Unusual pulmonary diseases

Unusu~[

Pulmonary Diseases J O H N H. K N E L S O N R O B E R T A. DE LEMOS MARY ELLEN AVERY

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IDIOPATttlC I~UL,XIONARY HE,MOSIDEROSIS

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PULMONARY I'~IAN1FESTATIONS OF HISTIOCYTOSIS X CONGENITAL PULMONARY LYMPttANGIECTASIS .

XV1LsoN-MIKn'Y S~'NORO.XIE .

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INFANTILE LOBAR E M P t t Y S E M A

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IDIOPATtlIC UNILATERAL H Y P E R L U C E N T LUNG PNEUMOCYST1S CARINII PNEUMONIA ~[ELIOIOOSI$

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was graduated from ,Manchester College in 1955. After a year at the Ijniversity of Paris as a Fnlbright Scholar he attended Northwestern Ijniversity Medical School, obtaining the M.D. in 1960. Internship and resident" in pediatrics at the University of Michigan was interrupted by tssn years of service as a medical officer with the Ij. S. Army Special Forces, He s~'as a fellos, r in respiratory diseases in children at the University of Michigan from 1964 to 1968, d u r i n g which time he also obtained a masters degree in epidemiologT. At present, he is a fellow in pediatric respiratory physiology at the Johns Hopkins IIospital.

was graduated from Amherst College in 1958 and from Harvard Medical School in 1962. He completed his internship and residency in pediatrics at the Children's Hospital Medical Center, Boston, Massachnsetts. On active duty in the United States Air Force since 1965, he completed a fellos*'ship in neonatology at Johns Hopkins Hospital under Air Force sponsorship. His research interests include the pulmonaD' effects of oxygen exposure and the variety of factors involved in fetal maturation.

is ProFessor of Pediatrics and Chairman of the Department at McGill University and Physician-in-Chief, Montreal Children's Hospital. A graduate of Wheaton College, Massachusetts, and the Johns }topkins School of Medicine, she was an intern and resident in pediatrics at Johns Hopkins, and later Associate ProFessor of Pediatrics and Pediatrician-ln-Charge of the ne~sborn nurseries. She is known for her research on respiratory problems of infants and children, and is the author of a book, The Lung and Its Disorders in the Newborn InIant.

T H E S E L E C T I O N of topics under tile sweeping title, "Unusual Pulmonary Diseases," may strike the reader as unusual in itself, and perhaps deserves a fe~v words of explanation. T h e authors are pediatricians, which may explain the choice of several conditions found mostly in infancy. One of the authors (R. A. deL.) is also in the United States Air Force and

thus is aware of the increasing problem with melioidosis. A section on oxygen toxicity was included because of recent interest in this i m p o r t a n t topic, and because most of the severe pulmonary disorders described may require oxygen therapy. T h e disorders discussed are not representative of a group of diseases, nor do they have anything in common apart from being unusal, and, for one reason or another, of special interest to the autllors. T h e autllors hope that the readers will also find them of interest.

Idiopathic Pulmonary Hemosiderosis Although first reported by Ceelen in 1931, idiopathic pulmonary hemosiderosis remains a rare, enigmatic disease of unknown cause and unpredictable course. T h e r e is no known, satisfactory treatment. INCIDENCE Idiopathic pulmonary hemosiderosis (IPH) is virtually restricted to children, but it occasionally occurs in young adults. Of 112 patients reviewed by Soergel and Sommers, symptoms first appeared in 91 before 16 years of age; tile onset of symptoms was between 1 and 7 years of age in most children and before 30 years in the adults (their youngest patient was 4 months old and the oldest 47 years) (1). A review of all reported cases of i P H fails to reveal any sexual, racial, geographic or familial aggregation. T a k e n alone, however, the cases of Matsaniotis et al. demonstrate what is t a n t a m o u n t to epidemic proportions in a particularly isolated region already noted for a tendency to consanguinuity and an increased incidence of hentoglobinopathies and other genetically determined disorders (2). T w o of tile patients were twins, probably monozygous. T h i s series also showed a 2 to 1 male to female incidence. CLINICAL ~IANIFESTATIONS Recurrent intra-alveolar hemorrhages account for most of the clinical manifestations of I P H . T h e most important of these are tachypnea, dyspnea, wheezing, cough, hemoptysis,

cyanosis and pallor. Frequent, but not invariable, physical findings are fine tales scattered throughout both lung fields, diminished breath sounds and an enlarged spleen. Typically the child is cyanotic, pale and dyspneic when presenting with an exacerbation. Early in the disease anemia, hemoptysis and digital clubbing may not be evident but almost ahvays are present eventually. Remissions often occur with complete disappearance of symptoms, but exercise intolerance may persist. RADIOGRAPHIC CHANGES

A chest film taken at the onset of symptoms usually shows many small, ill-defined alveolar infiltrates distributed randomly throughout both lungs. These infiltrates are characteristically transient early in tile disease, appearing when there is alveolar hemorrhage and disappearing as the blood is reabsorbed (Fig. 1). Sequestration of iron in lung tissue eventually leads to permanent radiographic changes as the disease progresses. Tile changes are variable and may consist of peribronchial infiltrates, segmental or lobar atelectasis, miliary infiltrates or interstitial fibrosis. LABORATORY FINDINGS

Tile typical microcytic, hypochromic anemia is due to repeated hemorrhage withresulting depletion of utilizable iron stores. There is usually a low serum iron, a normal or slightly elevated iron-binding capacity and a moderate reticulocytosis. The peripheral blood smear is normal, save for a frequent eosinophilia, sometimes to 207o of tile leukocyte count. Studies with 51Cr-labeled erythrocytes indicate normal red cell survival in patients with clinical remission, but in patients with active disease there is shortened survival of circulating red cells and the appearance of 51Cr activity in lung tissue (3). Jaundice can occur because of reabsorption of blood pigments from lung tissue. This may lead to the erroneous diagnosis of hemolytic anemia in patients who also have an unexplained positive Coombs test. There have been no confirmed reports of immunoglobulin deficiencies, increased bleeding or clotting time, increased red cell fragility, capillary fragility or pro-

Fw,. 1.--Chest films of a 5-year-old Negro boy who was well until 4 years of age when he began to have easy fatigability, dyspnea on exertion and pallor. Extensive evaluation of the anemia failed to reveal any specific etiolo~-; transfusion resulted in marked clinical improvement. Symptoms recurred 8 months later. Over the next 2 months the RUL infiltrate seen ill ~1 cleared completely to be replaced by LUL and some RLL infiltrate, B, demonstrating the transient natt, re of radiographic findings in IPH. lie is now in a period of relative remission on corticosteroid therapy. l o n g e d p r o t h r o m b i n t i m e . I n s h o r t , t h e r e is n o e v i d e n c e f o r a n y a s s o c i a t e d m e t a b o l i c o r d e v e l o p m e n t a l a b n o r m a l i t y in patients with IPH. T h e sine q u a n o n of d i a g n o s i s is r e c o v e r y of h e r n o s i d e r i n laden macrophages from sputum, gastric washings or biopsy

material and the exclusion of primary heart disease. T h e siderocytes must be carefully examined with a specific stain for iron, otherwise other material in macrophages can be confused with hemosiderin. T h e specimen shonld be stained for 1 hour in a fresh 1% solution of potassium ferrocyanide in 0.06 N HC1, then washed in 1% acetic acid or 0.01 N HC1. This gives the classic Prussian blue reaction with ferric ion. A positive reaction is usually seen in 10-15 m n u t e s , but the longer period must be used before ruling out the presence of hemosiderin (4). Siderocytes are necessary for the diagnosis, but are not pathognomonic. T h e y are well known as "heart failure cells" in conditions such as mitral stenosis, which cause elevated left atrial pressure, and are seen in pulmonary henmrrhage of an)' origin (5). For these reasons the diagnosis of I P H should be restricted to patients in whom heart disease is carefully ruled OUt and who sllow some of the other clinical characteristics mentioned. T h e presence of siderocytes in the alveoli of a patient who dies following an acute ptdmonary hemorrlmge does not automatically imply the diagnosis of IPH. Serial imhnonary function studies have not been reported in enough patients to correlate changes in hmg function and structure in IPH. Lung volumes, i n t r a p u h n o n a r y gas distribution and diffusing capacity may be normal in some patients even after years of symptoms. A consistent finding is relative alveolar hyperventilation with low PaCO2 and normal pH, indicating a compensated, chronic respiratory alkalosis (6). T h i s seemingly paradoxic situation may be a rellection of A-V slmnting, decrease in diffusing capacity or alteration in peripheral puhnonary reflex mechanisms. Measurements of compliance do not seem to be available, but the frequent observation of rapid, shallow respirations in these patients suggests that decreased compliance may often occur. COURSE AND PROGNOSIS

