Acta Path. Jap. 29(2): 259-268, 1979
ACUTE DIFFUSE INTERSTITIAL FIBROSING PNEUMONITIS AND BILATERAL RENAL CORTICAL NECROSIS
Takehiro MITSUHASHIand Kenji HOJO Department of Pathology, Osaka City University Medical School
(Received on July 3, 1978)
An autopsy case of a 69-year-old male with acute diffuse interstitial fibrosing pneumonitis complicated by bilateral renal cortical necrosis was presented. Autopsy revealed acute diffuse interstitial fibrosing pneumonitis, bilateral renal cortical necrosis, non-bacterial thrombotic endocarditis, involving the aortic and mitral valves, and some interesting vascular lesions, dissemination of fibrinoid change of arterioles and fibrin thrombus of small vessels in various organs; accumulation of polymorphonuclear leukocytes in the lumen of the smaller interlobular arteries and arterioles of the kidney with cellular infiltration and disintegration of the wall; severe disorganization of the wall with intraluminar and intramural fibrinous exudation in smaller branches of the hepatic artery; diminution and disarrangment of muscle fibers and patchy hyalinization in the media of the renal and interlobar arteries. The inter-relationship between acute dif€use interstitial fibrosing pneumonitis, bilateral renal cortical necrosis which may be regarded as a ‘hallmark’ of the generalized Shwartzman reaction, and disseminated intravascular coagulation was discussed. ACTA PATH. JAP. 29: 259-268,1979.
Diffuse interstitial fibrosing pneumonitis refers to a poorly understood pulmonary disorder characterized histologically by a diffuse interstitial pneumonitis. The pulmonary lesion comprises of edema of the alveolar lining cells, followed eventually by interstitial pulmonary fibrosis and widening of alveolar septa. However, there has yet been no report of diffuse interstitial fibrosing pneumonitis complicated by bilateral renal cortical necrosis.3,13,14 The purpose of this report is to describe a patient in whom acute diffuse interstitial fibrosing pneumonitis was complicated by bilateral renal cortical necrosis associated with fibrinoid changes of arterioles and disseminated thrombosis in various organs and tissues. Also in this case, non-bacterial thrombotic endocarditis and some conspicuous alterations of arterial walls were present in the kidneys, liver and other organs.
Case Repmt Clinical Findings
A 69-year-old Japanese man was admitted to the Osaka City University Hospital 31
SF%,3LE
All communications and reprint requests to ; Takehiro MITSUHASHI,Department of Pathology, Osaka City University Medical School, Asahi-machi, Abeno, Osaka 545, Japan. 259
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DIFFUSE INTERSTITIAL FIBROSING PNEUMONITIS
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on January 4, 1976, because of somnolence, dyspnea and fever. Information about him was limited, but he was reported t o have been well until 8 days previously, when dry cough, mild fever (37.0-37.5"C) and general fatigue developed. These symptoms did not change until on the evening of two days before admission, when he was found unresponsive and dyspneic, and he was admitted to another hospital. He mas alert, somnolent and dehydrated with a temperature of 39.8"C, pulse of 108 per minute, respiration of 40 and blood pressure of 130170 mmHg. He was dyspneic a t rest and had signs of inflammation in the lungs. The patient was given Cephaloridine and oxygen inhalation was begun, and he was transferred to this hospital. There was no history of diabetes mellitus, hypertension or pulmonary tuberculosis. The temperature was 38.0°C, and the pulse 92. The blood pressure was 136190 mmHg. On physical examination he was stuporous, dyspneic and dehydrated. Cyanosis of the lips and acra but no petechiae or lymphadenopathy were observed. 'Velcro' rales were audible throughout the lung field of the back. The heart was normal. A specimen of arterial blood, drawn with the patient breathing room air, showed that the partial pressure of oxygen (Pao,) was 24.1 mmHg, and partial pressure of carbon dioxide (Paco,) 29.6 mmHg; the p H was 7.69. And a specimen of arterial blood, drawn while he was breathing about 100 per cent oxygen, revealed that the Pao, was 55.8 mm Hg, and Paco, 33.1 mrn Hg; the pH was 7.59. On the second hospital day, abdominal distension and diminution of the bowel sounds were observed and in the evening of the day he was found to be anuric and his blood pressure was 180/90 mniHg. The hematocrit was 37.4 per cent; the white-cell count was 12,400 with 56 per cent neutrophils, 24 per cent band forms, 2 per cent metamyelocytes, and one erythroblast per 100 white-cell count. The erythrocyte sedimentation rate was 12 mm per hour. The urea nitrogen was 57 rng/dl, and the protein 6.1 g/dl (the albumin 43.8%, alpha-1 globulin l0.6%, alpha-2 globulin 9.5%, beta globulin 15.1% and gamma globulin 21.0%).
Fig. 1. Chest roentgenogram of the patient on January 7, 1976, showing diffuse, fluffy, ill defined densities throughout both lung fields, more prominent on the right side.
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The thymol turbidity test was 0.9 U, the bilirubin 3.1 mg/dl and the cholesterol 196 mg/dl. The serum glutamic oxalacetic transaminase was 130 mIU, the serum glutamic pyruvic transaminase 48 mIU and the choline esterase 0.48 The alkaline phosphatase was 15.0 K.A.U., and the lactic dehydrognease 5437 U (normal, 50 to 450 U). The sodium was 144 m Eq/l, the potassium 4.0 m Eq/l and chloride 100 mEq/l. The test for rheumatoid factor was negative. The antistreptolysin-0 titer was less than 40 U and the C-reactive protein (H). The serum test for syphilis was negative. The film of the chest (Pig. 1) demonstrated diffuse, fluffy, ill-defined densities throughout the right lung field. I n the morning of the third hospital day, the blood pressure was 170/110 mm Hg, and anuria continued. He died a short time thereafter.
