to quit smoking on any single attempt than are smokers without psychiatric disorders. In patients with schizophrenia, perhaps even more than in the general population, physicians should consider smoking a chronic, relapsing condition and should expect patients to require multiple attempts at cessation before they achieve sustained abstinence. A substantial reduction in smoking during a smoking-cessation attempt in patients with schizophrenia is associated with an increased rate of abstinence in subsequent cessation attempts.32 Thus, patience and continued counseling are needed.
For this patient, I would recommend following established guidelines for the management of smoking in schizophrenia.34,35 Her physician should inquire at every visit whether she is still smoking, ask her to document the number of cigarettes smoked per day, advise her to quit smoking, and ask her whether she would like to try to quit. If she is not ready, her physician should encourage her to discuss her perception of the pros and cons of smoking and of quitting at every visit.
Quitting is urgent for this patient because of her established lung disease. If she is ready to quit, smoking-cessation treatment should begin as follows: first, the management of her psychiatric symptoms should be optimized. Then, when her psychiatric symptoms are stable and she is not having a major depressive episode, a cessation attempt should be initiated. The patient should be educated about nicotine-withdrawal symptoms and their time course, since they can mimic early symptoms of psychotic relapse. Pharmacologic treatment can be combined with supportive and behavioral therapy in an 8-to-12-week trial. First-line treatment is bupropion or nicotine-replacement therapy; second-line treatment is clonidine, nortriptyline, or combination nicotine-replacement therapy. For this patient with a history of depression, bupropion or nortriptyline should be used, possibly in conjunction with nicotine-replacement therapy. Changes in clinical symptoms and side effects during and after the smoking-cessation attempt should be monitored closely. Smoking cessation changes the pharmacokinetics of many medications, which may necessitate dose adjustment. This patient with a history of depression should be followed closely for depressive symptoms for six months after smoking cessation.
Dr. Harris: Dr. Barker, can you tell us about the patient's treatment and follow-up?
Dr. Barker: She was treated with corticosteroids, and her symptoms improved. She was discharged to her group home on the eighth hospital day. However, despite the use of a nicotine patch and a smoking-cessation program, she continued to smoke and had three more hospital admissions over the next five months with flare-ups of her desquamative interstitial pneumonia. She became dependent on supplemental oxygen. Bupropion was added to her other medications. Eventually, with the help of other services at the hospital, her living situation was changed to a setting with closer supervision where her civil right to smoke was less well preserved than it had been before. She abstained from smoking for one year; she then moved to a less closely supervised group home, where she began smoking again within a few months. She was recently readmitted to the hospital with dyspnea and oxygen desaturation, due to a flare-up of her desquamative interstitial pneumonia, two years after the diagnosis. Since this most recent discharge, she has again abstained from smoking.
Dr. Harris: The physicians who saw this patient during her multiple admissions considered her to have chronic obstructive pulmonary disease with superimposed pneumonia. Should these two entities have been distinguishable clinically?
Dr. O'Donnell: There is a tendency for physicians to assume that any lung disease in a smoker is chronic obstructive pulmonary disease. The fact is that many people who smoke, even heavily, do not have clinically significant chronic obstructive pulmonary disease. A careful physical examination, pulmonary-function tests, and appropriate imaging should distinguish chronic obstructive pulmonary disease from other smoking-related illnesses.
Anatomical Diagnosis
Smoking-related interstitial lung disease (respiratory bronchiolitis with interstitial lung disease–desquamative interstitial pneumonitis).
Source Information
From the Pulmonary and Critical Care Unit, Department of Medicine (W.J.O., R.L.K.), and the Departments of Pathology (R.L.K.), Psychiatry (A.E.E.), and Radiology (C.W.), Massachusetts General Hospital; and the Departments of Medicine (W.J.O., R.L.K.), Pathology (R.L.K.), Psychiatry (A.E.E.), and Radiology (C.W.), Harvard Medical School.