T h e clinical course is extremely variable. Initially there may often be long periods of remission between progressively worse episodes of alveolar hemorrhage. Occasionally the disease may be fnlminant, with death occurring only a few days after the

onset of symptoms. More commonly, periods of partial remission occur during a prolonged and downhill course, terminating in progressive pulmonary fibrosis and cor pulmonale. T h e amount of fibrosis seen post rnortem does not correlate with the duration or severity of the disease. In the series of Matsaniotis et al. (2), 20 patients have been followed up to 5 years. Of these, 4 died after an average survival of 3.5 )'ears following onset of symptoms. T h e remaining 16, with an average follow-up of 2.8 )'ears, were symptom free, save for one who has mild hemoptysis. I P H may exist in aduhs in a milder form. Karlish and Hemsted (7) cite two cases to iIIustrate this point: FolIowing an acute respiratory infection, a 32-year-old man had extensive and persistent radiologic findings consistent with IPH. Thoracotomy showed a brown, granular-appearing lung surface, and widespread hemosiderosis was seen in the biopsy specimen. This patient remained asymptomatic and had neither hemoptysis nor anemia. Another patient, age 22, had daily helnoptysis and mild anemia with no symptoms and normal chest fihns for 5 years. His sputum had a consistently heavy concentration of siderocytes. Samuels et a l . (8) reported IPH in a 22year-old woman who has been asymptomatic, with normal chest films, and has had three uneventful pregnancies during a 4-year remission. PATHOGENESIS Several theories of etiology have been proposed. Tile long, intermittent course, occasional eosinophilia, splenomegaly and the possible value of steroid therapy prompt some authors to place IPH in tile general category of collagen diseases. Buerger and Hathaway reported a case of IPH with allergic pulmonary vascnlitis anti reviewed tile possible relationships between / P H , Sch/inlein-Henoch syndrome, purpura and arthritis (9). Goodpasture described 24 cases of pulmonary hemorrhage associated with severe gtomerulonephritis (10). It is still controversial whether Goodpasture's syndrome and IPH are separate or overlapping entities. Lack of autoimmune antibodies and the usual absence of other organ involvement mitigate against classifying IPH with the collagen diseases. Sprecace reported

an intriguing series of six cases in one hospital within a 10month period. Five of these young men had occupational exposure to gasoline and its products of combustion. T w o of them had associated proteinuria and hematuria (11). Occasional viral isolations have been made in IPH, but without sufficient consistency to substantiate that theory of pathogenesis. A defect in fibrous tissue in the interalveolar septae, with consequent loss of mechanical support for pulmonary capillaries, has been suggested, but this is not confirmed by the lfistologic appearance of the h m g in most cases of IPH. Soergel and Sommers (12) have done a most careful review of autopsy and biopsy material, and have concluded that the primary defect is in the ah'eolar epithelial cells. T h e y believe that the "striking degeneration, shedding and hyperplasia of alveolar epithelial cells, and marked localized alveolar capillary dilatation" present in all stages of the disease, even during remission, is the characteristic microscopic lesion in IPH. Interstitial fibrosis, degeneration of alveolar, interstitial and vascular elastic fibers, dilatation and moderate subendothelial sclerosis of pulmonary vessels are considered by them to be secondary to the alveolar hemorrhage. T h e y suggest that the bleeding is a consequence of decreased mechanical stability of the alveolar capillary wall due to changes in the overlying alveolar epithelial cell. THERAP'*" Evaluation of any therapeutic approach in a disease of unpredictable course and unknown etiology is nearly impossible. Heiner has emphasized the relationship between IPH and milk allergy and believes that man), patients improve on a milk-free diet (13). This has not been a universal experience; however, too few patients have been studied from this aspect. Most authors report the use of steroids, but agree that they are of uncertain value. Matsaniotis et al. believe that steroids accelerate remissions and improve the immediate prognosis in acute exacerbations, but that long-term use neither prevents crises nor prolongs survival. Desferrioxamine has been reported to aid in mobilizing sequestered iron from hmg tissue, reversing some of the x-ray findings and aiding in the treat-

ment of the occasionally refractor)' iron deficiency anemia (14). In general, though, the treatment of a patient with I P H is supportive. Acute p u h n o n a r y hemorrhage and shock must be treated with transfusions, and symptomatic cyanosis must be treated with oxygen. T h e general debilitation and susceptibility of these patients to pneumonia may justify the use of antibiotics during exacerbations, but infection has not been a major complication, even terminally. If steroids are to be used, 2 mg./kg, prednisone or its equivalent should be used during the acute phase then tapered quickly as symptoms permit. If long-term steroid therapy seems advisable, an attempt at alternate-day dosage shoukl be made in order to minimize the side effects. Althougll I P H has been considered a rare disease, it is being diagnosed with increasing frequency, probably due to increased awareness. Prognosis is difficult and must remain guarded.

Pulmonary Manifestations of Histiocytosis X Eosinophilic granuloma, Schiiller-Christian disease and Letterer-Siwe disease are designations for a disorder sometimes called reticuloendotheliosis or histiocytosis X. T h e nomenclature is not as important as the awareness that the lung may be the principal or sole organ of im'olvement; it is useful, however, to note that the histologic expression of the disease may be identical in some of the cases called by any of the above names. INCIDENCE

A h h o u g h tlle condition was first recognized in children, and remains most frequent in tile younger age group, histiocytosis may occur at any age. Nine of the 40 patients described by Aver), et al. were over age 20 at the onset of symptoms (15). A series of 12 adults with hmg involvement was reported from tile Brompton Hospital by Lewis (16). Pulmonary changes are among the common findings in tile disease, noted in 10 of the 40 patients from Jolms Hopkins, and in 10 of the 52 patients reported froln Paris by Nezelof and Guibert (17). Lahey noted clinical or radiograpllic evidence of h m g disease in 35 of his 69 10

patients (18). The disease has been described more frequently in white than in Negro populations, somewhat more in males than females, and rarely within families. CLINICAL FINDINGS The disease may present in a variety of ways, including isolated bone lesions, diabetes insipidus, gum lesions, loose teeth, eczema or exophthalmos. Pulmonary manifestations are rarely the presenting ones, although at times they have been noted on routine chest films in asymptomatic individuals. Cough and dyspnea are the commonest symptoms. Chest pain may be related to the frequent complication of pneumothorax, or to an associated osteolytic lesion of a rib. Fever, anorexia, fatigue and weight loss are inconstant findings. Auscultatory changes are usually unimpressive. RADIOGRAPttIC FINDINGS The classic changes are diffuse, bilateral, and best described as nodular. A reticular pattern is evident, often with multiple radiolucencies, sometimes giving a honeycomb appearance. Superimposed suppurative disease may occur, giving areas of radiodensity. Pneumothoraces are commonly found. The hilar nodes are not nsually enlarged (Fig. 2). Very rarely, a discrete puhnonary nodule may have the histologic characteristics of eosinophilic granuloma. LABORATORY FINDINGS The hemograln is usually normal. Eosinophilia is rarely seen. Even though cholesterol may be accumulated in the histiocytes in the lesions, serum cholesterol levels are normal. Pulmonary function changes inclnde a significant reduction in vital capacity, reduction in diffusion capacity and no evidence of airway obstruction. Hypoxemia may be present in the severe forms of the disease; CO 2 retention is a late phenomenou.

Diagnosis usually depends on lung biopsy. When the lungs are the only organ involved, biopsy is essential. If there is .