Gross and Histological Findittgs At autopsy, both lungs were found to be voluminous, rubbery-fim and heavy, the right lung weighing 910 g and the left 740 g, respectively. On cut section there was a net-work of very fine, translucent gray lines throughout all lobes of both lungs with prominence of the lower portion of the right upper lobe, except for both hilar areas (Fig. 2). There were no large scars and focal areas of emphysema. There was a thrombus in a branch of the left pulmonary artery. Microscopically, many sections from each lung showed that the interstitium was edematous with fibroblastic proliferation being still in progress and infiltration with lymphocytes and plasma cells (Fig. 3). The sections obtained from the lower portion of the right upper lobe showed that there was widening of the alveolar septa, up to 10 to 15 times the normal thickness. While, the sections from both hilar areas showed that the alveolar septa were of normal thickness. I n many areas from almost all sections from the lungs there was prominent hyperplasia of the alveolar lining cells which sometimes showed to be greatly enlarged and bizarre in shape. A few sections were found to be studded with mass of a pseudostratified layer of alveolar and/or bronchiolar epithelium, the appearance resembling those during recovery phase of influenza virus pneumonitis. Hyaline membrane, amorphous and slightly basophilic to layered and faintly eosinophilic, were plastered against the walls of one-fourth to two-third of the alveolar ducts and sacs in every section taken from each lung except for the sections of the lower portion of the right upper lobe. Intra-alveolar exudate of edema fluid, red blood cells and desquamated macrophages, as well as Masson-like structures which consisted of fibrinoid materials covered by proliferated alveolar lining cells were also discernible. Occasionally, microthrombi in capillaries and venules, and fibrinoid change and hyalinization of the vessel walls were noted. Epithelial hyperplasia with edema of the propria in the bronchioles occurred in both lungs, but in the main stem-bronchi and trachea they were within normal limits. The kidneys were edematous, dark red in color and had a tense capsule, the right kidney weighing 140 g and the left 170 g. The surface showed many petechial and punctate hemorrhages, and scattered grayish-white areas. On cut-section the cortices except for the juxtamedullary portions and thin subcapsular layers of intact tissue
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revealed many discrete, circumscribed, grayish-white areas of necrosis accompanied with hemorrhage, although no thrombi were demonstrable in the large renal vessels (Fig. 4). Microscopically, the principal lesions were represented by widespread necrosis of the renal cortex consisting of coalescence of focal necrosis, affecting all tissue components involved, with a marginal zone of congestion and hemorrhage (Fig. 4). The areas of necrosis involved over 50 per cent of the renal cortex. In almost every glomeruli the capillaries appeared occluded by dense, refractile, granular or homogeneous eosinophilic materials. Similar materials were sometimes noted in the lumen of the arterioles (Fig. 5) and venules, and the walls of the arterioles appeared loosened with fibrin precipitation. The arterioles, in places, were distended and contained numerous polymorphonuclear leukocytes in the lumen and also the wall underwent leukocytic infiltration and disorganization (Fig. 9). The walls of the renal and interlobar arteries were edematous, and diminution and disarrangement of muscle fibers (Fig. 6 ) , prominent perinuclear vacuolation of the muscle cells and hyalinized patches were also found in the media (Fig. 7). The heart weighed 490 g; the right ventricle thickened up to 0.5 cm and the left 1.5 cm, and the right ventricle was also dilated. It contained multiple friable, redbrown verrucous excrescences on the free edges of both aortic cusps and mitral leaflets. They varied in size from 0.1 to 0.5 cm in diameter. Microscopic sections revealed normal underlying valves with superimposed amorphous, adherent, fibrin-like material. Bacteria and evidence of tissue response were absent. Fibrin thrombi were also often found in the small vessels of the myocardium. The spleen weighed 180 g, and appeared purplish-red. A small subcapsular infarct was present. Microscopically, fibrin thrombi were scattered throughout in the splenic sinusoids, and numerous fibrin deposits were lying beneath the lining cells of the pulp cords. Fibrinoid change was often seen beneath the endothelium of the follicular arteries. The liver was enlarged, weighing 1680 g. Microscopically, the hepatic sinusoids appeared markedly congested with a few thrombi. Although there were no areas of focal necrosis, some interlobular arteries were obliterated by the intra-luminal and intra-mural exudates and fibrin droplets, the latter extending outward into the media (Fig. 8). Bone m r r o w ; the marrow from the sternum, ribs and vertebrae as a whole showed a moderate hyperplasia of myeloid and megakaryocytic elements. The erythroid elements ~
~ _ _
Fig. 2. Cut section of the right lung revealed a net-work of very fine, translucent gray lines throughout all lobes, except for hilar areas. Fig. 3. Lung section showing diffuse fibrosis of the alveolar walls, lined by cuboidal cells, often by enlarged and anaplastic cells, with infiltration of lymphocytes and plasma cells. ' 1 Hematoxylin and eosin stain x400. Fig. 4. A section from the right kidney showing widesprekd cortical necrosis exce@ for juxtamedullary and a rim of subcapsular cortex. Hematoxylin and eosin stain x 16. Fig. 5. A section from the right kidney showing that the capillaries of almost all glomeruli and the arterioles in the non-necrotic areas were occluded by fibrin thrombi, and the wall of the arteriole was necrotic. Hematoxylin and eosin stain x 200.
