Beitr. Path. Bd. 155,3 09-3 1 5 (1975)
Case Reports
Departments of Pathology, Tel Aviv University Sadder School of Medicine, and Government Hospital, Jaffa, Israel
Congenital Bronchiolitis Obliterans N. ROSEN and E. GATON With 3 Figures· Received July 4, 1974 . Accepted in revised form September 12, 1974
Key words: Bronchiolitis - Lung - Pneumonia - Congenital - Pediatrics
Bronchiolitis obliterans is a disease characterized by the development of granulation tissue masses in the terminal bronchiolar lumina, following severe damage to their walls with failure to regenerate properly. Generalized bronchiolitis obliterans is a rare condition of obscure etiology which occurs mainly in adults. The lesion is known to be produced by massive inhalation of irritant fumes or gases, particularly nitrogen dioxide as in the "Silo-Fillers Disease". There have been a few cases described following viral or bacterial infections, and the diseases has been reported in "Wegener's Granulomatosis" of the lung. In children the disease is even more rare (Nezelof et aI., 1970; Sir, 1962). The following is an interesting case of generalized bronchiolitis obliterans occurring in a premature infant who died 35 hours post delivery. In our search of the literature we found only two other descriptions of congenital bronchiolitis obliterans (Meister and Wockel, 1964; Sir, 1962 ).1)
Report of a Case The patient, a male premature infant, was born to a 20-year-old gravida 7, para 6, abortus I, Rh-positive healthy mother. 1) After completion of the present article an additional case appeared in the literature (Sueishi et al.: Intrauterine Bronchiolitis Obliterans, Virchows Arch. Abt 362, 223-229, 1974)·
3 10 . N. Rosen and E. GatOn The infant was 27 gestational weeks old with a birth weight of 1,530 g and C-H length 42 cm. Delivery was spontaneous from a vertex presentation immediately after rupture of membranes. The umbilical cord prolapsed during labor but was reposed immediately. Family history was noncontributory. Both parents and the five living children are healthy. One sister died at the age of seven months, the cause of death heing unknown. On initial physical examination the infant was found to be in a moderate condition with weak tonus and respiratory distress manifested by irregular superficial breathing witli intercostal retractions. The heart sounds were normal. The liver was palpable 2 cm and the spleen 0.5 cm below the costal margins. The liver edge was soft. The kidneys were palpable and the left one appeared enlarged. A few hours after delivery nasal aspiration was performed and a yellowish fluid was removed. The infant's condition however, deteriorated, with increasing respiratory distress, cyanosis and diffuse rales throughout both lung fields. He died 35 hours after birth.
Autopsy findings The premature male infant weighed 1,480 g with a crown-heel length of 42 cm and showed mild cyanosis.
Macroscopic Findings. The pleural cavities were empty and the pleura thin, smooth and glistening. The combined lung weight was 43 g (normal 33.7 g). Pale areas were seen on the external surfaces. The parenchyma was solid and dark red. Small irregular yellowish foci were scattered throughout, which were often confluent, especially in the periphery and along bronchi. Focal emphysema was present in the central part of the lung. The large bronchi were normal, but some of the smaller bronchi were dilated (Fig. I). Hilar lymph nodes were normal. The right kidney weighed 10 g, was normal and its vessels were patent. The left kidney was enlarged weighing 15 g, and part of the left adrenal gland was involved by hemorrhagic infarction due to complete occlusion of the renal vein by an organizing thrombus. The heart weighed 23 g (10.8 g normal), and the liver 80 g (66 g normal). The thymus was hypoplastic. The brain showed congestion of meninges. The white matter, especially in the peri ventricular region, showed patches of dark, grey discoloration. Other organs were unremarkable. Microscopic Findings. Microscopical examination of the lung revealed premature lung tissue with signs of severe pneumonia. The alveoli were partially expanded and filled with foam cells and neutrophilic leukocytes. Here and there multinucleated giant foam cells could be seen. The main changes involved the terminal and respiratory bronchioles, in a great number of which the lumen was obliterated by polypoid structures
Congenital Bronchiolitis Obliterans . 3 I
I
Fig. 1. A cut section through the lung after formaldehyde fixation showing pale areas of consolidation along the bronchial tree and at the periphery with patchy emphysema centrally.
Fig. 2. A microphotograph of the lung showing dense p.eribronchiolar inflammatory infiltrations extending into the alveolar interstitium and expanded peripheral alveoli containing foam cells. The bronchiole in the center is obliterated by a polypoid mass.