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Fie,. 2.--This patient is a 3-year-old white male with a history of seborrhca from birth and a temporal bone defect at 16 months, when he also had exophthahnos. Systemic symptoms became evident at 2 years of age, when the pulmonary infiltrate appeared. Despite high doses of steroid, he died at 3 )'ears and 2 months of age. The lu,lgs grossly were firm, with an infiltrate of yellow tissue in all the septae. Histiocytes were the dominant cells. otber organ involvement, and radiographic findings in bones and hmgs are typical, the diagnosis may be made without biopsy. Grossly the lung may have a granular appearance, and nodules may be palpable. T o demonstrate lipoid changes the specimen obtained at biopsy should be 2-3 cm.2, and examined by routine frozen and paraffin sections. T h e changes are focal collections of eosinophils, lymphocytes, histiocytes and, sometimes, giant cells. T h e diagnostic cell is the histiocyte, with a pale, oval nucletts and pale or eosinophilic cytoplasm. Cholesterol crystals may be seen in the cytoplasm. Later in the disease, fibrosis and emphysema occur, often without eosinophilic infiltration. A proliferative endarteritis may he an early change (19). COURSE AND TIIERAPY Tile radiographic cbanges may be marked, even when tile symptoms are mild, and in this respect tile disorder resembles sarcoidosis. Other similarities include the possibility of spon12

taneous regression, response to steroids and associated diabetes insipidns. T h e y can be distinguished by tile rarity of hilar node involvement in histiocytosis, tile greater likelihood of lmeumothorax in histiocytosis and the positive Kveim skin test in sarcoid. Insufficient numbers of patients with puhnonary involvemeat in histiocytosis ltave been followed long enough to permit an over-all assessment of prognosis. Extensive lesions lmve been noted to disappear spontaneously, with no recurrence over man)' years. Resolution with steroid therapy has also been reported. On the other hand, visceral involvement, unlike skin and bone involvement, carries a serious prognosis, and death may occnr from pulmonary failure after a ftdminatlug course or up to 20 years after recognition of the lesion. Lahey noted that death occurred in almost 60% of his patients with pulmonary involvement, and was less likely when only the skeleton was involved. T h e treatment of the pulmonary lesions should be considered in tire context of tile extent of the disease in other organs, rate of progression of the pulmonary lesions and the symptomatology. Survival can be prolonged with antimetabolites or steroids. T h e effect of any form of therapy will be greatest if used at a relatively early stage of progressive disease. Prednisone, in full therapeutic doses, can be used until the maximal response is obtained, tlien the dosage decreased, preferably by alternate-day administration, to the minimal dose needed to prevent an exacerbation. Antimetabolites may be beneficial in some patients, and are indicated in the severely affected group. Vinblastine sulfate is such an agent, used in cltildren in doses of 0.2-0.3 mg./kg, in courses of eight to fifteen injections. Similarly, chlorambucil 0.2-0.3 mg./kg./day for 3 to 4 weeks may be useful. Both agents may cause leukopenia, and weekly white counts are indicated during the course of therapy. Even though the infiltrates are radiosensitive, it seems inappropriate to use a form of therapy that in itself may produce pulmonary fibrosis; therefore it is not recommended for the puhnonary lesions. 13

Congenital Pulmonary Lymphangiectasis Congenital puhnoimry lymphangiectasis, a rare disorder first described over 100 years ago by Virchow, has been reported in only about 25 infants. It is usually lethal in infancy, and diagnosed only on postmortem examination. Sometimes, however, it is compatible with longer life, and may even be asymptontatic (20, 21). CLINICAL FINDINGS In the nmjority of infants reported, respiratory distress was noted at birth and cyanosis was marked and persistent. T h e duration of life in such infants has usually ranged from a few minutes to 30 days. Very rarely symptoms abate, and survivals up to ,t years are known (22). Clfildren with asymptomatic pulmonary lymphangiectasis have usually had associated malformations of the lymphatic system, such as lymphangiomas of the extremities or intestinal lymphangiectasis. T h e pulmonary lesion has on occasion been recognized only after a routine chest film. T h e condition has been reported twice as commonly in males as in females, and usually after term birth. Other congenital malformations, partictdarly of the cardiovascular system, have been noted in more than half the cases coming to autopsy. RADIOGRAPttlC FEATURES

Tile hmgs are usually diffusely involved with a reticular pattern; sometimes the fissures are prominent. Hyperaeration is regularly noted and helps to distinguish the condition from hyaline membrane disease, with which it may be confused (Fig. 3). PATHOLOGV Grossly tile hmgs show thin-walled vesicles on their surfaces, and thickened, interlobnlar septae; they tend to be heavy and airless. T h e cut surface reveals a honeycomb pattern of irregularly shaped flukl-filled cysts which, on microscopic examination, are dilated lymphatic vessels lined by a 14

FIG. 3.--Anteroposterior and lateral chest films of a 5-year-old white male with lymphangioma of the arm and intestinal lymphangiectasis. He had no pulmonary symptoms; hmg function measurements were normal. Note tile reticular infiltrate and prominence of the fissure.. t h i n l a y e r of e l o n g a t e d e n d o t h e l i a l cells. T i l e s u r r o u n d i n g c o n n e c t i v e tissue is loose a n d e m b r y o n a l , a n d t h e p u l m o n a r y l ) a r e n c h y m a airless a n d u n d e r d e v e l o p e d (Fig. 4 ) . 15

Fw.. 4.--A 3.03-kg. female infant who required resuscitation at birth and remained deeply cyanotic through her 13 hours of life. Tile photomicrograph shows the greatly distended endothelial-lined l)mphatics, which contain a proteinaceous coagtflum (X50). PATttOGENESIS T h i s congenital m a l f o r m a t i o n presumably results from persistence of wide, fetal l y m p h trunks in the connective tissue septae of the hmg. T h e reason for tltis developmental defect a n d the c o m m o n l y associated cardiovascular and other lymphatic anomalies remains obscure. T h e disorder is not known to be familial.

TttERAP~" N o definitive therapy has been found.

Wilson-Mikity Syndrome As more attention has been focused on p r e m a t u r e infants, and more chest films obtained, it is not surprising that new syndromes have been identified. One of these was first reported in 1960 by Wilson and Mikity, and in recent years has borne their names (23). 16

INCIDENCE T h e disorder has been reported in widely separated centers in Europe anti North America. Mikity et al. estimate the incidence at 1:450 live births of premature infants (24). Apparently the condition is restricted to infants of less than 36 weeks gestational age, and it appears to be more frequent in those of very low birth weight. It has been noted in Negro and white infants of both sexes. CLINICAL FINDINGS No consistent abnormalities of pregnancy have been noted. Some infants may have some respiratory distress at birth, occasionally severe and thought to be hyaline lnembrane disease. Others may have no respiratory symptoms, and receive no added oxygen, but some weeks later have the insidious onset of cyanosis and a rapid respirator)' rate. Even those with early respiratory distress usually improve for a week or more before cyanosis and retractions reappear. On the whole, the symptoms increase over a 2- to 6-week interval, and may persist for several months. T h e infants characteristically appear in good general condition, gain weight and are active. T h e i r symptomatology is restricted to the hmg, and is characterized by a striking oxygen dependency. Fine tales and, sometimes, wheezing have been noted, but more commonly the breath sounds have a grating, sandpaper quality to them. As associated finding of interest in several reported series is a fractured rib. T h e etiology of the rib fracture has not been determined, and fractures in other bones have not been reported (25, 26). LABORATORY FINDINGS Exhaustive attempts to define an etiologic agent by laboratory studies during life and by postmortem examination of the hmgs have failed to unearth a causative organism. T h e association of E C H O 19 virus was noted in one infant, but has not been found in others. Serologic studies for respiratory viruses, routine blood studies anti sweat-chloride determinations have all been negative. Definite abnormalities of pulmonary func17

tion have been documented, mostly by Swyer et al. (27), who report CO o retention, substantial right-to-left shunts, a reduction in hmg compliance and an increase in airway resistance. Cardiovascular function is usually normal, except very late in the illness when cor pulmonale may occur. RADIOGRAPHIC FINDINGS In the first weeks of life, the chest film may be normal. Early abnormalities are a bilateral, coarse, streaky infiltrate aDd, later, cystic lesions in both hmgs. T h e walls of the cysts average 0.5-1 ram. in thickness, and the cysts themselves 1-4 ram. in diameter. Later the cysts enlarge and coalesce, and overexpanded hyperlucent lungs are seen. Resolution of these changes lags behind clinical improvement; complete radiographic clearing may not occur until the patient is 2 years of age (Fig. 5). PATHOLOGIC FINDINGS A histologic similarity to interstitial fibrosis was noted by Wilson and Mikity in their original article, but since then major differences have become apparent. T h e excised lung, inflated, has a characteristic hobnail appearance on the surface, as though the terminal airspaces are overdistended and the restricting fibrous septae are prominent. T h e lung contains more air per gram of tissue than would be expected, unlike interstitial fibrosis. Histologically, there are no pathognomonic features. Some of the alveolar septae appear thick; however, no increase in fibrotic tissue is found. Electron microscope studies have not uncovered any characteristic lesion (27). It is thought that an arrest in lung development may have occurred, with an inadequate alveolarcapillary interface to support gas exchange in the growing infant. TREAT.MENT Supportive measures only can be reconunended at this time. It is of critical importance to use only as nmch added oxygen as needed to overcome cyanosis, or to maintain the arterial 18

FI6.5.--1300-gram white female, born after a 7-month gestation, had some respiratory distress in the first days of life, which improved markedly by 2 weeks of age, when her chest fibn was normal. Tiffs film was taken at 2 months of age when she had tachypnea, cyanosis out of oxygen and carbon dioxide retention. She improved over the subsequent months, with markexl radiographic clearing by 8 months of age. These findings are illustrative of the Wilson-Mikity syndrome. b l o o d tensions in a safe r a n g e , p r e s u m a b l y 60-80 m m . Hg. A t t e m p t s to a l t e r the course of t h e disease by d i g i t a l i z a t i o n , use of steroids a n d a n t i b i o t i c s h a v e b e e n fruitless.