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She had smoked two to three packs of cigarettes daily for 35 years. During the two decades before admission, she had been treated for many episodes of pneumonia, often designated as "atypical." Her treatment over the years had included antibiotics as well as adrenocorticosteroids for bronchospasm. The earliest chest radiographs showed a slight increase of the interstitial markings bilaterally, but no focal parenchymal disease; the heart size was normal.
Nine years before the current admission, the patient had been admitted to this hospital for the first time with a nonproductive cough. The results of laboratory tests at that time were normal, except for a lactate dehydrogenase level of 422 U per liter. Chest radiographs had revealed bilateral ground-glass opacification and consolidation, predominantly in the middle and lower lung zones. The heart was enlarged. Treatment with antibiotics was given, and her condition improved.
Two years later, the patient returned to this hospital because of dyspnea and dry cough, and a diagnosis of chronic obstructive pulmonary disease with superimposed pneumonia was made. A chest radiograph again showed diffuse ground-glass opacification and patches of consolidation. Hypersensitivity screening for pneumonitis revealed a normal IgE level, and tests for antibodies to a standard panel of inhaled aeroallergens were negative. An examination of fluid from bronchoalveolar lavage revealed bronchial epithelial cells, neutrophils, and lymphocytes and no eosinophils or malignant cells; tests for influenza A antigen, respiratory syncytial virus antigen, and viral cultures were negative. A transbronchial biopsy specimen revealed a few pigment-laden alveolar histiocytes. There was no evidence of infection, and the results of special stains for microorganisms were negative. Tests for the presence of rheumatoid factor, antinuclear antibodies, antiglomerular basement-membrane antibodies, and antineutrophil cytoplasmic autoantibodies were negative. Cytologic examination of sputum was negative. Multiple antibiotics and a beclomethasone inhaler were given, and she improved.
Five years later, two years before the current admission, dyspnea and dry cough recurred, and the patient was readmitted to this hospital. The oxygen saturation was 85 percent while she was breathing ambient air and 91 percent while she was receiving oxygen at 1 liter per minute. Chest radiographs revealed diffuse consolidation with sparing of the upper lobes. The trachea was intubated; methylprednisolone and nebulizers were given. A computed tomographic (CT) study of the thorax after the intravenous injection of contrast material showed extensive bilateral patchy ground-glass opacities with interlobular septal thickening and more focal consolidation in the lower lobes. The heart was enlarged. The results of a bronchoscopic examination were negative; an evaluation of bronchoalveolar-lavage fluid disclosed neutrophils and lymphocytes without eosinophils, and cultures were negative for bacteria. Cytologic examination disclosed chronic and acute inflammation and abundant foamy macrophages, without malignant cells. A planned open-lung biopsy was canceled because there was evidence of improvement on chest radiography. The patient was discharged with instructions to continue with prednisone treatment (40 mg daily for two weeks), and then to slowly taper off the medication.
At home, for the next two years, the patient used inhalers, but no prednisone or oxygen, and she was in a reasonably good state of health. Two days before the current admission, a cough productive of yellow sputum developed, with reported fevers and chilliness. Worsening dyspnea prompted her return to the hospital, where she was admitted.
The patient had a 20-year history of schizoaffective disorder, with multiple depressive episodes that led to drug overdoses in attempts at suicide. She had received nine courses of electroconvulsive therapy eight years before the current admission and took multiple psychotropic medications. She had been married for nine years and was divorced. She resided in a group home for patients with psychiatric illnesses. She smoked two packs of cigarettes daily and did not drink alcohol or use illicit drugs. Her medications included fluticasone nasal spray, paroxetine, benztropine, buspirone, loxapine, risperidone, gabapentin, omeprazole, tramadol, calcium carbonate, an antacid, and ipratropium, fluticasone, and albuterol inhalers.
The temperature was 36.2°C, the pulse 86 beats per minute, and the respiratory rate 18 breaths per minute. The blood pressure was 100/70 mm Hg. The oxygen saturation was 91 percent while the patient was breathing oxygen by way of a nasal cannula at 4 liters per minute. On physical examination, the patient appeared well. There were diffuse crackles and rhonchi throughout the lungs, with intermittent wheezes. The heart sounds were normal, as were the results of examination of the abdomen and extremities.