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often revealed nuclear pyknosis, fragmentation and karyorrhexis. The striking feature was the nuclear damage of the megakaryocytes, including pyknosis and marked vacuolation. Fibrinoid changes and/or fibrin thrombi were encountered also in the arterioles and venules of the pancreas, testes and so forth (Fig. 10). I n search of the pathogenesis of the bilateral renal cortical necrosis in this case, the modified limulus lysate test for the evaluation of bacterial endotoxin was examined, using the frozen tissues obtained from the kidney and heart a t necropsy instead of the patient's serum. The frozen tissue was homogenized in the Dulbecco's phosphate buffered saline (Iml per g of the frozen tissue) by Waring blender and glass homogenizer. The suspension was centrifuged a t 2,000 g for 20 min. and then the supernatant was kept a t -20°C until assayed. The amoebocytes obtained from the Tachypheus tridentatus (an oriental Limulus) were homogenized and centrifuged. The lysate and the supernatant from the tissue were incubated together. The results of the test are shown in Table 1. As may be seen in this table, in these patient's tissue there was no convicing endotoxin activity over that obtained in controls. Table 1. Evaluation of Bacterial Endotoxin by Modijied Limulus Lysate Test,
Using the Supernatants Obtained from Homogenized Frozen Tissues with Phosphate Buffered Naline without Caa+ and Mg2+ Solution Frozen tissue
Incubation time 10 min
30 rnin
60 min .
Presented Case
kidney heart
(-1 (-1
_
_
(+t)
(it)
(*t)fg
(+)fg
120 min _
_
(tt) (+)fg
over-night ~
~
(it)
(+)fg
Normal Serum Note; the degree of gelation was scored by tilting the tubes to 45OC as follows; 3+, firm gel; 2+, transformable gel; 1+, semi-liquid gel; f, flocculation; g, starchy granule; -, no change.
Discussion
I n the present case, this 69-year-old man, who did not have a chronic illness of any kind, began t o have dry cough, fever (37.0-37.5"C) and general fatigue for 8 days, and suddenly developed obtunded state, fever (39"C), severe respiratory distress, accompanied Fig. 6-10. A section from the right renal artery revealing diminution and disarrangment ofthe muscle fibers (Fig. 6), a section from the right kidney showing marked perinuclear vacuolation of the muscle cells and a focal hyalinized area in the media of the interlobar artery (Fig. 7), and fibrin precipitate and leukocyte infiltration in the wall of the arterioles (Fig. 9), a liver section showing fibrin materials which deposit within the lumen and just beneath the endothelium, extending outward into the media of the interlobular artery (Fig. 8), and a testis section showing focal fibrinoid change in the wall of the arteriole (Fig. 10). Hematoxylin and eosin stain Fig. 6; x40, 7; x110; 8; x l l 6 , 9; x297, 10; x231.
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by acute renal failure and hypertension. He died on the 12th day after the onset. Radiographic appearance of his chest film has been referred to as an interstitial fibrosis of the lungs, more prominent on the right side. At autopsy, diffuse interstitial fibrosing pneumonitis of both lungs, bilateral renal cortical necrosis, fibrinoid changes of the arterioles and fibrin thrombi in the vessels of the various organs and tissues, and non-bacterial thrombotic endocarditis involving the aortic and mitral valves were conkmed. Some investigators described that renal cortical necrosis was considered to be the morphologic criterion or ‘hallmark’ of the generalized Shwartzman reaction (GSR).5,12 In this reaction, severe alterations in the clotting mechanism with consumption of plasma clotting factors have led to intravascular fibrin deposition, and when the phagocytotic function of the reticuloendothelial system is previously depressed or impaired by any causes, fibrin cannot be cleared and the precipitate remains within the vessels. Recently, it has been well documented that non-bacterial thrombotic endocarditis is associated with disseminated intravascular coagulation (DIC)5,7,9. KIM et al.’ reported that in the study of 36 patients with non-bacterial thrombotic endocarditis histopathologic evidence of DIC was found in 18 cases (50%), and the mitral valve alone was involved in 14 cases, aortic valve 14 cases; both aortic and mitral valve, 3 cases; tricuspid valve, 2 cases. Pulmonary hyaline membrane formation is also associated with DIC5115. In the present case it can be considered that GSR and DIC may be inferred from bilateral renal cortical necrosis, fibrinoid changes of the arterioles and fibrin thrombi in the vessels, and non-bacterial thrombotic endocarditis. The possibility of a relationship existing between acute diffuse interstitial fibrosing pneumonitis, GSR, and DIC should be discussed here. In this case, although he had had respiratory disorders, he was found unresponsive, dyspneic and high fever 8 days after the onset, and also anuria on the 11th day. It was clearly suggested that a new factor was inflicting the respiratory disorder. STACKet al.I4 reviewed 96 cases of idiopathic diffuse interstitial lung disease. In the 59 fatal cases, most patients died from diffuse interstitial lung disease, 4 from bronchial carcinoma, and 2 died after lung biopsy. SCAD DING^^, and GRANTet ~ 1 also . reported ~ many cases of diffuse interstitial fibrosing pneumonitis, but there has been no report on the case accompanied by bilateral renal cortical necrosis. DUFF and MURRAY~ reviewed 71 cases of bilteral renal cortical necrosis; the 48 cases were associated with pregnancy. Moreover, MARCUSSENet aL8 reported 6 cases of renal cortical necrosis in 5,994 postmortem examinations; all the patients were women. As far as can be seen from these studies of bilateral renal cortical necrosis, there were no patients with associated fibrosing pneumonitis. On the contrary, BONEet al.1 reported that DIC developed in Seven of 30 consecutive Datients with the adult respiratory syndrome.