HE; X
160
3 12 . N. Rosen and E. Gaton
Fig. 3. Bronchiolitis obliterans. Solid mass of fibroblastic granulation tissue growing into the bronchiolar lumen from a denuded area of the wall. Massive mononuclear infiltration of peri bronchiolar tissue, HE; X 250
of granulation tissue growing from the bronchiolar wall at points were they were denuded of epithelium. The granulation tissue contained numerous fibroblasts, histiocytes and foreign body giant cells, some of which contained iron pigment, fat droplets or empty clefts. At the base of the polypoid outgrowths the bronchiolar wall was damaged, heavily infiltrated by polymorphonuclear cells, and a very rich network of reticulum fibers extended from the wall into the granulation tissue masses. The larger bronchi had patent lumina, some exhibiting metaplastic changes of the mucosa towards stratified epithelium, while others had a hypersecretory intact mucosa. The interstitial tissue surrounding the small bronchioles was heavily infiltrated with polymorphous inflammatory cells. Some of the alveolar walls had ruptured, producing cystic emphysematous cavities (Fig. 2 and 3). Special stains for micro-organisms were negative. No inclusion bodies were seen. Microscopical examination of the left kidney showed confluent hemorrhagic infarcts which were calcified around the edges and contained clusters of hemosiderin-laden macrophages. The left renal pelvis contained
Congenital Bronchiolitis Obliterans . 3 I 3
fresh blood with collections of similar iron-laden macrophages. The left renal vein was obstructed by a large organizing thrombus. Other microscopical findings were hemorrhages in the left adrenal, recent focal periventricular hemorrhages in the brain, and depletion of the thymocytes in the thymus. Other organs showed no relevant pathological changes.
Discussion Bronchiolitis obliterans follows senous Injury to the bronchiolar wall with destruction of the mucosa and its failure to regenerate. The healing process leads to the development of granulation tissue masses from the denuded areas of the wall into the bronchial lumen. Although the air passages are exposed continuously to a multitude of noxious agents the occurrence of generalized bronchiolitis obliterans is rare. It appears mainly in adults (Baar and Galinda, 1966) and less frequently in children. In a study of 5.000 autopsies of children Sir (1962) found only two cases. Nezelof et al. (1970) reported another two cases in a 21/2-yearold boy and a 9-month-old infant. To our knowledge only two cases of congenital bronchiolitis obliterans have been reported in the literature, one by Sir (1962) in a premature infant who lived 80 minutes, and the other by Meister (1964) in a premature who lived 7 hours. Our patient was a premature infant who lived for 35 hours. Pregnancy and delivery were normal, with the exception of the umbilical cord prolapse which was immediately reposed, but the infant presented from birth with signs of respiratory insufficiency. The obliterative process of the bronchioles was accompanied by a severe pneumonia with interstitial and peribronchial infiltrations suggesting its intra-uterine origin. Other findings were massve infarction of the left kidney and adrenal due to an organizing renal vein thrombosis, equally acquired in utero, as well as severe congestion of the brain. Congenital pneumonia is quite frequent in premature infants. It results from contamination of the lung by infected amniotic fluid or by hematogenous infection from the mother. Histologically it is characterized by intra-alveolar leukocytic exudation and interstitial peribronchial infiltrates but without involvement of the bronchial tree. In the case presented above the striking lesion was the bronchiolar damage. The terminal and respiratory bronchioles were obstructed by plugs of granulation tissue. The large bronchi showed epithelial metaplasia of the mucosa. The presence of an
314 . N. Rosen and E. Gaton
organizing renal vein thrombosis with infarctions in the kidney is additional evidence of severe intrauterine injury, but does not clarify the exact etiology in this case. Renal vein thrombosis in the newborn is not a rare finding. It may be due to dehydration, infection, shock or therapeutic agents, as well as toxemia of pregnancy, birth trauma and anoxemia. The search for specific etiological factors, such as bacteria, viruses or foreign material was negative in our case. However, the renal infarction may explain the presence of the foreign body giant cells within the alveolar exudate, the infarction probably being the source of contamination from which necrotic material, blood and iron-laden macrophages were expelled into the amniotic sac. This material reaching the air spaces in the lung may have evoked the foreign body reaction we found. Our case has much in common with the two other cases in the literature. All three were premature infants, born after normal labor, weighing about 1,400 g. They presented with respiratory insufficiency and had identical pathological pictures. No relevant events occurred during the pregnancy and labor period, except in Sir's case where the mother had an episode of posttraumatic uterine hemorrhage two months prior to delivery. The exact etiology and pathogenesis of bronchiolitis obliterans could not be established in any of the three cases. However, among the possible causes considered were aspiration of infected amniotic fluid, maternal virus infection during pregnancy, a special predisposition for proliferation of granulation tissue, local circulatory disturbances, hypersensitivity and lowering of body resistance (Sir, 1962). Thus, the etiology of this condition remains obscure.