The results of urinalysis, a complete blood count, and the levels of urea nitrogen, creatinine, calcium, phosphorus, magnesium, electrolytes, alpha1-antitrypsin, total complement, C3, C4, C1-inhibitor protein, and thyrotropin were normal, and a test for thyroid autoantibodies was negative. The level of lactate dehydrogenase was elevated, at 275 U per liter. A blood culture was sterile, and tests for antibodies to the human immunodeficiency virus (HIV), types 1 and 2, were negative. A test for antinuclear antibodies was positive at a titer of 1:80 and negative at 1:160, and a test for antineutrophil cytoplasmic autoantibodies was negative. A chest radiograph disclosed peribronchial thickening and diffuse ground-glass opacification throughout the lungs that had worsened since a study performed six months earlier.
A course of treatment with ceftriaxone and azithromycin was begun, and the patient continued with her usual nebulizers. She was afebrile at all times. A CT scan of the thorax performed after the administration of contrast material showed considerable improvement in the diffuse parenchymal disease observed on the previous CT scan two years earlier, with residual patchy diffuse ground-glass opacities and septal thickening. The patient repeatedly left the floor to smoke cigarettes, and a nicotine patch was placed.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Walter J. O'Donnell: May we review the radiologic studies?
Dr. Conrad Wittram: The chest radiograph taken nine years before this admission shows mild cardiac enlargement; there is diffuse ground-glass opacification and more confluent opacities indicating air-space consolidation (Figure 1A). The films from an admission two years later also showed diffuse ground-glass opacification with more confluent patches of consolidation located centrally and peripherally in the right lung and in the left lower lobe.
Figure 1. Chest Imaging Studies.
A chest radiograph obtained with a portable device nine years before the patient's current admission (Panel A) shows diffuse ground-glass opacification and patches of consolidation. Another chest radiograph, obtained two years before the current admission (Panel B), shows diffuse consolidation and mild cardiac enlargement, which is worse than shown in the previous chest radiograph. A high-resolution CT image obtained at the time the second radiograph was obtained (Panel C) shows extensive bilateral ground-glass opacities with interlobular septal thickening; the combination of these radiographic signs has been described as "crazy paving." More focal consolidation is also evident.
The films from an admission two years ago show mild cardiac enlargement. The pulmonary consolidation has worsened (Figure 1B). A high-resolution CT scan obtained during that admission shows a mosaic pattern of ground-glass opacification with interlobular septal thickening (Figure 1C). Some lobules are spared, and in dependent areas of the lung there are regions of consolidation. The combination of ground-glass opacification and septal thickening, which creates a mosaic appearance, is called the "crazy-paving pattern."
A radiograph taken during the current admission showed diffuse ground-glass opacification. A high-resolution CT scan again demonstrated ground-glass opacification and interlobular septal thickening. As compared with the study obtained two years earlier, there was improvement in the ground-glass opacification and consolidation.
Dr. O'Donnell: This 52-year-old woman with a schizoaffective disorder who was a heavy smoker had a long history of respiratory illnesses requiring hospital admission. These illnesses were characterized by mild hypoxemia, an absence of fever and systemic symptoms, negative cultures, and responsiveness to corticosteroid treatment. During the episodes, chest-imaging studies showed air-space opacification and septal fibrosis — a pattern on CT known as crazy paving; between episodes, the air-space opacification resolved but the increase in interstitial markings remained. On physical examination, she appeared well and had diffuse crackles and rhonchi throughout the lungs, but no physical signs of emphysema, and no clubbing of the fingers was reported, which would indicate chronic hypoxemia. The only laboratory abnormality had been a persistently elevated level of lactate dehydrogenase.
This patient had an atypical pneumonia syndrome. This clinical syndrome is characterized by findings that are atypical for the usual bacterial pneumonia: a lack of fever or systemic symptoms, negative cultures, unusual radiographic features, or a combination of these. In this case, the atypical pneumonia syndrome was recurrent. The causes of recurrent atypical pneumonia are listed in Table 1.