They emphasized that DIC was a
frequent complication in patients with severe adult respiratory distress syndrome. HAMILTON4 also described a case of psittacossis who had severe pneumonia and DIG. HUBERet aL6 induced DIC in mongrel dogs by the intravenous infusion of thrombin, and alterations in lung morphology were similar to the clinically analogous respiratory distress syndrome.
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Commonly, it is thought that renal cortical necrosis is derived from severe DIC, but in practice DIC is rarely associated with bilateral renal cortical necrosis. ROBBOY et al.ll reported the analysis of 26 cases of DIC; no instance of renal cortical necrosis was identified. THALand EGNERl' described that sublethal dose of staphylococcus toxin given intravenously produced renal cortical necrosis in rabbits. In its initial stages, this lesion appeared to be the result of selective renal vasospasm, and in animals surving over 24 hours, histological examination showed destruction of the muscular media of arcuate arteries. In the rabbits treated with staphylococcus toxin the muscular media of several mesenteric arteries and femoral arteries were found to be transformed into a homogeneous anuclear zone, although the intimal cells as well as periadventitial connective tissue cells appeared to be viable. Most recently, TAKEUCHIet al. have emphasized that the perinuclear vacuolic change of the vascular medial muscle is indicative of vasospasm of the medial artery. Accordingly, the remarkable lesions found in arteries of the kidneys, liver and other organs in this case may be interpreted to be caused by vasospasm due to bacterial toxin and/or GSR, in part as due to severe hypoxemia from the pneumonitis, although we could not secure a positive result in the limulus lysate test for assessement of bacterial endotoxin activitylO. Acknowledgement: The authors wish thank to Doctor Makoto NIWA,Department of Microbiology, Osaka City University Medical School, for his kind advice on the performance of the limulus lysate test.
References 1. BONE,R.C., FRANCIS,P.B., and PIERCE, A.K. : Intravascular coagulation associated with the adult respiratory distress syndrome. Am. J. Med. 61: 585-589, 1976. 2. DUPF, G.L. and MURRAY, E.G.D.: Bilateral cortical necrosis of the kidneys. Am. J. Med. Sci. 201: 428451, 1941. 3. GRANT,I.W.B., HILLIS, B.R., and DAVIDSON, J.: Diffuse interstitial fibrosis of the lungs (Hamman-Rich syndrome); a review with a report of three additional cases. Am. Rev. Tuberc. Pulm. Dis. 74: 485-510, 1956. 4. HAMILTON, D.V. : Psittacosis and disseminated intravascular coagulation. Brit. Med. J. 1 : 370, 1975. 5. HORWITZ,C.A., and WARD P.C.J. : Disseminated intravascular coagulation, nonbacterial thrombotic endocarditis and adult pulmonary hyaline membranes - an interrelated triad ? ; report of a case following small bowel resection for a strangulated inguinal hernia. Am. J. Med. 51: 272-280, 1971. 6. HUBER,G., MASON, R., PEW,C., and NORMAN, J.: Production, reversal and prevention of experimental hyaline membrane disease following disseminated intravascular coagulation. Clin. Res. 17: 415, 1969 (abstract). 7. KIM, H-S., SUZUKI,M., LIE, J.T., and TITSU,J.L. : Nonbacterial thrombotic endocarditis (NBTE) and disseminated intravascular coagulation (DIC); autopsy study of 36 patients. Arch. Pathol. Lab. Med. 101: 65-68, 1977. 8. MARCUSSEN, H., and ASNAES,S. : Renal cortical necrosis; an evaluation of the possible relation to Shwartzman reaction. Acta. Pathol. Microbiol. Scand. Sect. A Pathol. 80: 351-356, 1972. 9. MCKAY,D.G., and WAHLE,JR.,G.H.: Disseminated thrombosis in colon cancer. Cancer 8: 970-978, 1955. 10. NIWA, M., HIRBMATSU, T., and WACURI,0.: The gelation reaction between horseshoe crab amoebocytes and endotoxins studied by the quantitative clot protein method. Jpn. J. Med. Sci. Biol. 27: 108-111, 1974.
268 11. 12. 13. 14. 15. 16.
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ROBBOY, S.J., COLMAN, R.W., and MINNA,J.D. : Pathology of disseminated intravascular coagulation (DIC); analysis of 26 cases. Hum. Pathol. 3 : 327-343, 1972. RODRIGUEZ-ERDMANN, F. : Pathognesis of bilateral renal cortical necrosis ; its production by means of exogenous fibrin. Arch. Pathol. 79: 615-618, 1965. SCADDING, J.G.: Chronic diffuse interstitial fibrosis of the lungs. Brit. Med. J. 2: 443450, 1960. STACK,B.H.R., CHOO-KANG, Y.F.J., and HEARD,B.E.: The prognosis of cryptogenic fibrosing alveolitis. Thorax 27: 535-542, 1972. STARK,C.R., ABRAMSON, D., and ERKAN,V.: Intravascular coagulation and hyaline membrane disease of the newborn. Lancet 1 : 1180-1181, 1968. TAKEUCHI, T., MORI, Y., and OZAWA,U.: On the morphological analysis of renal arterial vasospasm and alteration of hernodynamics in the kidney; 1. morphological study of arterial vasoconstriction and dilatation with special reference to perinuclear vacuole of medial smooth muscle of the kidney. Nihon Univ. J. Med. 15: 193-208, 1973. THAL,A.P., and EGNER,W.: The site of action of the staphylococcus alpha toxin. J. Exp. Med. 113: 67-82, 1961.