Infantile Lobar Emphysema ETIOLOGY L o b a r e m p h y s e m a in i n f a n c y results f r o m i n a b i l i t y to deflate o n e or m o r e lobes because of a n a b n o r m a l i t y t h a t is e i t h e r c o n g e n i t a l o r was a c q n i r e d in tile first days of life. T h e r e a r e f o u r s e p a r a t e e t i o l o g i c categories: (1) lack of elastic recoil; (2) lack of b r o n c h i a l c a r t i l a g e , r e s u I t i n g in a c o l l a p s e o n e x p i r a t i o n ; (3) i n t r i n s i c o b s t r u c t i o n , such as b r o n c h i a l stenosis, m u c o s a l web o r m u c o u s p l u g , a n d (4) e x t r i n s i c ob19

struction, such as that produced by an aberrant vessel, an enlarged lymph node, a bronchogenic cyst or kinking of a bronchus. T h e most common finding in the excised lobes of infants with lobar emphysema is a lack of elastic recoil, without any evidence of an anatomic obstruction. In a review of 113 cases by Hendren and McKee, 50% of the infants fell in this category (28). Another finding, second in frequency, is a localized or widespread deficiency in the bronchial cartilage, demonstrated in 25% of the lobes. Identifiable causes of intrinsic or extrinsic bronchial obstruction are relatively rare. Opsahl and Berman in 1962 found only 31 cases of bronchogenic cyst in the literature and added one of their own (29). About two-thirds of these cases were diagnosed only at autopsy. Isolated cases of bronchial compression by an aberrant artery, an aneurysmal vein, or, more frequently, by a ductus arteriosus have been reported. Leape and Longino reported three cases of localized bronchial stenosis treated by lobectomy (30). Chang et al. reported successful treatment of bronchial stenosis by resection of the stenotic area, titus sparing the lobe (31). Twisting and kinking of a bronchus due to a defect in the mediastinum, lymph node compression or invasion of a bronchus anti r e d u n d a n t mucosal folds have been reported as mechanisms causing lobar emphysema. Inspissated mucous secretions have been suggested as a possible etiology. Murray et al. reported successful treatment of tension emphysema in the right upper lobe by removal of a mucus plug front the right main-stem bronchus through a bronchotomy (32). CLINICAL t~IANIFESTATIONS

About one-half of these infants have symptoms in the first days of life; the rest present in the first weeks. Expiratory wheezing and generalized decrease in breath sonnds are usually found, and localized hyperresonance over the affected area can occasionally be detected. R a d i o ~ a p h i c changes are striking. T h e hyperinflated lobe compresses the ipsilateral hmg, often so much tlmt the entire hemithorax appears radiolucent. T h e r e is accompanying mediastinal shift with compression of 20

tile contralateral h m g and, often, herniation of the distended lobe across the midline. T h e left u p p e r and the right middle lobes are most often involved, and the invoh'ement can be bilateral (30). It is important to distinguish between congenital lobar emphysema, pneumothorax, and atelectasis with compensator)' emphysema. In p n e u m o t h o r a x there are no vascular markings in the radiolucent area, and usually the collapsed h m g can be seen near the hilum. These h m g markings also differentiate lobar emphysema from localized cystic disease or a large, solitary bronchial cyst. With compensatory emphysema the mediastinum will be seen on fluoroscopy to shift toward the intlated side with expiration, whereas with obstructive emphysema it shifts in the opposite direction. Auscultation may also aid in distinguishing between the two, since breath sounds will be absent in the affected area of obstructive emphysema and present in compensatory emphysema. Progression of symptoms is determined by the nature of the lesion. A minority of infants have respiratory distress immediately after birth, and their clinical condition deteriorates because of rapidly developing tension phenomena. Evaluation and management of these patients constitutes a surgical emergency. More usually, though, recurrent symptoms of respiratory distress and infection during the first weeks of life lead to a chest x-ray film in which a hyperinflated lobe is seen and the diagnosis suspected. ~IANAGEMENT

W h e n an infant presents with overinllation of a lobe of tile hmg, the first concern is whether the child is symptomatic and whether the symptoms are progressive. A severely ill infant should be considered an emergency, and constant attendance and the immediate pursuit of an anatomic diagnosis is mandatory. Delineation of the anatomic lesion may be accomplished by barium swallow, bronchoscopy or bronchography. Barium swallow is often particularly helpful in outlining a subcarinal bronchogenic cyst (29). If a vascular anomaly is suspected, angiography often demonstrates the specific lesion. W h e n 21

bronchoscopy is considered advisable, it must be clone in an operating room where immediate thoracotomy can be clone if necessary. Once tile diagnosis has been confirmed and symptoms are progressive, thoracotomy is usually indicated. Korngold and Baker (33) reported permanent cure following needle aspiration of a lobe in two of their patients, but this approach has been widely criticized (30). If a localized anatomic lesion is known prior to thoracotomy, specific correction can be attempted. Division or reronting of an aberrant vessel, resection of a stenotic bronchial se~nent and removal of a mucosal web or mucus ping are procedures that can result in permanent cm-e without unnecessarily sacrificing a lobe. The prognosis is generally good. When done by an experienced team of pediatric surgeons and anesthesiologists, lobectomy in infancy has a low mortality. The patient usually is markedly improved following surgery, and convalescence is uncomplicated. Leape and Longino had no mortality or significant morbidity in 21 cases of lobectomy for infantile lobar emphysema (30). Recovery is not uniformly complete or permanent, however. Some residual pulmonary disability may persist even after lobectomy in "idiopathic" infantile lobar emphysema. DeMuch and Sloan reported long-term follow-up with pulmonary function studies in 6 patients (34). Two of these patients still had diminished exercise tolerance and evidence of residual disease on physical examination several years after surgical therapy. Reduction in vital capacity and diffusing capacity was comparable to the amount of tissue removed in all cases, and maximum breathing capacity was significantly diminished in 4 of these patients.

Idiopathic Unilateral Hyperlucent Lung In 1953 Swyer and James reported a case of unilateral puhnonary emphysema that could not be explained on the basis of any congenital abnormality of tile bronchus, tile hmgs or surrounding structures (35). Their patient, age 6, had a history of recurrent pneumonia and bronchitis from infancy. The roentgenographic changes included radiolucency of the right hmg, with some loss of volume, reduced diaphragmatic 22

excnrsion on the right and, on bronchograplly, poor tilling of peripheral bronchi. A pneumonectonly was performed, with identification of a normal pulmonary artery, despite its having been thought to be hypoplastic on angiography. On microscopic examination, obliteration of peripheral capillary networks and some chronic inflammation was found. "File authors concluded that pulmonary hypoperfilsion and radiolucency were secondary to widespread acquired tmilateral hmg disease. One )'ear later MacLeod (36) reported nine similar cases in adults. Since then many otlters have appeared. Reid et al. present persuasive evidence of the development of this syndrome following measles in two previously normal boys (37), and Berdon et al. report a case following radiation therapy (38). Unilateral hyperlucent h m g is both a physiologic anti radiographic syndrome. There is expiratory obstruction with a decrease in ventilation, diffusing capacity, oxygen consumption and perfusion of the affected lung. Factors influencing perfusion and ventilation may be well balanced, so that shunting of venous blood through underventilated areas of lung is not usually seen (39). Radiographically there is a characteristic unilateral hyperlucency with normal or slightly small size of the affected lung, constant lung size tltrouglmut the respiratory cycle, small hilum and diminished vascular markings on that side, and an unusual failure of peripheral bronchi to fill with contrast medium (40). T h e case of a 5-year-old child seen at the Jolms Hopkins Hospital illustrates tlfis disease. This child presented with a history of recurrent pneumonia and persistent atelectasis of tlte lower lobe of tire left hmg. Bronchography showed tubtdar and sacctdar bronchiectasis of that lobe witlt failure to fill the upper lobe bronchi. At lobectomy, the left pulmonary artery and branches were of normal caliber. T h e persistence of unilateral hypoventilation following surgical intervention led to pulmonary arteriography and hmg scan (Figs. 6 and 7). These films demonstrated the striking hypoperfusion of the affected side e3"en after the bronchiectatic lobe had been removed. In retrospect, chest films taken preoperatively showed a hyperlucent left upper lobe. T h e observation of normal vessels at Operation suggested that the vascular obliterative lesion was in the smaller vessels. 23