Table 1. Causes of Recurrent Atypical Pneumonia.
Recurrent episodes of infection can occur with bronchiectasis, but it is unlikely that this condition would be missed on repeated CT scans. The organisms commonly responsible for causing atypical pneumonia, such as tuberculosis or legionella, do not tend to recur in an immunologically intact person. Atypical pneumonia due to pneumocystis may recur in patients who are HIV-positive, and it is responsive to steroids, as this patient's condition was, but she was HIV-negative. Aspiration pneumonia can be recurrent and produce an atypical pneumonia syndrome. This patient had a psychiatric disorder and could be having episodes of aspiration pneumonia associated with altered consciousness as a result of her primary condition, the drugs used to treat it, or the drug overdoses during her suicide attempts. Recurrent episodes of pulmonary edema are unlikely in this patient, who had no history of coronary artery disease, but the mild cardiac enlargement shown on chest radiographs raises the possibility of cardiac failure. The negative serologic studies and the absence of involvement of other organs tend to rule out the rheumatologic diseases as likely diagnoses.
The differential diagnosis can be narrowed further by the finding of a crazy-paving pattern on the chest CT scan. Crazy paving was first described in a report that characterized the CT appearance of pulmonary alveolar proteinosis, in which the feature was seen in all of six patients.1 Pulmonary alveolar proteinosis, described by Dr. Benjamin Castleman and colleagues in 1958,2 is characterized by periodic acid–Schiff–positive proteinaceous alveolar deposits, without inflammatory cells or septal fibrosis. Its estimated incidence is 0.3 to 1.0 per 1 million people. The median age at onset is 39 years; 72 percent of the patients with this condition are smokers.3 It is associated with immunologic defects and hematologic cancers. The presentation of pulmonary alveolar proteinosis is subacute, with dyspnea and cough; about one third of the patients are asymptomatic, but have signs that are detected on chest radiographs. The chest is often clear to auscultation, and clubbing is uncommon, but hypoxemia is common. An elevated level of lactate dehydrogenase, present in this case, is found in 82 percent of patients. Pulmonary alveolar proteinosis is usually a slowly progressive disease, and the treatment is whole-lung lavage; steroids are not known to be effective.
What is the specificity of the crazy-paving pattern for pulmonary alveolar proteinosis? A study of more than 5000 CT scans revealed 46 with this pattern.4 All five cases of pulmonary alveolar proteinosis had the crazy-paving pattern, but images of the lungs from patients with 14 other diseases also showed this pattern, although with decreased frequency. Since most of these disorders — acute respiratory distress syndrome, bacterial pneumonia, acute interstitial pneumonitis, and drug-induced pneumonitis — are more common than pulmonary alveolar proteinosis, they made up the majority of the cases. Thus, the positive predictive value of crazy paving for pulmonary alveolar proteinosis is low. Whereas several features of this case suggest pulmonary alveolar proteinosis — the patient's age and history of smoking, the relatively mild symptoms, and the crazy-paving pattern on CT scanning — other features are not typical of this rare disease, and this is unlikely to be the diagnosis.
Idiopathic pulmonary hemosiderosis usually is manifested before the patient reaches 10 years of age, but it can affect adults, in whom the presentation is usually subacute, with dyspnea, iron-deficiency anemia, and hemoptysis. Acute respiratory failure and pulmonary fibrosis may occur. Imaging studies show ground-glass opacities with interstitial fibrosis. Bronchoalveolar lavage shows alveolar macrophages with hemosiderin. Steroids are effective, especially acutely. However, in this patient, the bronchoalveolar lavage did not show hemosiderin or hemorrhage, there was no hemoptysis, and she was not anemic.
Bronchiolitis obliterans with organizing pneumonia, which has been renamed cryptogenic organizing pneumonia, should also be considered. Patients have an atypical pneumonia syndrome, often with constitutional symptoms. Bronchoalveolar lavage may show features similar to those in this case, including foamy macrophages, and fulminant presentations can occur. However, spontaneous remission is rare; rapid relapse occurs in about one third of patients when steroids are discontinued,5 and nonsmokers outnumber smokers by two to one. Hypersensitivity pneumonitis may be chronic, subacute, or acute. Elevated levels of lactate dehydrogenase are common. A CT scan will show a patchy, ground-glass pattern, and it recurs on reexposure to the inciting agent. However, smokers appear to be at much lower risk for hypersensitivity pneumonitis than those who have never smoked.