ACUTE DIFFUSE INTERSTITIAL FIBROSING PNEUMONITIS AND BILATERAL RENAL CORTICAL NECROSIS
Takehiro MITSUHASHIand Kenji HOJO Department of Pathology, Osaka City University Medical School
(Received on July 3, 1978)
An autopsy case of a 69-year-old male with acute diffuse interstitial fibrosing pneumonitis complicated by bilateral renal cortical necrosis was presented. Autopsy revealed acute diffuse interstitial fibrosing pneumonitis, bilateral renal cortical necrosis, non-bacterial thrombotic endocarditis, involving the aortic and mitral valves, and some interesting vascular lesions, dissemination of fibrinoid change of arterioles and fibrin thrombus of small vessels in various organs; accumulation of polymorphonuclear leukocytes in the lumen of the smaller interlobular arteries and arterioles of the kidney with cellular infiltration and disintegration of the wall; severe disorganization of the wall with intraluminar and intramural fibrinous exudation in smaller branches of the hepatic artery; diminution and disarrangment of muscle fibers and patchy hyalinization in the media of the renal and interlobar arteries. The inter-relationship between acute dif€use interstitial fibrosing pneumonitis, bilateral renal cortical necrosis which may be regarded as a ‘hallmark’ of the generalized Shwartzman reaction, and disseminated intravascular coagulation was discussed. ACTA PATH. JAP. 29: 259-268,1979.
Diffuse interstitial fibrosing pneumonitis refers to a poorly understood pulmonary disorder characterized histologically by a diffuse interstitial pneumonitis. The pulmonary lesion comprises of edema of the alveolar lining cells, followed eventually by interstitial pulmonary fibrosis and widening of alveolar septa. However, there has yet been no report of diffuse interstitial fibrosing pneumonitis complicated by bilateral renal cortical necrosis.3,13,14 The purpose of this report is to describe a patient in whom acute diffuse interstitial fibrosing pneumonitis was complicated by bilateral renal cortical necrosis associated with fibrinoid changes of arterioles and disseminated thrombosis in various organs and tissues. Also in this case, non-bacterial thrombotic endocarditis and some conspicuous alterations of arterial walls were present in the kidneys, liver and other organs.
Case Repmt Clinical Findings
A 69-year-old Japanese man was admitted to the Osaka City University Hospital 31
SF%,3LE
All communications and reprint requests to ; Takehiro MITSUHASHI,Department of Pathology, Osaka City University Medical School, Asahi-machi, Abeno, Osaka 545, Japan. 259
260
DIFFUSE INTERSTITIAL FIBROSING PNEUMONITIS
Acta Path. Jap.
on January 4, 1976, because of somnolence, dyspnea and fever. Information about him was limited, but he was reported t o have been well until 8 days previously, when dry cough, mild fever (37.0-37.5"C) and general fatigue developed. These symptoms did not change until on the evening of two days before admission, when he was found unresponsive and dyspneic, and he was admitted to another hospital. He mas alert, somnolent and dehydrated with a temperature of 39.8"C, pulse of 108 per minute, respiration of 40 and blood pressure of 130170 mmHg. He was dyspneic a t rest and had signs of inflammation in the lungs. The patient was given Cephaloridine and oxygen inhalation was begun, and he was transferred to this hospital. There was no history of diabetes mellitus, hypertension or pulmonary tuberculosis. The temperature was 38.0°C, and the pulse 92. The blood pressure was 136190 mmHg. On physical examination he was stuporous, dyspneic and dehydrated. Cyanosis of the lips and acra but no petechiae or lymphadenopathy were observed. 'Velcro' rales were audible throughout the lung field of the back. The heart was normal. A specimen of arterial blood, drawn with the patient breathing room air, showed that the partial pressure of oxygen (Pao,) was 24.1 mmHg, and partial pressure of carbon dioxide (Paco,) 29.6 mmHg; the p H was 7.69. And a specimen of arterial blood, drawn while he was breathing about 100 per cent oxygen, revealed that the Pao, was 55.8 mm Hg, and Paco, 33.1 mrn Hg; the pH was 7.59. On the second hospital day, abdominal distension and diminution of the bowel sounds were observed and in the evening of the day he was found to be anuric and his blood pressure was 180/90 mniHg. The hematocrit was 37.4 per cent; the white-cell count was 12,400 with 56 per cent neutrophils, 24 per cent band forms, 2 per cent metamyelocytes, and one erythroblast per 100 white-cell count. The erythrocyte sedimentation rate was 12 mm per hour. The urea nitrogen was 57 rng/dl, and the protein 6.1 g/dl (the albumin 43.8%, alpha-1 globulin l0.6%, alpha-2 globulin 9.5%, beta globulin 15.1% and gamma globulin 21.0%).
Fig. 1. Chest roentgenogram of the patient on January 7, 1976, showing diffuse, fluffy, ill defined densities throughout both lung fields, more prominent on the right side.
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The thymol turbidity test was 0.9 U, the bilirubin 3.1 mg/dl and the cholesterol 196 mg/dl. The serum glutamic oxalacetic transaminase was 130 mIU, the serum glutamic pyruvic transaminase 48 mIU and the choline esterase 0.48 The alkaline phosphatase was 15.0 K.A.U., and the lactic dehydrognease 5437 U (normal, 50 to 450 U). The sodium was 144 m Eq/l, the potassium 4.0 m Eq/l and chloride 100 mEq/l. The test for rheumatoid factor was negative. The antistreptolysin-0 titer was less than 40 U and the C-reactive protein (H). The serum test for syphilis was negative. The film of the chest (Pig. 1) demonstrated diffuse, fluffy, ill-defined densities throughout the right lung field. I n the morning of the third hospital day, the blood pressure was 170/110 mm Hg, and anuria continued. He died a short time thereafter.