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Fit;,. 6.--d, a n t e r o p o s t e r i o r chest fihn of a 5-year-old N e g r o f e m a l e w i t h a hyperh~cent left u p p e r lobe. N o t e t h e loss of v o l u m e a n d opacification of the left l o w e r lobe b e h i n d t h e heart. B, a l u n g scan w i t h mact~o-aggregated a l b u m e n tagged w i t h I131 shows t h e a b s e n c e of p e r f u s i o n of t h e left l u n g . 24

Fl(;. 7.--A, on bronchograplly, the left lower lobe shows extensive saccular and t u b u l a r bronchiectasis. T h e r e was no filling of tile left u p p e r lobe with contrast medium. B, an angiogram showing diminished perfusion of tile left lung, with p r o m i n e n t vessels on the right. 25

Agenesis, or hypoplasia of the main or lobar branches of tire pulmonary artery, usually restflts in hypoplasia of the lung or lobe, often with recurrent infection and bronchiectasis (41). Unilateral hyperlucent lung can occur, however, as a result of congenital pulmonary artery hypoplasia (42). These cases may be indistinguishable from the Swyer-James or MacLeod syndrome. In total agenesis of a main branclt of the puhnonary artery, however, angiograplty shows a smooth, uninterrupted vascular arc to one side. T h e ptflmonary arteriogram of an idiopathic hyperlucent lung usually shows diminished flow to the affected side and, on thoracotomy, a normal-sized vessel is seen. Unilateral hyt~erlucent h m g is not a disease entity but a radiograplfic finding common to several clinical syndromes. Careful evaluation can usually lead to tlte diagnosis of an anatomic lesion or point to the etiologic mechanisms, and permit optimum management.

Pneumocystis carinil Pneumonia

Pneumocystis carinii pneumonitis is a subacute and chronic lmlmonary infection caused by an organism of low virulence. Nearly all the cases reported have occurred eitlter in persons with immtmologic deficiencies or among newborn and premature infants (43, 't4). ETIOLOGY A ubiquitous parasite, presmnably a protozoan, P. carinii, has been identified worldwide. Although it appears to have a peculiar predilection for the pulmonary alveolar spaces and surrounding supporting structures, all attempts at in vitro isolation have been unsnccessful. No pure antigenic strain for serologic stndies is available. T h e mode of transmission of the parasite, its metabolic requirements and its morphology outside the h m g are unknown. Tile infection is widespread in animals, including rats, mice, rabbits, gtfinea pigs, dogs, cats, sheep, goats and monkeys. Infection by P. carinii has occurred in epidemic form among premature and newborn infants maintained in close contact with one another. More tlmn 700 cases were reported in Switz26

erland between 1941 and 1948, but no epidemics have been described in North America. In these infants, and in the few healthy adults in whom infection has occurred, exposure to large numbers of organisms appears to be a factor. T h e incubation period is thought to be 30-60 days. Most of the isolated cases of P. carinii pneumonia lmve occurred in patients with leukemia, lymphoma or immnnologic disease. Cytomegalic inclusion disease, disseminated tuberculosis, cryptococcosis and some bacterial infections also appear to predispose to infection with tiffs agent. T h u s it seems that infection depends either on close contact with infected individuals (i.e., a large inoctflum) or on some defect in host resistance.

CLINICAL FEATURES In premature infants, tile illness has been recognized most commonly between the ninth and sixteenth weeks, but the paucity of clinical findings early in the course of closely documented infections suggests tlmt the disease may be present for some time before it is clinically recognizable. T h e outstanding physical abnormalities are perioral cyanosis, cough, tachypnea and retractions. Auscultatory findings are minimal. Fever may be present but is usually intermittent. T h e r e are no clinical features to distinguish pneumonitis associated with pneumocystis infection from other forms of pneumonitis, anti this fact slmuld be considered i n t h e differential diagnosis of subacute or chronic pneumonia in infants, in persons with immunologic disorders or debilitating disease, or in close contacts of persons with known pneumocystis pneumonia. T h e clinical course is usually 4-6 weeks.

PxADIOGRAPItlC FINDINGS Initially, perillilar involvement is tile customary finding witla progression to a fine, granular, diffuse parenchymal infiltrate. Areas of consolidation or atelectasis may appear. Late in the disease the lung fields appear foamy with isolated areas of overdistention. Hilar adenopathy is found only when related to an associated disease. Pleural reaction and effusion 27

are rare, whereas pneumothorax and pneumomediastintun are common complications (45). LABORATORY FINDINGS

Laboratory findings of pulmonary dysfunction are usually out of proportion to the clinical signs. Arterial Po 2 is usually decreased, as is diffusing capacity. In adults, the Pco 2 is decreased and the pH is elevated, except in the terminal phases. Infants usually have a normal to elevated Pco 2 and a reduced pH. Vital capacity and tidal vohune are decreased. T h e h e m o ~ a m is usually normal. T h e demonstration of pnenmocystis cysts is necessary for precise clinical diagnosis. A few investigators have been able to demonstrate the presence of the cysts in sputum, but either needle aspiration or open h m g biopsy has proved more rewarding. T h e cysts, usually ,t-I0~ in diameter, are best seen with silver impregnation technics, a h h o u g h they can be observed with Giemsa or Gram-Weigert stains. On histologic examination the terminal airspaces are distended, with a spongy exudate, in tile midst of which the organism may be found. Mononuclear cells are usually present in the septae. Immunoglobulin determinations are helpful because of the high correlation between immunologic disorders and pneumocystis infections. PROGNOSIS AND TREATMENT

Because of the difficulty in establishing an accurate diagnosis, an adequate evaluation or prognosis cannot be made. Moreover, this problem is compounded by the nature of the predisposing disease process and the difficulty, in many cases, of determining whether the pneumonitis is caused by pneumocystis or by an underlying disease process. Estimates of mortality in newborns and in premature infants affected range from 66 to 100~o without therapy. Pentamidine isethionate, 4 mg./kg./day, intramuscularly in a single dose for 12-14 days is now recommended as a therapeutic agent in this disease. Signs of folic acid deficiency must be watched for since this is the major complication of therapy. There have been reports of dramatically successful treatment in adults, and mortality in one pediatric series was said to have fallen from 66 to 9%. 28

Melioldosis Melioidosis is a fulminating and often lethal infectious disease first described in 1912 and deriving its name from its similarity to glanders, an infection of horses. Most of the more than 300 cases described thus far occurred in the endemic areas of Ceylon, Burma, Malaya, T h a i l a n d or Vietnam (46). T h e recent exposure of large numbers of Americans to these geogxaphic areas, an incubation period that may extend for years and the often fatal outcome if this disease is inadequately treated, make knowledge of melioidosis imperative for all physicians (47, 48). ETIOLOGY Melioidosis is caused by a motile gram-negative pleomorphic bacillus, Pseudomonas pseudomallei. In endemic areas this organism is found to infect rodents. H u m a n infection is thought to occur either by accidental inoculation of contaminated rat excreta or, perhaps, by the ingestion of contaminated food. No cases of lauman-to-human transmission are known. CLINICAL COURSE Melioidosis may present as an acute, subacute or chronic illness in which the severity of the illness seems out of proportion to the physical findings. T h e incubation period usually is between 2 and 8 days, although cases have been described in which clinical disease first appeared years after the patient had left an endemic area. Pulmonary manifestations of melioidosis predominate. T h e patient usually presents with a short history of fever, malaise, chills and a cough productive of scanty sputum. Hemoptysis is uncommon, and weight loss occurs in tile less acute cases. Physical findings suggest pneumonitis. If untreated, respiratory distress ensues and death occurs from respiratory failure. Septicemia occurs uncommonly, even in untreated patients. P u h u o n a r y involvement is seen only as a terminal episode in the septicemic form of melioidosis. T h e hematogenous dissemination of the organisms results in abscess formation in all organs, but high fever and signs of circulatory collapse are the 29