We do have an important clue to the diagnosis in this case. The patient is a long-term heavy smoker. Smoking-related interstitial lung diseases are listed in Table 2. The disease that most closely fits this patient's clinical picture is the entity now known as respiratory bronchiolitis with interstitial lung disease–desquamative interstitial pneumonitis, or, as it is sometimes called, smoking-related interstitial lung disease. The American Thoracic Society and the European Respiratory Society have concluded that desquamative interstitial pneumonia and respiratory bronchiolitis with interstitial lung disease represent points on a continuum, with desquamative interstitial pneumonia the result of more extensive filling of alveoli with macrophages.6,7
Table 2. Smoking-Related Interstitial Lung Diseases.
Respiratory bronchiolitis, with the characteristic features of increased peribronchial and interstitial markings on radiographs and peribronchial clusters of pigmented histiocytes on pathological examination, is found in virtually all smokers, regardless of age.8,9 Desquamative interstitial pneumonia is more likely to develop in older persons with a longer smoking history than in younger persons; in this disease, both interstitial thickening and ground-glass opacities are found, and the alveoli are filled with pigmented histiocytes.10 Respiratory bronchiolitis with interstitial lung disease appears to be an intermediate stage. Patients with desquamative interstitial pneumonia may show a restrictive pattern of abnormality on pulmonary-function tests, and digital clubbing may develop. Such patients may present with acute hypoxemic respiratory failure, and when treated with high-dose corticosteroids may have striking immediate improvement. Spontaneous resolution may occur. Both disorders respond to smoking cessation, with the addition of steroids in desquamative interstitial pneumonia. The prognosis is good in respiratory bronchiolitis with interstitial lung disease, with virtually all patients responding to cessation of smoking; in about one third of patients, desquamative interstitial pneumonia may continue to progress despite treatment.11
I suspect that the diagnostic test in this case was a thoracoscopic lung biopsy. The biopsy probably showed changes on the spectrum of respiratory bronchiolitis with interstitial lung disease and desquamative interstitial pneumonia and showed, in particular, features of desquamative interstitial pneumonia. The treatment should be smoking cessation and, if necessary, steroids.
Dr. Nancy Lee Harris (Pathology): Dr. Barker, you took care of this patient on some of her admissions; would you comment on your thinking before the diagnostic procedure?
Dr. George F. Barker (Pulmonary Medicine): I believed that she had an interstitial lung disease that was responsive to smoking cessation, environmental change, or steroid therapy, all of which took place each time she was admitted. I suspected either desquamative interstitial pneumonia or hypersensitivity pneumonitis but could not rule out bronchiolitis obliterans with organizing pneumonia.
Clinical Diagnosis
Respiratory bronchiolitis with interstitial lung disease–desquamative interstitial pneumonitis.
Dr. Walter J. O'Donnell's Diagnosis
Respiratory bronchiolitis with interstitial lung disease–desquamative interstitial pneumonitis.
Pathological Discussion
Dr. Harris: Dr. Richard Kradin will describe the diagnostic procedure and the pathological findings.
Dr. Richard L. Kradin: The procedure was a video-assisted thoracoscopic lung biopsy. The right middle lobe and the superior segment of the right lower lobe were sampled. The findings in the two biopsy specimens were similar. There was patchy consolidation centered on small airways (Figure 2A). Respiratory bronchioles were distorted by mural fibrosis and showed intraluminal filling by pigmented macrophages (Figure 2B). Many alveolar spaces were filled with pigmented macrophages (Figure 2C). The pulmonary macrophages did not react to staining for CD1a, a marker of Langerhans' cells. A trichrome stain showed mild interstitial fibrosis of the alveolar septa. The findings are consistent with smoking-associated interstitial lung disorder, with overlapping features of respiratory bronchiolitis with interstitial lung disease and of desquamative interstitial pneumonitis.