Gross and Histological Findittgs At autopsy, both lungs were found to be voluminous, rubbery-fim and heavy, the right lung weighing 910 g and the left 740 g, respectively. On cut section there was a net-work of very fine, translucent gray lines throughout all lobes of both lungs with prominence of the lower portion of the right upper lobe, except for both hilar areas (Fig. 2). There were no large scars and focal areas of emphysema. There was a thrombus in a branch of the left pulmonary artery. Microscopically, many sections from each lung showed that the interstitium was edematous with fibroblastic proliferation being still in progress and infiltration with lymphocytes and plasma cells (Fig. 3). The sections obtained from the lower portion of the right upper lobe showed that there was widening of the alveolar septa, up to 10 to 15 times the normal thickness. While, the sections from both hilar areas showed that the alveolar septa were of normal thickness. I n many areas from almost all sections from the lungs there was prominent hyperplasia of the alveolar lining cells which sometimes showed to be greatly enlarged and bizarre in shape. A few sections were found to be studded with mass of a pseudostratified layer of alveolar and/or bronchiolar epithelium, the appearance resembling those during recovery phase of influenza virus pneumonitis. Hyaline membrane, amorphous and slightly basophilic to layered and faintly eosinophilic, were plastered against the walls of one-fourth to two-third of the alveolar ducts and sacs in every section taken from each lung except for the sections of the lower portion of the right upper lobe. Intra-alveolar exudate of edema fluid, red blood cells and desquamated macrophages, as well as Masson-like structures which consisted of fibrinoid materials covered by proliferated alveolar lining cells were also discernible. Occasionally, microthrombi in capillaries and venules, and fibrinoid change and hyalinization of the vessel walls were noted. Epithelial hyperplasia with edema of the propria in the bronchioles occurred in both lungs, but in the main stem-bronchi and trachea they were within normal limits. The kidneys were edematous, dark red in color and had a tense capsule, the right kidney weighing 140 g and the left 170 g. The surface showed many petechial and punctate hemorrhages, and scattered grayish-white areas. On cut-section the cortices except for the juxtamedullary portions and thin subcapsular layers of intact tissue
262
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revealed many discrete, circumscribed, grayish-white areas of necrosis accompanied with hemorrhage, although no thrombi were demonstrable in the large renal vessels (Fig. 4). Microscopically, the principal lesions were represented by widespread necrosis of the renal cortex consisting of coalescence of focal necrosis, affecting all tissue components involved, with a marginal zone of congestion and hemorrhage (Fig. 4). The areas of necrosis involved over 50 per cent of the renal cortex. In almost every glomeruli the capillaries appeared occluded by dense, refractile, granular or homogeneous eosinophilic materials. Similar materials were sometimes noted in the lumen of the arterioles (Fig. 5) and venules, and the walls of the arterioles appeared loosened with fibrin precipitation. The arterioles, in places, were distended and contained numerous polymorphonuclear leukocytes in the lumen and also the wall underwent leukocytic infiltration and disorganization (Fig. 9). The walls of the renal and interlobar arteries were edematous, and diminution and disarrangement of muscle fibers (Fig. 6 ) , prominent perinuclear vacuolation of the muscle cells and hyalinized patches were also found in the media (Fig. 7). The heart weighed 490 g; the right ventricle thickened up to 0.5 cm and the left 1.5 cm, and the right ventricle was also dilated. It contained multiple friable, redbrown verrucous excrescences on the free edges of both aortic cusps and mitral leaflets. They varied in size from 0.1 to 0.5 cm in diameter. Microscopic sections revealed normal underlying valves with superimposed amorphous, adherent, fibrin-like material. Bacteria and evidence of tissue response were absent. Fibrin thrombi were also often found in the small vessels of the myocardium. The spleen weighed 180 g, and appeared purplish-red. A small subcapsular infarct was present. Microscopically, fibrin thrombi were scattered throughout in the splenic sinusoids, and numerous fibrin deposits were lying beneath the lining cells of the pulp cords. Fibrinoid change was often seen beneath the endothelium of the follicular arteries. The liver was enlarged, weighing 1680 g. Microscopically, the hepatic sinusoids appeared markedly congested with a few thrombi. Although there were no areas of focal necrosis, some interlobular arteries were obliterated by the intra-luminal and intra-mural exudates and fibrin droplets, the latter extending outward into the media (Fig. 8). Bone m r r o w ; the marrow from the sternum, ribs and vertebrae as a whole showed a moderate hyperplasia of myeloid and megakaryocytic elements. The erythroid elements ~
~ _ _
Fig. 2. Cut section of the right lung revealed a net-work of very fine, translucent gray lines throughout all lobes, except for hilar areas. Fig. 3. Lung section showing diffuse fibrosis of the alveolar walls, lined by cuboidal cells, often by enlarged and anaplastic cells, with infiltration of lymphocytes and plasma cells. ' 1 Hematoxylin and eosin stain x400. Fig. 4. A section from the right kidney showing widesprekd cortical necrosis exce@ for juxtamedullary and a rim of subcapsular cortex. Hematoxylin and eosin stain x 16. Fig. 5. A section from the right kidney showing that the capillaries of almost all glomeruli and the arterioles in the non-necrotic areas were occluded by fibrin thrombi, and the wall of the arteriole was necrotic. Hematoxylin and eosin stain x 200.