Summary A case is described of intrauterine pneumonia with "Congenital Bronchiolitis Obliterans" in a premature infant who died 35 hours after delivery. The patient presented from birth with increasingly severe respiratory insufficiency. Post-mortem histological examination of the lung revealed obliterative bronchiolitis, a rare disease which the patient most probably develop.ed in utero. Only two other similar cases of congenital obliterative bronchiolitis have been reported in the literature, both with obscure etiology. A detailed pathological description of pulmonary changes is given and the literature is reviewed. Acknowledgment We thank Dr. K. Schaffler, Mrs. Frances Zedand and Miss Rosemarie Spiegel for their helpful assistance. Mrs. Liliane Dattner and Mrs. Shelly Mitrani for their valuable technical work and Mr. Z vi Y osef for the photomicrographs.
Congenital Bronchiolitis Obliterans . 3 I 5
References Baar, H. S. and Galinda, J.: Bronchiolitis Fibrosa Obliterans. Thorax 21, 209 (1966) Meister, H. and Wockel, W.: Bronchiolitis Obliterans Connata. Zbl. AUg. Path. Anat. 10 5, 501 (19 64) 3· Nezelof, Ch., Meyer, B., DaUoz, ]-CI., ]oly, Ph., Paupe, ]. and Vialatte, J.: La Bronchiolite Obliterante. A propos de deux observations anatemo-c1iniques infantiles. Ann. Pediat. (Paris) 17, 534, ([970) 4. Sir, G.: Bronchiolitis Obliterans Connata. Zbl. AUg. Path. Path. Anat. 103, 129 (1962) I.
2.
Dr. Edith Gaten, Department of Pathology, Tel-Aviv University Sadder School of Medicine, Ramat-Aviv, 61999, Israel
Case Reports
Departments of Pathology, Tel Aviv University Sadder School of Medicine, and Government Hospital, Jaffa, Israel
Congenital Bronchiolitis Obliterans N. ROSEN and E. GATON With 3 Figures· Received July 4, 1974 . Accepted in revised form September 12, 1974
Key words: Bronchiolitis - Lung - Pneumonia - Congenital - Pediatrics
Bronchiolitis obliterans is a disease characterized by the development of granulation tissue masses in the terminal bronchiolar lumina, following severe damage to their walls with failure to regenerate properly. Generalized bronchiolitis obliterans is a rare condition of obscure etiology which occurs mainly in adults. The lesion is known to be produced by massive inhalation of irritant fumes or gases, particularly nitrogen dioxide as in the "Silo-Fillers Disease". There have been a few cases described following viral or bacterial infections, and the diseases has been reported in "Wegener's Granulomatosis" of the lung. In children the disease is even more rare (Nezelof et aI., 1970; Sir, 1962). The following is an interesting case of generalized bronchiolitis obliterans occurring in a premature infant who died 35 hours post delivery. In our search of the literature we found only two other descriptions of congenital bronchiolitis obliterans (Meister and Wockel, 1964; Sir, 1962 ).1)
Report of a Case The patient, a male premature infant, was born to a 20-year-old gravida 7, para 6, abortus I, Rh-positive healthy mother. 1) After completion of the present article an additional case appeared in the literature (Sueishi et al.: Intrauterine Bronchiolitis Obliterans, Virchows Arch. Abt 362, 223-229, 1974)·
3 10 . N. Rosen and E. GatOn The infant was 27 gestational weeks old with a birth weight of 1,530 g and C-H length 42 cm. Delivery was spontaneous from a vertex presentation immediately after rupture of membranes. The umbilical cord prolapsed during labor but was reposed immediately. Family history was noncontributory. Both parents and the five living children are healthy. One sister died at the age of seven months, the cause of death heing unknown. On initial physical examination the infant was found to be in a moderate condition with weak tonus and respiratory distress manifested by irregular superficial breathing witli intercostal retractions. The heart sounds were normal. The liver was palpable 2 cm and the spleen 0.5 cm below the costal margins. The liver edge was soft. The kidneys were palpable and the left one appeared enlarged. A few hours after delivery nasal aspiration was performed and a yellowish fluid was removed. The infant's condition however, deteriorated, with increasing respiratory distress, cyanosis and diffuse rales throughout both lung fields. He died 35 hours after birth.
