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Hyaline-membrane Formation in the Adult Lung
362
training in the provinces ". In promoting these reforms, certainly it would be wrong to divert large resources from the undergraduate medical schools, in which the foundations of a lifelong ability to learn must be laid. Still less should we accept any distinction between undergraduate medical teachers " and " postgraduate medical teachers ": any good teacher can and should do both, and be the better for doing so. Just as trainees in regional hospitals can benefit from access to the facilities of the teaching centre, so medical students can learn a great deal from the rich practice of regional hospitals; and there is a good case for some concentration of special facilities in a hospital group adjacent to the university. But can we really be content with medical education until every hospital in the land is in some sense " a teaching hospital " ? "
Hyaline-membrane
Formation in the
Adult Lung HYALINE-MEMBRANE formation in the lung has
lately regarded as a prominent feature of the respiratory-distress syndrome in the newborn.12 It is also sometimes a complicating factor in some severe illnesses in older children and adults. Hyaline membranes were seen in the lungs of patients dying during the great influenza epidemic of 1919 and were described in detail by WOLBACH3 and others.45 In acute rheumatism some patients have pulmonary complications, with cough, dyspnoea, and a bloody sputum 6; and lung changes were outlined by HADFIELD.7 The primary lesion is a widespread fibrinous alveolitis with mononuclear-cell infiltration and hyaline-pseudomembrane come to
be
formation in most of the alveolar ducts. EpSTEIN and GREENSPANdescribed a similar picture of rheumatic pneumonia in the lungs of 16 out of 45 patients with rheumatic fever, and they thought the membrane was the result of damaged capillaries and increased permeability to plasma-proteins. NEUBERGER et awl. found 8 patients with distinctive pulmonary changes among 63 consecutive cases of active and quiescent rheumatic fever in older children and young adults between 12 and 22 years of age. In 5 of the 8 patients hyaline membranes were found in the lungs at necropsy. Histologically, in addition to the membrane formation, there was a fibrinous alveolar exudate composed of polymorphonuclear leucocytes, lymphocytes, and red cells, fibrinoid necrosis of the alveolar walls, fibrinoid swelling of pulmonary arterioles, and distinctive granulomatous lesions in the lumen of alveoli and alveolar ducts (Masson bodies). Hyaline-membrane formation has also been seen in the lungs of patients dying from pneumonic plague 10 and in lungs damaged by mustard gas.l1 Less commonly, hyaline membranes have been noted 1. Lancet, 1958, ii, 945. 2. ibid. 1960, ii, 1014. 3. Wolbach, S. B. Bull. Johns Hopk. Hosp. 1919, 30, 104. 4. Le Count, E. R. J. Amer. med. Ass. 1919, 72, 650. 5. Bruman, D., Goodpasture, E. W. Arch. intern. Med. 1924, 34, 739. 6. Masson, P., Rispelle, J. L., Martin, P. Ann. anat. path. 1937, 14, 359. 7. Hadfield, G. Lancet, 1938, ii, 710. 8. Epstein, E. C., Greenspan, E. B. Arch. intern. Med. 1941, 68, 1074. 9. Neuberger, K. T., Greeves, E. F., Rutledge, E. K. Arch. path. 1944, 37, 1. 10. Johnson, W. C. Proc. N.Y. path. Soc. 1923, 23, 138. 11. Kuczinski, M. H., Wolff, E. K. Ergebn. allg. Path. path. nat. 1921, 19, 947.