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often revealed nuclear pyknosis, fragmentation and karyorrhexis. The striking feature was the nuclear damage of the megakaryocytes, including pyknosis and marked vacuolation. Fibrinoid changes and/or fibrin thrombi were encountered also in the arterioles and venules of the pancreas, testes and so forth (Fig. 10). I n search of the pathogenesis of the bilateral renal cortical necrosis in this case, the modified limulus lysate test for the evaluation of bacterial endotoxin was examined, using the frozen tissues obtained from the kidney and heart a t necropsy instead of the patient's serum. The frozen tissue was homogenized in the Dulbecco's phosphate buffered saline (Iml per g of the frozen tissue) by Waring blender and glass homogenizer. The suspension was centrifuged a t 2,000 g for 20 min. and then the supernatant was kept a t -20°C until assayed. The amoebocytes obtained from the Tachypheus tridentatus (an oriental Limulus) were homogenized and centrifuged. The lysate and the supernatant from the tissue were incubated together. The results of the test are shown in Table 1. As may be seen in this table, in these patient's tissue there was no convicing endotoxin activity over that obtained in controls. Table 1. Evaluation of Bacterial Endotoxin by Modijied Limulus Lysate Test,
Using the Supernatants Obtained from Homogenized Frozen Tissues with Phosphate Buffered Naline without Caa+ and Mg2+ Solution Frozen tissue
Incubation time 10 min
30 rnin
60 min .
Presented Case
kidney heart
(-1 (-1
_
_
(+t)
(it)
(*t)fg
(+)fg
120 min _
_
(tt) (+)fg
over-night ~
~
(it)
(+)fg
Normal Serum Note; the degree of gelation was scored by tilting the tubes to 45OC as follows; 3+, firm gel; 2+, transformable gel; 1+, semi-liquid gel; f, flocculation; g, starchy granule; -, no change.
Discussion
I n the present case, this 69-year-old man, who did not have a chronic illness of any kind, began t o have dry cough, fever (37.0-37.5"C) and general fatigue for 8 days, and suddenly developed obtunded state, fever (39"C), severe respiratory distress, accompanied Fig. 6-10. A section from the right renal artery revealing diminution and disarrangment ofthe muscle fibers (Fig. 6), a section from the right kidney showing marked perinuclear vacuolation of the muscle cells and a focal hyalinized area in the media of the interlobar artery (Fig. 7), and fibrin precipitate and leukocyte infiltration in the wall of the arterioles (Fig. 9), a liver section showing fibrin materials which deposit within the lumen and just beneath the endothelium, extending outward into the media of the interlobular artery (Fig. 8), and a testis section showing focal fibrinoid change in the wall of the arteriole (Fig. 10). Hematoxylin and eosin stain Fig. 6; x40, 7; x110; 8; x l l 6 , 9; x297, 10; x231.
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by acute renal failure and hypertension. He died on the 12th day after the onset. Radiographic appearance of his chest film has been referred to as an interstitial fibrosis of the lungs, more prominent on the right side. At autopsy, diffuse interstitial fibrosing pneumonitis of both lungs, bilateral renal cortical necrosis, fibrinoid changes of the arterioles and fibrin thrombi in the vessels of the various organs and tissues, and non-bacterial thrombotic endocarditis involving the aortic and mitral valves were conkmed. Some investigators described that renal cortical necrosis was considered to be the morphologic criterion or ‘hallmark’ of the generalized Shwartzman reaction (GSR).5,12 In this reaction, severe alterations in the clotting mechanism with consumption of plasma clotting factors have led to intravascular fibrin deposition, and when the phagocytotic function of the reticuloendothelial system is previously depressed or impaired by any causes, fibrin cannot be cleared and the precipitate remains within the vessels. Recently, it has been well documented that non-bacterial thrombotic endocarditis is associated with disseminated intravascular coagulation (DIC)5,7,9. KIM et al.’ reported that in the study of 36 patients with non-bacterial thrombotic endocarditis histopathologic evidence of DIC was found in 18 cases (50%), and the mitral valve alone was involved in 14 cases, aortic valve 14 cases; both aortic and mitral valve, 3 cases; tricuspid valve, 2 cases. Pulmonary hyaline membrane formation is also associated with DIC5115. In the present case it can be considered that GSR and DIC may be inferred from bilateral renal cortical necrosis, fibrinoid changes of the arterioles and fibrin thrombi in the vessels, and non-bacterial thrombotic endocarditis. The possibility of a relationship existing between acute diffuse interstitial fibrosing pneumonitis, GSR, and DIC should be discussed here. In this case, although he had had respiratory disorders, he was found unresponsive, dyspneic and high fever 8 days after the onset, and also anuria on the 11th day. It was clearly suggested that a new factor was inflicting the respiratory disorder. STACKet al.I4 reviewed 96 cases of idiopathic diffuse interstitial lung disease. In the 59 fatal cases, most patients died from diffuse interstitial lung disease, 4 from bronchial carcinoma, and 2 died after lung biopsy. SCAD DING^^, and GRANTet ~ 1 also . reported ~ many cases of diffuse interstitial fibrosing pneumonitis, but there has been no report on the case accompanied by bilateral renal cortical necrosis. DUFF and MURRAY~ reviewed 71 cases of bilteral renal cortical necrosis; the 48 cases were associated with pregnancy. Moreover, MARCUSSENet aL8 reported 6 cases of renal cortical necrosis in 5,994 postmortem examinations; all the patients were women. As far as can be seen from these studies of bilateral renal cortical necrosis, there were no patients with associated fibrosing pneumonitis. On the contrary, BONEet al.1 reported that DIC developed in Seven of 30 consecutive Datients with the adult respiratory syndrome.