Autopsy findings The premature male infant weighed 1,480 g with a crown-heel length of 42 cm and showed mild cyanosis.
Macroscopic Findings. The pleural cavities were empty and the pleura thin, smooth and glistening. The combined lung weight was 43 g (normal 33.7 g). Pale areas were seen on the external surfaces. The parenchyma was solid and dark red. Small irregular yellowish foci were scattered throughout, which were often confluent, especially in the periphery and along bronchi. Focal emphysema was present in the central part of the lung. The large bronchi were normal, but some of the smaller bronchi were dilated (Fig. I). Hilar lymph nodes were normal. The right kidney weighed 10 g, was normal and its vessels were patent. The left kidney was enlarged weighing 15 g, and part of the left adrenal gland was involved by hemorrhagic infarction due to complete occlusion of the renal vein by an organizing thrombus. The heart weighed 23 g (10.8 g normal), and the liver 80 g (66 g normal). The thymus was hypoplastic. The brain showed congestion of meninges. The white matter, especially in the peri ventricular region, showed patches of dark, grey discoloration. Other organs were unremarkable. Microscopic Findings. Microscopical examination of the lung revealed premature lung tissue with signs of severe pneumonia. The alveoli were partially expanded and filled with foam cells and neutrophilic leukocytes. Here and there multinucleated giant foam cells could be seen. The main changes involved the terminal and respiratory bronchioles, in a great number of which the lumen was obliterated by polypoid structures
Congenital Bronchiolitis Obliterans . 3 I
I
Fig. 1. A cut section through the lung after formaldehyde fixation showing pale areas of consolidation along the bronchial tree and at the periphery with patchy emphysema centrally.
Fig. 2. A microphotograph of the lung showing dense p.eribronchiolar inflammatory infiltrations extending into the alveolar interstitium and expanded peripheral alveoli containing foam cells. The bronchiole in the center is obliterated by a polypoid mass.
HE; X
160
3 12 . N. Rosen and E. Gaton
Fig. 3. Bronchiolitis obliterans. Solid mass of fibroblastic granulation tissue growing into the bronchiolar lumen from a denuded area of the wall. Massive mononuclear infiltration of peri bronchiolar tissue, HE; X 250
of granulation tissue growing from the bronchiolar wall at points were they were denuded of epithelium. The granulation tissue contained numerous fibroblasts, histiocytes and foreign body giant cells, some of which contained iron pigment, fat droplets or empty clefts. At the base of the polypoid outgrowths the bronchiolar wall was damaged, heavily infiltrated by polymorphonuclear cells, and a very rich network of reticulum fibers extended from the wall into the granulation tissue masses. The larger bronchi had patent lumina, some exhibiting metaplastic changes of the mucosa towards stratified epithelium, while others had a hypersecretory intact mucosa. The interstitial tissue surrounding the small bronchioles was heavily infiltrated with polymorphous inflammatory cells. Some of the alveolar walls had ruptured, producing cystic emphysematous cavities (Fig. 2 and 3). Special stains for micro-organisms were negative. No inclusion bodies were seen. Microscopical examination of the left kidney showed confluent hemorrhagic infarcts which were calcified around the edges and contained clusters of hemosiderin-laden macrophages. The left renal pelvis contained
Congenital Bronchiolitis Obliterans . 3 I 3
fresh blood with collections of similar iron-laden macrophages. The left renal vein was obstructed by a large organizing thrombus. Other microscopical findings were hemorrhages in the left adrenal, recent focal periventricular hemorrhages in the brain, and depletion of the thymocytes in the thymus. Other organs showed no relevant pathological changes.