Figure 2. Lung-Biopsy Specimen (Hematoxylin and Eosin).
At low magnification, there is consolidation centered on a small airway, a feature of respiratory bronchiolitis (Panel A). The periphery of the field is relatively uninvolved. At higher magnification, the bronchiole (Panel B) contains a small amount of mucin and numerous pigmented macrophages, features of respiratory bronchiolitis. Numerous alveoli (Panel C) also contain pigmented macrophages, features of desquamative interstitial pneumonitis.
Respiratory bronchiolitis was first described in the lungs of young smokers at autopsy.12 In 1987, Myers and coworkers13 described six smokers with respiratory bronchiolitis who had radiographic and physiological evidence of interstitial lung disease. This disorder, termed respiratory bronchiolitis with interstitial lung disease, is one of several interstitial pulmonary diseases linked to cigarette smoking (Table 2).14 All include the intraalveolar accumulation of macrophages and interstitial fibrosis, which appear to be cardinal features of smoking-associated interstitial lung disorders. In one study,15 all current smokers and 49 percent of former smokers had the histologic features of respiratory bronchiolitis, which in some cases had persisted for many years after smoking cessation. The number of pack-years of smoking correlated with the degree of macrophage pigmentation and peribronchiolar fibrosis. The authors concluded that distinguishing respiratory bronchiolitis from respiratory bronchiolitis with interstitial lung disease on purely histologic grounds was not possible.
In a review of respiratory bronchiolitis with interstitial lung disease,16 4 of 10 patients had overlapping histologic features associated with desquamative interstitial pneumonia. The authors suggested that the term "smoking-associated interstitial lung disorder" be adopted, because it can be difficult to distinguish the histologic findings of respiratory bronchiolitis with interstitial lung disease from those of desquamative interstitial pneumonia.
Dr. Harris: I have asked Dr. Eden Evins to discuss smoking and schizophrenia and the problems with getting patients such as the one we are discussing to quit smoking.
Dr. A. Eden Evins: This case illustrates an important problem in the care of patients with schizophrenia. Seventy-five to 85 percent of people with schizophrenia in the United States smoke cigarettes, as compared with 23 percent in the general population17,18; 20 to 40 percent smoke more than 30 cigarettes per day, as did the patient in this case,17 and smokers with schizophrenia acquire more nicotine per cigarette than do control smokers, presumably through deeper inhalation.19 Age-adjusted rates of death due to pulmonary disease are as much as 130 percent higher among people with schizophrenia than in the general population.20 Thus, there is an important opportunity to prevent tobacco-related morbidity and mortality in a vulnerable population, yet patients with schizophrenia seldom receive advice or treatment for smoking cessation. In one analysis of outpatient visits, physicians identified the smoking status at 78 percent of visits with schizophrenic patients but provided advice to quit smoking at only 11 percent of visits and offered nicotine replacement therapy at only 0.4 percent of visits.21
In advocating smoking cessation for a patient with schizophrenia, it is important to recognize that nicotine may provide specific therapeutic benefits. Patients with schizophrenia have abnormal neuronal nicotine-receptor expression and function22; nicotine transiently normalizes a sensory-gating deficit that is associated with schizophrenia.23,24 Nicotine is associated with improvement in attention, concentration, and extrapyramidal symptoms.25,26,27
Clinical trials have shown that patients with schizophrenia remain clinically stable during attempts at smoking cessation when they use nicotine-replacement therapies or bupropion.28,29,30 Bupropion treatment also appears to reduce negative and depressive symptoms during and after an attempt at smoking cessation and should have been considered for this patient, who had a history of depression. Six-month rates of successful smoking cessation that range from 11 to 19 percent have been reported among patients with schizophrenia when bupropion or nicotine-replacement therapy plus behavioral treatment was added to the usual antipsychotic-medication regimen, as compared with 0 to 6 percent with placebo and behavioral therapy.28,29,30,31,32,33 Patients may be more likely to quit smoking when treated with clozapine or other atypical antipsychotic medications.30
Smokers with schizophrenia are less likely to quit smoking on any single attempt than are smokers without psychiatric disorders. In patients with schizophrenia, perhaps even more than in the general population, physicians should consider smoking a chronic, relapsing condition and should expect patients to require multiple attempts at cessation before they achieve sustained abstinence. A substantial reduction in smoking during a smoking-cessation attempt in patients with schizophrenia is associated with an increased rate of abstinence in subsequent cessation attempts.32 Thus, patience and continued counseling are needed.