They emphasized that DIC was a
frequent complication in patients with severe adult respiratory distress syndrome. HAMILTON4 also described a case of psittacossis who had severe pneumonia and DIG. HUBERet aL6 induced DIC in mongrel dogs by the intravenous infusion of thrombin, and alterations in lung morphology were similar to the clinically analogous respiratory distress syndrome.
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Commonly, it is thought that renal cortical necrosis is derived from severe DIC, but in practice DIC is rarely associated with bilateral renal cortical necrosis. ROBBOY et al.ll reported the analysis of 26 cases of DIC; no instance of renal cortical necrosis was identified. THALand EGNERl' described that sublethal dose of staphylococcus toxin given intravenously produced renal cortical necrosis in rabbits. In its initial stages, this lesion appeared to be the result of selective renal vasospasm, and in animals surving over 24 hours, histological examination showed destruction of the muscular media of arcuate arteries. In the rabbits treated with staphylococcus toxin the muscular media of several mesenteric arteries and femoral arteries were found to be transformed into a homogeneous anuclear zone, although the intimal cells as well as periadventitial connective tissue cells appeared to be viable. Most recently, TAKEUCHIet al. have emphasized that the perinuclear vacuolic change of the vascular medial muscle is indicative of vasospasm of the medial artery. Accordingly, the remarkable lesions found in arteries of the kidneys, liver and other organs in this case may be interpreted to be caused by vasospasm due to bacterial toxin and/or GSR, in part as due to severe hypoxemia from the pneumonitis, although we could not secure a positive result in the limulus lysate test for assessement of bacterial endotoxin activitylO. Acknowledgement: The authors wish thank to Doctor Makoto NIWA,Department of Microbiology, Osaka City University Medical School, for his kind advice on the performance of the limulus lysate test.
References 1. BONE,R.C., FRANCIS,P.B., and PIERCE, A.K. : Intravascular coagulation associated with the adult respiratory distress syndrome. Am. J. Med. 61: 585-589, 1976. 2. DUPF, G.L. and MURRAY, E.G.D.: Bilateral cortical necrosis of the kidneys. Am. J. Med. Sci. 201: 428451, 1941. 3. GRANT,I.W.B., HILLIS, B.R., and DAVIDSON, J.: Diffuse interstitial fibrosis of the lungs (Hamman-Rich syndrome); a review with a report of three additional cases. Am. Rev. Tuberc. Pulm. Dis. 74: 485-510, 1956. 4. HAMILTON, D.V. : Psittacosis and disseminated intravascular coagulation. Brit. Med. J. 1 : 370, 1975. 5. HORWITZ,C.A., and WARD P.C.J. : Disseminated intravascular coagulation, nonbacterial thrombotic endocarditis and adult pulmonary hyaline membranes - an interrelated triad ? ; report of a case following small bowel resection for a strangulated inguinal hernia. Am. J. Med. 51: 272-280, 1971. 6. HUBER,G., MASON, R., PEW,C., and NORMAN, J.: Production, reversal and prevention of experimental hyaline membrane disease following disseminated intravascular coagulation. Clin. Res. 17: 415, 1969 (abstract). 7. KIM, H-S., SUZUKI,M., LIE, J.T., and TITSU,J.L. : Nonbacterial thrombotic endocarditis (NBTE) and disseminated intravascular coagulation (DIC); autopsy study of 36 patients. Arch. Pathol. Lab. Med. 101: 65-68, 1977. 8. MARCUSSEN, H., and ASNAES,S. : Renal cortical necrosis; an evaluation of the possible relation to Shwartzman reaction. Acta. Pathol. Microbiol. Scand. Sect. A Pathol. 80: 351-356, 1972. 9. MCKAY,D.G., and WAHLE,JR.,G.H.: Disseminated thrombosis in colon cancer. Cancer 8: 970-978, 1955. 10. NIWA, M., HIRBMATSU, T., and WACURI,0.: The gelation reaction between horseshoe crab amoebocytes and endotoxins studied by the quantitative clot protein method. Jpn. J. Med. Sci. Biol. 27: 108-111, 1974.
268 11. 12. 13. 14. 15. 16.
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ROBBOY, S.J., COLMAN, R.W., and MINNA,J.D. : Pathology of disseminated intravascular coagulation (DIC); analysis of 26 cases. Hum. Pathol. 3 : 327-343, 1972. RODRIGUEZ-ERDMANN, F. : Pathognesis of bilateral renal cortical necrosis ; its production by means of exogenous fibrin. Arch. Pathol. 79: 615-618, 1965. SCADDING, J.G.: Chronic diffuse interstitial fibrosis of the lungs. Brit. Med. J. 2: 443450, 1960. STACK,B.H.R., CHOO-KANG, Y.F.J., and HEARD,B.E.: The prognosis of cryptogenic fibrosing alveolitis. Thorax 27: 535-542, 1972. STARK,C.R., ABRAMSON, D., and ERKAN,V.: Intravascular coagulation and hyaline membrane disease of the newborn. Lancet 1 : 1180-1181, 1968. TAKEUCHI, T., MORI, Y., and OZAWA,U.: On the morphological analysis of renal arterial vasospasm and alteration of hernodynamics in the kidney; 1. morphological study of arterial vasoconstriction and dilatation with special reference to perinuclear vacuole of medial smooth muscle of the kidney. Nihon Univ. J. Med. 15: 193-208, 1973. THAL,A.P., and EGNER,W.: The site of action of the staphylococcus alpha toxin. J. Exp. Med. 113: 67-82, 1961.