in the lungs of patients dying of uraemia. In an intensive study 12 of 107 such cases, 66 (62%) showed changes indicative of " uraemic pneumonitis ". The lungs were increased in weight and had a diffuse rubbery consistence. The cut surface was pale red, and a fibrinous pleurisy was often present. Microscopically the alveoli contained a granular protein precipitate which was sometimes arranged in a fine network, and at other times in dense hyaline masses, or was adherent to the alveolar walls in the form of a hyaline membrane. A cellular exudate was present in some alveoli but consisted largely of macrophages. No granulocytes were seen except in zones of actual bronchopneumonic consolidation, which was found in 38 of the 66 affected lungs. More recently, CAPERS 13 has found hyaline membranes in the lungs of adults who had died from a wide variety of conditions. He studied all lungs examined at necropsy at Dallas Veterans Administration Hospital in 1960, and 10 examples of hyaline-membrane formation emerged from 352 cases. 8 further examples were discovered among patients dying in the three previous years, and there were another 19 cases of slight membrane formation, giving a total of 37. In 18 patients the lesion was bilateral, in 10 it was unilateral, and in 9 the distribution was unknown. 13 patients had neoplastic disease, and 6 of these had lung cancer. The other neoplasms were malignant melanoma, carcinomas of larynx, hypopharynx, adrenal gland, and kidney, and Hodgkin’s disease; and 1 patient had a thymoma. There were 3 cases of chronic liver disease, 3 of arteriosclerotic heart-disease, and 6 of coronary thrombosis. Other conditions included rheumatoid arthritis, interstitial
pneumonitis, pulmonary tuberculosis, nephrosclerosis, uraemia, diabetes mellitus, and acute pancreatitis. The patients’ ages ranged from 31 to 80 years, and the average was 54 years. There seemed to be no association between the presence of pulmonary oedema and hyalinemembrane formation in the affected lungs, but nearly half the patients had had blood-transfusion shortly before they died. A patient with aplastic anaemia had needed 192 transfusions over a long period and the hyaline membranes gave a strongly positive reaction for iron. It is thus possible that circulatory overload associated with blood-transfusion may be a factor in the development of a hyaline membrane in the adult lung. Hyaline membrane has been seen after radiotherapy 14 and total-body irradiation 15; but only 3 patients in CAPERS’ series had had radiotherapy. The gross pulmonary changes in the adult closely resemble those in the newborn infant.16 Histologically, the membrane in both adult and infant is composed of layers of strongly eosinophilic material, presumably mainly fibrin. The walls of both alveolar ducts and alveoli may be lined with this material, and the ducts are often the commoner site in the adult7 as in the infant,16 Here, as is to be expected, the resemblance between the Hopps, H. C., Wissler, R. W. Amer. J. Path. 1955, 31, 261. Capers, T. H. Amer. J. Med. 1961, 31, 701. Warren, S., Gates, O. Arch. path. 1940, 30, 440. Fleming, W. H., Szabacs, J. E., Hartney, T. C., King, E. R. Lancet, 1960, ii, 1010. 16. ibid. 1959, i, 1234.
12. 13. 14. 15.
363
conditions ends. In the infant lung the picture is that of a severe diffuse atelectasis, which is very rare in the adult.12 Any atelectasis there may be in the adult two
usually very patchy. (Edema is also fairly common in the lungs of newborn infants with membrane lung
is
formation, but it is seldom found in the adult, and the large pools17 of protein seen in pulmonary alveolar proteinosis are not usually accompanied by membrane formation. Pulmonary congestion is more constantly associated with membrane formation in the infant lung. The adult and infant hyaline membranes react similarly to special stains. They both give positive results with the periodic-acid/ Schiff stain and both are largely devoid of fat. The adult membranes may give a positive stain for fibrin, whereas the infant membranes are usually negative. Careful study of membranes in both adults and infants suggests that they are very similar and that fibrin is one of the chief components. This seems to indicate that the membrane is formed by the escape of protein from the pulmonary vascular bed into the air spaces. The presence of iron in the hyaline membrane of the patient who had had many bloodtransfusions supports this view. The cause of the transudate into the lung is very variable. Sometimes, as in influenza and acute rheumatism, an inflammatory reaction is responsible. Or an irritant such as mustard gas may be implicated. Hyaline membranes can also be produced experimentally by oxygen poisoning,18 and, in 14 out of 18 severe cases reported by CAPERS, oxygen had been inhaled, with or without positive-pressure breathing. In the newborn, the cause of membrane formation is complex. It is probably associated with changes in the alveolar surface tension 19 and in the hxmodynamics of the pulmonary circulation immediately after birth. It has been suggested that deficiency of lung fibrinolysin 20 may also play a part in membrane formation in the newborn lung. It is not yet known whether fibrinolysin is similarly lacking in the lungs of adults with membrane formation. Both the adult and the newborn infant suffer much respiratory embarrassment when hyaline membrane forms, and there seems little doubt that the membrane, when widespread, seriously interferes with gaseous exchange in the lungs. It is of some clinical interest that membrane is now known to form in many different conditions in the adult and not merely in association with inflammatory lesions.