Discussion Bronchiolitis obliterans follows senous Injury to the bronchiolar wall with destruction of the mucosa and its failure to regenerate. The healing process leads to the development of granulation tissue masses from the denuded areas of the wall into the bronchial lumen. Although the air passages are exposed continuously to a multitude of noxious agents the occurrence of generalized bronchiolitis obliterans is rare. It appears mainly in adults (Baar and Galinda, 1966) and less frequently in children. In a study of 5.000 autopsies of children Sir (1962) found only two cases. Nezelof et al. (1970) reported another two cases in a 21/2-yearold boy and a 9-month-old infant. To our knowledge only two cases of congenital bronchiolitis obliterans have been reported in the literature, one by Sir (1962) in a premature infant who lived 80 minutes, and the other by Meister (1964) in a premature who lived 7 hours. Our patient was a premature infant who lived for 35 hours. Pregnancy and delivery were normal, with the exception of the umbilical cord prolapse which was immediately reposed, but the infant presented from birth with signs of respiratory insufficiency. The obliterative process of the bronchioles was accompanied by a severe pneumonia with interstitial and peribronchial infiltrations suggesting its intra-uterine origin. Other findings were massve infarction of the left kidney and adrenal due to an organizing renal vein thrombosis, equally acquired in utero, as well as severe congestion of the brain. Congenital pneumonia is quite frequent in premature infants. It results from contamination of the lung by infected amniotic fluid or by hematogenous infection from the mother. Histologically it is characterized by intra-alveolar leukocytic exudation and interstitial peribronchial infiltrates but without involvement of the bronchial tree. In the case presented above the striking lesion was the bronchiolar damage. The terminal and respiratory bronchioles were obstructed by plugs of granulation tissue. The large bronchi showed epithelial metaplasia of the mucosa. The presence of an
314 . N. Rosen and E. Gaton
organizing renal vein thrombosis with infarctions in the kidney is additional evidence of severe intrauterine injury, but does not clarify the exact etiology in this case. Renal vein thrombosis in the newborn is not a rare finding. It may be due to dehydration, infection, shock or therapeutic agents, as well as toxemia of pregnancy, birth trauma and anoxemia. The search for specific etiological factors, such as bacteria, viruses or foreign material was negative in our case. However, the renal infarction may explain the presence of the foreign body giant cells within the alveolar exudate, the infarction probably being the source of contamination from which necrotic material, blood and iron-laden macrophages were expelled into the amniotic sac. This material reaching the air spaces in the lung may have evoked the foreign body reaction we found. Our case has much in common with the two other cases in the literature. All three were premature infants, born after normal labor, weighing about 1,400 g. They presented with respiratory insufficiency and had identical pathological pictures. No relevant events occurred during the pregnancy and labor period, except in Sir's case where the mother had an episode of posttraumatic uterine hemorrhage two months prior to delivery. The exact etiology and pathogenesis of bronchiolitis obliterans could not be established in any of the three cases. However, among the possible causes considered were aspiration of infected amniotic fluid, maternal virus infection during pregnancy, a special predisposition for proliferation of granulation tissue, local circulatory disturbances, hypersensitivity and lowering of body resistance (Sir, 1962). Thus, the etiology of this condition remains obscure.
Summary A case is described of intrauterine pneumonia with "Congenital Bronchiolitis Obliterans" in a premature infant who died 35 hours after delivery. The patient presented from birth with increasingly severe respiratory insufficiency. Post-mortem histological examination of the lung revealed obliterative bronchiolitis, a rare disease which the patient most probably develop.ed in utero. Only two other similar cases of congenital obliterative bronchiolitis have been reported in the literature, both with obscure etiology. A detailed pathological description of pulmonary changes is given and the literature is reviewed. Acknowledgment We thank Dr. K. Schaffler, Mrs. Frances Zedand and Miss Rosemarie Spiegel for their helpful assistance. Mrs. Liliane Dattner and Mrs. Shelly Mitrani for their valuable technical work and Mr. Z vi Y osef for the photomicrographs.
Congenital Bronchiolitis Obliterans . 3 I 5
References Baar, H. S. and Galinda, J.: Bronchiolitis Fibrosa Obliterans. Thorax 21, 209 (1966) Meister, H. and Wockel, W.: Bronchiolitis Obliterans Connata. Zbl. AUg. Path. Anat. 10 5, 501 (19 64) 3· Nezelof, Ch., Meyer, B., DaUoz, ]-CI., ]oly, Ph., Paupe, ]. and Vialatte, J.: La Bronchiolite Obliterante. A propos de deux observations anatemo-c1iniques infantiles. Ann. Pediat. (Paris) 17, 534, ([970) 4. Sir, G.: Bronchiolitis Obliterans Connata. Zbl. AUg. Path. Path. Anat. 103, 129 (1962) I.
2.
Dr. Edith Gaten, Department of Pathology, Tel-Aviv University Sadder School of Medicine, Ramat-Aviv, 61999, Israel