usual positive pllysical findings. These manifestations of melioidosis are indistinguishable from the septicemic fornt of plague and from other causes of overwhehning septicemia. A few cases of chronic osteomyelitis caused by P. pseudomallei have been described, occurring in patients with extremity wounds. Chronic abscesses in oilier organs may be seen. LABORATORY DATA T h e recovery and isolation of P. [oseudomallei are the only definitive means of establishing the diagnosis of melioidosis. T h e organism can be recovered from the sputum in about 80~o of patients with pneumonia or hmg abscess. Blood cultures are positive only in the septicemic form, but isolation is usttally too late to be of assistance in tlterapy. T h e organism grows readily on most media. Small white nmcoid colonies are formed on blood agar; biochemical reactions establish definitive identification (see accompanying table). T h e use of nutrient agar with 3~o glycerin, crystal violet, penicillin and polymyxin allows for more rapid diagnosis. After 72 hours the colonies are purple-stained, with a characteristic wrinkled irregular appearance. Serologic testing provides a helpful adjunct to diagnosis, ahltough approximately I~o of persons transiently in endemic areas and 7-10~o of the population in these areas ltave positive serologic reactions. A hemagghltination titer of 1:40 or above or a complement fixation reaction of 1:4 is considered significant. Unlike tile case in some other infections diseases, serologic titers may remain high for )'ears after the initial infection. A normocllromic normocytic anemia is often seen in association with melioidosis. Other laboratory tests are not helpful. RADIOGRAPtIIG FINDINGS Tile pneumonic involvement of melioidosis is confined to the upper lobes in more than 95% of cases (47). T w o patterns predominate. Most commonly the radiographic pattern consists of irregular, small (4-10 ram.) nodular densities that tend to coalesce or cavitate with progression of the disease (Fig. 8). An nnderlying lobar pattern may be evident. Hilar adenopathy and pleural effusion are tmcommon. 30

DIFFERENTIATION OF ORGANISMS BY BIOCIIEMICAL REACTIONS KLIGLFR$ IRON A G A R GEI-~TIN LACTOSE SUCROSE SLANT[BUTr LIQUEFACTION FERXlENfATION FERMENTATION

Pseudomonas pseudomallei Pseudomonas aerogenosa Aerobacter aerogenes

sl. acid,/no change

positive

acid

acid

sl. acid/no change

positive

negative

negative

aeid,/acid & gas Alkaligenes fecalis alkaline/no change

negative negative

acid & gas negative

variable negative

FIG. 8.--A, 30-year-old male with fever, malaise, cough of 5 days' duration. Note the lobar infiltrate with nodular densities. B, complete clearing after 6 weeks of tetracyclii:e and sttlfonanlide therapy.

31

Single or multiple cavitary lesions may be the sole abnormal x-ray finding (Fig. 9). These lesions are indistinguishable from the lesions o[ tuberculosis, and several patients tlmught initially to have tuberculosis have had positive sputnm cnltures for P. pseudomallei (49). PATHOLOGY T h e striking features of tile lesions are marked tissue necrosis with cellnlar karyorrhexis. T h e abscesses have a rubbery consistency, and no caseation is seen. Although tile lesions have been described as grannlomas and epithelioid cells are sometimes seen at tile periphery, they are not granulomatous in the classic sense. Rather, one sees the nonspecific fibroblastic organization fouml in abscess formation from an), cause. TttERAPY AND PROGNOSIS I11 vitro studies of tile antibiotic sensitivities of P. pseudomallei have correlated well with clinical response. Tile organism is usually sensitive only to tetracycline, chloromycetin, sulfonamides, novobiocin and kanamycin, ahhottgh specific sensitivity tests are indicated in each case. Fit;. 9.--Cavitary lesions in right upper lobe of 32-)ear-old male with fever, cough. PPD negative. Sputunl, titers positive for P. pseudomallei.

32

Tetracycline 2-3 Gm./day appears to be the most effective therapeutic agent. It is usually used in combination with chloromycetin a n d / o r kanamycin in the more serious cases and with stflfonamide in the milder cases. A minimum of 30 days, and more commonly 60-90 days, of therapy is indicated. T h e r a p y sltould be continued tmtil the x-ray film is clear and the sputum culture is negative. Sputtnn cultures should be obtained for a least 1 )'ear after the cessation of antibiotic therapy, since a n u m b e r of patients will remain sputum positive. A small percentage may suffer clinical relapse. W i t h appropriate therapy the mortality of melioidosis pneumonia will approach zero; the mortality of the septicemic form has been reduced to 5 0 ~ . This reduction in mortality will be attained, however, only if a high dega'ee of clinical suspicion is maintained toward any person previously in an endemic area who presents with upper lobe pneumonia or cavitary disease.

Oxygen Toxicity Shortly after the identification of oxygen as an element in 1785, Lavoisier described the lethal p u l m o n a r y effects of excess oxygen environments in guinea pigs. Subsequent experimental efforts in man and animals confirmed that oxygen toxicity occurs in all species. It is now clear that clinically significant pulmonary damage c a n and does occur in man from the administration of excess oxygen. T h e degree and nature of tlte pulmonary injury are dependent on the a m o u n t of oxygen delivered anti the time over wlfich it is administered. ACUTE PULMONARY OXYGEN TOXICITY T h e administration of oxygen in a concentration exceeding 90% at one atmosphere pressure has eventually led to death in all animal species thus far studied, and significant pulmonary changes have been noted. T h e time to onset of symptoms or death varies among species and among individual animals within a species, but, despite such variability, there are common clinical and pathologic findings. In many animals, pulmonary symptoms will occnr at partial pressures of oxygen as low as 600 mln. Hg. 33

Respirator), distress begins witltin hours to days after the onset of exposure, and is characterized by rapid, shallow breathing and, uhimately, cyanosis in oxygen. Respiratory acidosis eventually occurs. On postmortem examination the lungs are found to be heavy and hemorrhagic in appearance, and surface blebs and p n e u m o t h o r a x are often noted. T h e lesion appears spotty in distribution. Foamy effluent is noted in the tracheobronchial tree. Microscopically, edema is seen with appropriate fixation. Lymphatic dilatation and vascular engorgement are also present. Hyaline membranes may occur. Electron microscopy reveals defects in the alveolar capillary wall. Surface tension measurements of hmg washings or extracts have shown abnormalities in some species, but not in all. Exposure of human volunteers to high concentrations of oxygen for short periods usually results in shortness of breath and substernal pain in 12-36 hours (50). Vital capacity and diffusing capacity are decreased, consistent with early pulmonary edema. Despite the abundant evidence that oxygen can be toxic to hmgs, it is often used in excessive concentrations .in humans. For example, a recent review of p u h n o n a r y complications of burns reveals a significant n u m b e r of patients with unexplained pulmonary edema, apparently unrelated to fluid overload and found only in persons receiving high concentrations of oxygen via a tracheostomy (51). Inadvertent exposure to hyperoxic environments may occur when positive pressure ventilators requiring pressurized gas for activation are used in settings wltere compressed air is unavailable and oxygen is used instead. T h e catastrophic consequences of such exposure are illustrated below. A 17-year-old Negro female with known myasthenia gravis had the sudden onset of generalized weakness. On admission to the hospital she was noted to have significant paralysis, and because she had difficulty in handling secretions and shallow respirations, a tracheostomy was performed. Chest x-ray and hemograrn were normal. The patient was placed on assisted ventilation with compressed oxygen powering the respirator. 34

Eighteen bours after the start of assisted ventilation she was noted to have bubbling rales and pink copious tracheal secretions. Although her generalized weakness had regressed, she was unable to ventilate without assistance. Roentgenograms revealed changes suggestive of pulmonary edema (Fig. 10). Cyanosis developed and became progressive. Death occurred after 96 hours of assisted ventilation. Postmortem examination of the lungs revealed pulmonary hemorrhage and edema and hyaline membranes (Fig. 11). I n summary, acute oxygen toxicity mnst be suspected when a patient receiving high concentrations of oxygen develops clinically evident pulmonary edema. T h e differential diagnosis includes all other causes of p u l m o n a r y edema and interstitial pnetnnonia. Once the edema is manifest, there is no effective therapy, although reduction in the a m o u n t of inspired oxygen to the minimal a m o u n t needed to maintain arterial tensions of 50-60 mm. H g is in order. Fie. 10.--Roentgenogram of 17-year-old Negro female with myasthenia gravis treated with a respirator and over 80% oxygen. The fluffy infiltrates are consistent with ptthnonary edema. Note normal heart size.