For this patient, I would recommend following established guidelines for the management of smoking in schizophrenia.34,35 Her physician should inquire at every visit whether she is still smoking, ask her to document the number of cigarettes smoked per day, advise her to quit smoking, and ask her whether she would like to try to quit. If she is not ready, her physician should encourage her to discuss her perception of the pros and cons of smoking and of quitting at every visit.
Quitting is urgent for this patient because of her established lung disease. If she is ready to quit, smoking-cessation treatment should begin as follows: first, the management of her psychiatric symptoms should be optimized. Then, when her psychiatric symptoms are stable and she is not having a major depressive episode, a cessation attempt should be initiated. The patient should be educated about nicotine-withdrawal symptoms and their time course, since they can mimic early symptoms of psychotic relapse. Pharmacologic treatment can be combined with supportive and behavioral therapy in an 8-to-12-week trial. First-line treatment is bupropion or nicotine-replacement therapy; second-line treatment is clonidine, nortriptyline, or combination nicotine-replacement therapy. For this patient with a history of depression, bupropion or nortriptyline should be used, possibly in conjunction with nicotine-replacement therapy. Changes in clinical symptoms and side effects during and after the smoking-cessation attempt should be monitored closely. Smoking cessation changes the pharmacokinetics of many medications, which may necessitate dose adjustment. This patient with a history of depression should be followed closely for depressive symptoms for six months after smoking cessation.
Dr. Harris: Dr. Barker, can you tell us about the patient's treatment and follow-up?
Dr. Barker: She was treated with corticosteroids, and her symptoms improved. She was discharged to her group home on the eighth hospital day. However, despite the use of a nicotine patch and a smoking-cessation program, she continued to smoke and had three more hospital admissions over the next five months with flare-ups of her desquamative interstitial pneumonia. She became dependent on supplemental oxygen. Bupropion was added to her other medications. Eventually, with the help of other services at the hospital, her living situation was changed to a setting with closer supervision where her civil right to smoke was less well preserved than it had been before. She abstained from smoking for one year; she then moved to a less closely supervised group home, where she began smoking again within a few months. She was recently readmitted to the hospital with dyspnea and oxygen desaturation, due to a flare-up of her desquamative interstitial pneumonia, two years after the diagnosis. Since this most recent discharge, she has again abstained from smoking.
Dr. Harris: The physicians who saw this patient during her multiple admissions considered her to have chronic obstructive pulmonary disease with superimposed pneumonia. Should these two entities have been distinguishable clinically?
Dr. O'Donnell: There is a tendency for physicians to assume that any lung disease in a smoker is chronic obstructive pulmonary disease. The fact is that many people who smoke, even heavily, do not have clinically significant chronic obstructive pulmonary disease. A careful physical examination, pulmonary-function tests, and appropriate imaging should distinguish chronic obstructive pulmonary disease from other smoking-related illnesses.
Anatomical Diagnosis
Smoking-related interstitial lung disease (respiratory bronchiolitis with interstitial lung disease–desquamative interstitial pneumonitis).
Source Information
From the Pulmonary and Critical Care Unit, Department of Medicine (W.J.O., R.L.K.), and the Departments of Pathology (R.L.K.), Psychiatry (A.E.E.), and Radiology (C.W.), Massachusetts General Hospital; and the Departments of Medicine (W.J.O., R.L.K.), Pathology (R.L.K.), Psychiatry (A.E.E.), and Radiology (C.W.), Harvard Medical School.
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