35

FI6. ll.--Photomicrograph of lung (X200) of patient in Figure 10. Note the increase in interstitial cellularity, atelectasis and the presence of hyaline membranes. The overdistended proximal air space is filled with a proteinaceous material. CItRONIC PULMONARY OXYGEN TOXICITY Although exposure to more titan 90% oxygen at one atmosphere leads to puhnonary edema and death within a few days, a lesser degree of hyperoxia may result in a different clinical and pathologic pattern. Rhesus monkeys, lambs and rats have been maintained in 50-80% oxygen for periods u p to 30 days (52, 53). Initially, some of the animals die and show the pathologic pattern of acute pulmonary oxygen toxicity. T h e survivors show pro~essively less respiratory distress and, by 2 weeks after exposure, many appear clinically normal. Weight gain and growth do not occur at normal rates, lVhen removed suddenly from oxygen, all animals show evidence of respiratory distress and cyanosis. U p o n death or sacrifice, the lungs are usually well aerated, but increased in weight. Lung volumes are reduced. Microscopic examination reveals variable amounts of proliferation and hypertrophy of the interstitial pulmonary tissue and of the alveolar lining layer. Collagenous and reticular fibers are increased. Lymphocytes and fibroblasts contribute to the septal thickness. Edema is mini36

F~c,. 12.--A, roentgenogram of 860-gram Negro male with respirator}" distress. T h e bilateral air bronchograms and diffuse granularity are consistent with hyaline membrane disease. B, after 27 days of respirator-oxygen therapy, there was marked deterioration in the chest (x-ray), characterized by extensive bilateral infiltration, multiple small cystic areas, atelectasis and cardiomegaly. Tracheal cultures were negative.

37

mni. Squamous metaplasia of the bronchial epithelium may occur. In tile few animals who have snrvived and have been weaned from oxygen, the cltange has been less than in those sacrificed during exposure. A proliferative p u l m o n a r y lesion has been described in adults with a variety of illnesses, all of w h o m received high concentrations of oxygen and artificial respiration (54). T h i s lesion, also called b r o n c h o p u h n o n a r y dysplasia, was noted by Northway, Rosan and Porter in infants with hyaline membrane disease treated in the same m a n n e r (55). The patient was the product of a 32-week gestation. Birth weight was 860 Gm., length 36 cm. He cried and breathed spontaneously, but retractions were noted at 10 rain. Because of Pco2 over 90 ram. Hg and Poe below 40, he was intubated and placed on a volume-controlled ventilator. X-ray revealed a reticulogranular pattern with bilateral air bronchograms. Intravenous fluids, penicillin and kanamycin were administered. He required 60-80% oxygen for the first 3 days. By day 4 the roentgenogram showed clearing. (Between day 6 to the time of death, the oxygen administered was 30-60%.) However, lie developed increasing radiographic signs of bronchopulmonary dysplasia, could not be weaned from the respirator and needed increasing respirator pressures to maintain adequate ventilation (Fig. 12). Tracheal cultures were negative. He died after developing severe hypoxia on the 45th day. Postmortem exanaination of the lungs revealed thickening septae, alveolar hyperplasia and bronchiolar metaplasia (Fig. 13). T h e patltogenesis of the lesion seen in infants who survive hyaline m e m b r a n e disease b u t are m a i n t a i n e d for weeks on respirators with high inspired oxygen remains tmclear. I t is possible tltat the late stage of healing hyaline m e m b r a n e disease could be a proliferative p u l m o n a r y lesion, ahltough the majority of infants recovering front this illness have normal hmgs. It has been suggested that the respirator or prolonged endotracheal intubation m i g h t be at fault. Experience with adults treated with respirators witltout added oxygen would lead one to d o u b t tltis tlteory. Moreover, short-term experiments in animals ltave shown no evidence of damage from the respirator itself (56, 57). T h e striking similarity between the lungs of animals exposed to oxygen over long periods and the hmgs of infants 38

~

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Flo. 13.--A, photomicrograph of lung (XIS0) of infant with hyaline membrane disease who was treated with a respirator and high oxygen for 45 days. Normal lung architecture is obliterated by hypertrophy of alveolar lining cells and interstitial tissue. B, section through bronchus o[ patient in A. Note the marked squamous metaplasia (XI50).

39

and adults with " b r o n c h o p u l m o n a r y dysplasia" suggests, b u t does not prove, that excess oxygen is the pathogenic agent. Further studies of patients with this lesion and careful docum e n t a t i o n of the a m o u n t of oxygen administered are indicated.

CO.Xf~XIENT A complicated situation faces the clinician who wants to administer oxygen to his hypoxic patient. Clearly, oxygen can be lifesaving when arterial oxygen tensions are low; equally clearly, excessive oxygen administration can cause p u l m o n a r y lesions in normal hmgs and presumably aggravate underlying p u l m o n a r y disease. T h e obvious question then is, W h a t concentrations are safe? Unfortunately, no simple answer is available. Susceptibility to oxygen poisoning appears to be related to a host of underlying factors, inclnding metabolic rate, activity of the atttonomic nervons system and drugs (58). In experimenFiG. 14.--Average time of onset of symptoms as function of partial pressure of inspired oxygen. Note that the time of onset of symptoms increases as the partial pressure of inspired oxygen increases. (Modified from data collected by XVelch, B. E., et al.: Fed. Proc. 22:1053, 1963.) 228( z

IR~

152(

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40

IN HOURS

tal animals there has been wide i n d i v i d u a l variation in susceptibility to p u l m o n a r y oxygen toxicity. T i l e onset of symptoms in h u m a n subjects, however, is d e p e n d e n t on the partial pressure of inspired oxygen (59) (Fig. 14). Lastly, the p u l m o n a r y i n j u r y appears to be i n d e p e n d e n t of the arterial P o 2. Stndies o n h u m a n volunteers show only m i n i m a l symptoms after 30 days in an e n v i r o n m e n t of 4 0 % oxygen; p r e s u m a b l y this is a safe level (59). W h e n h i g h e r m i x t u r e s are r e q u i r e d in o r d e r to m a i n t a i n arterial o x y g e n tensions at 60 mm. Hg, careful m o n i t o r i n g of arterial o x y g e n is indicated, so that the least a m o u n t of o x y g e n r e q u i r e d is administered. I n clinical situations tlte m a j o r p r o b l e m is the t e n d e n c y to use o x y g e n as a vehicle to generate mist or to provide humidification for a tracheostomy. T h e inspired m i x t u r e s as c o m m o n l y used m a y easily be 6 0 - 7 0 % oxygen, a level well tolerated by some b u t capable of p r o d u c i n g p u l m o n a r y e d e m a a n d the proliferative lesion of c h r o n i c p u l m o n a r y oxygen toxicity in animals a n d p r e s u m a b l y in m a n . O x y g e n should be a d d e d to the g r o w i n g list of agents that can be categorized as lifesaving in a p p r o p r i a t e doses a n d lethal in i n a p p r o p r i a t e ones. REFERENCES 1. Soergel, K. It., and Sommers, $. C.: Idiopathic pulmonary hemosiderosis and related syndromes, Am. J. Med. 32:499, 1962. 2. Matsaniotis, N., Karpouzas, J., Apostolopoulou, E., and Messaritakis, J.: Idiopathic pulmonary hemosiderosis in children, Arch. Dis. Childhood 43:307, 1968. 3. Hamilton, H. E., Sheets, R. F., and Evans, T. C.: Erythrocyte destruction in the lungs as the major cause for anemia in primary pulmonary hemosiderosis, Proc. Central Soc. Clin. Res. 33:44, 1960. 4. Lillie, R. D.: Histopathologic Technic and Practical Histochemist~ (3d ed.; New York: McGraw-Hill Book Company, 1965), p. 407. 5. Koss, L. G.: Diagnostic Cytology (2d ed.; Philadelphia: J. B. Lippincott Company, 1968), p. 323. 6. Repetto, G., Lisboa, C., Emparanza, E., Ferretti, R., Neira, M., Etchart, M., and Meneghello, J.: Idiopathic pulmonary hemosiderosis. Clinical, radiological, and respiratory function studies, Pediatrics 40:24, 1967. 7. Karlish, A. J., and Hemsted, E. H.: Idiopathic pulmonary hemosidexosis, Am. Rev. Resp. Dis. 90:467, 1964. 8. Samuels, M. L., IIowe, C. D., and Butler, J.: Idiopathic puhnonary hemosiderosis, Am. Rev. Resp. Dis. 92:479, 1964.

9. Buerger, L., and Hathaway, J.: Idiopathic pulmonary hemosiderosis with allergic pulmonary vasculitis, Thorax 19:311, 1964. 10. Goodpasture, E. W.: Tile significance of certain pulmonary lesions in relation to the etiology of influenza, Am. J. M. Sc. 158:863, 1919. I1. Sprecace, G. A.: Idiopathic pulmonary hemosiderosis, Am. Rev. Resp. Dis. 88:330, 1963 12. Soergel, K. H., and Sommers, S. C.: The alveolar epithelial lesion of idiopathic pulmonary hemosiderosis, Am. Rev. Resp. Dis. 85:540, 1962. 13. Heiner, D. C.: Pulmonary Hemosiderosis, in Disorders o[ the Respiratory Tract in Children (E. L. Kendig, ed.) (Philadelphia: W. B. Saunders Company, 1967). 14. Walsh, J. R., Mass, R. E., Smith, F. W., and Lange, V.: Desferrioxamine effect on iron excretion in hemachromatosis, Arch. Int. Med. 113:435, 1964. 15. Avery, M. E., MeAfee, J. G., and Guild, H. G.: The course and prognosis of reticuloendotheliosis (eosinophilic granuloma, Schiiller-Christian disease, and Letterer-Siwe disease), Am. J. Med. 22:636, 1957. 16. Lewis, J. G.: Eosinophilic granuloma and its variants, with special reference to lung invoh'ement, Quart. J. Med. 33:337, 1964. 17. Nezelof, C., and Guibert, C.: L'Histiocytose X Nosologie et pronostic, Arch. fran~, p~diat. 20:1063, 1963. 18. Lahey, M. E.: Prognosis in reticuloendotheliosis in children, J. Pediat. 60:664, 1962. 19. Williams, A. W., Dunnington, W. G., and Berte, S. J.: Pulmonary eosinophilic granuloma: A clinical and pathologic discussion, Ann. Int. Med. 54:30, 1961. 20. Laurence, K. M.: Congenital pulmonary lymphangiectasis, J. Clin. Path. 12:62, 1959. 21. Giammalvo, J. T.: Congenital lymphangiomatosis of the lung. A form of cystic disease, Lab. Invest. 4:450, 1955. 22. Javett, S. N., Webster, I., and Braudo, J. L.: Congenital dilatation of the pulmonary lymphatics, Pediatrics 31:416, 1963. 23. Wilson, M. G., and Mikity, V. G.: A new form of respiratory disease in premature infants, Am. J. Dis. Child. 99:489, 1960. 24. Mikity, V. G., Hodgman, J. E., and Tatter, D.: The radiological findings in delayed puhnonary maturation in premature infants, Prog. Pedlar. Radiol. 1:!49, 1967. 25. Baghdassarlan, O., Avery, M. E., and Neuhauser, E. B. D.: A form of pulmonary insufficiency in premature infants. Puhnonary dysmaturity, Am. J. Roentgenol. 89:1020, 1963. 26. Bucci, G., Iannaccone, G., Scalamandre, A., Savignoni, P. G., and Mendicini, M.: Observations on the Wilson-Mikity s)aadrome, Ann. Paediat. 206:135, 1966. 27. Swyer, P. R., Delivoria-Papadopoulos, M., Levison, H., Reilly, B. J., and Balls, J. U.: The pulmonary syndrome of Wilson and Mikity, Pediatrics 36:374, 1965. 28. Hendren, W. H., and McKee, D. M.: Lobar emphysema of infancy, J. l'ed. Surg. 1:24, 1966. 29. Opsahl, T., and Berman, E. J.: Bronchogenic mediastinal cysts in infants: 42

case report and review of tile literature, Pediatrics 30:372, 1962. 30. Leape, L. L., and Longino, L. A.: Infantile lobar emphysema, Pediatrics 34:246, 1964. 31. Chang, N., Hertzler, J. H., Gregg, R. H., Lofti, M. W., and Brot,gh, A. J.: Congenital stcnosis of the right main stem bronchus, Pediatrics 41:739, 1968. 3-'2. Murray, G. F., Talbert, J. L., and Hailer, J. A.: Obstructive lobar emphysema of the newborn infant, J. Thoracic & Cardiovas. Surg. 53:889, 1967. 33. Korngold, It. W., and Baker, J. w.: Non-surgical treatment of nnilobar obstruction emphysema of tile newborn, Pediatrics 14:296, 1954. 34. DeMuth, G. R., and SIoan, H.: Congenital lobar emphysema: Longterm effects and sequelae in treated cases, Surgery 59:601, 1966. 35. Swyer, P. R., and James, G. C. W.: A case of unilateral pulmonary emphysema, Thorax 8: I33, 1953. 36. MacLeod, W. M.: Abnormal transradiancy of one lung, Thorax 9:147, 1954. 37. Reid, L., Simon, G., Zorab, D. A., and Seidelin, R.: The development of unilateral hyper transradiancy of the lung, Brit. J. Dis. Chest 61:190, 1967, 38. Berdon, W. E., Baker, D. tL, and Boyer, J.: Unusual benign and malignant sequelae to childhood radiation therapy. Including "unilateral hyperlucent lung," Am. J. Roentgenol. 93:545, 1965. 39. Weg, J. G., Krumholz, R. A., and Hackleroad, L. E.: Unilateral hyperlucent lung. A physiologic syndrome, Ann. Int. Med. 62:675, 1965. 40. Margolin, H. N., Rosenberg, L. S., Felson, B., and Baum, G.: Idiopathic unilateral hyperlucent lung: A roentgenologic syndrome, Am. J. Roentgcnol. 82:63, 1951. 41. Ferencz, C.: Congenital abnormalities of pulmonary vessels and their relation to malformations of the lung, Pediatrics 28:993, 1961. 42. Newman, R. W., Tarasidis, G., and Chal, H. C.: Congenital absence or hypoplasia of pulmonary artery, J. Thoracic & Cardiovas. Surg. 47:740, 1964. 43. Robbins, J. B.: Pneumocystis carinii pneumonitis: A review, Pediat. Res. 1:131, 1967. 44. Rifkind, D., Faris, T. D., and Hile, R. B.: Pneumocystis carinii pneumonia, Ann. Int. Med. 65:943, 1966. 45. Ebel, K1-D, and Fendel, H.: T h e roentgen changes of pneumocystis pneumonia aud their anatomic basis, Prog. Pediat. Radiol. 1:177, 1967. 46. James, A. E., Dixon, G. D., and Johnson, H. F.: Melioidosis: A correlation of the radiographic and pathologic findings, Radiology 89:230, 1967. 47. Kmiecik, J.: Pulmonary disease service, Valley Forge General Hosp., Phoenixville, Pa., personal communication. 48. Patterson, M. C., Darling, C. L., and Blumenthal, J. B.: Acute melioidosis in a soldier home from South Vietnam, J.A.M.A. 200:117, 1967. 49. Sponitz, M., Rudnitzky, J., and Rambaud, J. J.: Melioidosis pneumonitis, J.A.M.A. 202:950, 1967. 50. Comroe, J. tI., Jr., Dripps, R. D., Dumke, I'. R., and Deming, M.: Oxygen toxicity, J.A.M.A. 128:710, 1945. 51. Foley, F. D., Moncrief, J. A., and Mason, A. D.: Pathology of the hmg in fatally bt, rned patients, Ann. Surg. 167:251, 1965. 43

52. Smith, F. J. C., tIeim, J. w., Thomson, R. M., and Drinker, C. K.: Bodily changes and development of pulmonary resistance in rats living under compressed air conditions, J. Exper. Med. 56:63, 1932. 53. Robinson, F. R., Harper, D. T., Thomas, A. A., and Kaplan, II. P.: l'roliferative pulmonary lesions in monkeys exposed to high concentrations of oxygen, Aerospace Med. 38:481, 1967. 54. Nash, G., Blennerhassett, J. B., and Pontoppidan, It.: Puhnonary lesions associated with oxygen toxicity and artificial ventilation, New England J. Med. 276:368, 1967. 55. Northway, W. H., Jr., Rosan, R. C., and Porter, D. Y.: Pulmonary disease following respirator)' therapy of hyaline membrane disease, New England J. Med. 276:357, 1967. 56. Lee, C. J., Lyons, J. tt., Konisberg, S., Morgan, F., and Moore, F. D.: Effects of spontaneous and positive pressure breathing of ambient air and pure oxygen at one atmosphere pressure on pulmonary surface characteristics, J. Thoracic 8: Cardiovas. Surg. 53:759, 1967. 57. deLemos, R., Wolfsdorf, J., Nachman, R., Block, A. J., Leiby, G., Wilkinson, H. A., Allen, T., Hailer, J. A., Morgan, W., and Avery, M. E.: A quantitative assessment of lung injury from oxygen (abstract), Pediat. Res. 2:317, 1968; also Anesthesiology (in press). 58. Bean, J. W.: Factors influencing clinical oxygen toxicity, Ann. N e w York Acad. Sc. 117:745, 1965. 59. Welch, B. E., Morgan, T. E., Jr., and Clamann, H. G.: Time-concentration effects in relation to oxygen toxicity in man, Fed. Proe. 22:i053, 1963.

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