O’nyong-nyong THE story of O’nyong-nyong fever is as fascinating as its name, which means " the joint breaker " in the tribal language of the Acholi district of Northern Uganda. The villagers first affected were unfamiliar with the condition and invented a name to describe it. Laboratory tests showed that the virus fell into the broad category of the arthropod-borne viruses, and within the serological group A, although O’nyong-nyong virus was clearly 17. Rosen,
S., Castleman, B., Liebow, A. A. New Engl. J. Med. 1958, 258, 1123. 18. Bruns, P. D., Shields, L. V. Amer. J. Obstet. Gynec. 1951, 61, 953. 19. Pattle, R. E. J. Path. Bact. 1961, 82, 333. 20. Lieberman, J. New Engl. J. Med. 1959, 260, 619; see also J. S. Crawford and P. E. G. Mitchell, Lancet, Feb. 3, 1962, p. 250.
distinct from any other group-A virus. Entomological studies indicated that the virus was carried by anopheles mosquitoes-agents which, though important vectors of malaria, have never before been shown to spread an epidemic virus disease of man. These findings, described in a series of papers, 1-5 are summarised in the latest report on Colonial Research.6 The disease is characterised by fever, headache, joint pains which are often crippling, an itching rash, and, in many cases, painful lymphadenopathy. The first cases were recognised in the north-western region of Uganda in February, 1959. From this focus the epidemic spread southeastward at a rate of 1.7 miles per day during the first eight months. All age-groups were affected, and attack-rates of 50-75% of the total population were general. It is estimated that there have been about a million cases in two years, and the condition is apparently still active in the southern parts of Uganda around the shores of Lake Victoria. No deaths directly attributable to the disease have been reported, but the epidemic was certainly a notable one in the public-health records of East Africa. The fever was thought to be probably of viral origin, and the Uganda Medical Department called on the staff of the Virus Research Institute in Entebbe to investigate its xtiology. Dengue or chikungunya viruses were suspected-particularly the latter since this virus had been isolated from clinically similar cases in Tanganyikain the Congo,and also in Uganda itself. This view was strengthened when serum from 9 of 11 convalescent patients was found to contain neutralising antibodies against chikungunya virus. Attempts to isolate virus from human material and from mosquito suspensions were at first unsuccessful, although no such difficulties had been experienced in earlier studies on chikungunya virus. Successful results were later achieved by the use of day-old mice, a curious patchy alopecia being used as evidence of infection in these animals. Two strains which were adapted to kill baby mice were sent to the National Institute for Medical Research, London, where they were tested against a battery of antisera, by means of tissue-culture methods instead of injection into mice. It was established that O’nyong-nyong was related to chikungunya, and that the virus was to some extent neutralised by chikungunya antiserum (the converse did not hold). O’nyong-nyong was clearly distinct from fourteen other group-A arthropod-borne viruses isolated in Africa, North and South America, and Asia. Meanwhile, entomological studies in Uganda had shown that O’nyong-nyong was almost certainly being spread by anopheles mosquitoes. This finding cuts right across all previous vector studies with arthropod-borne viruses. Different viruses have occasionally been 1.
2. 3. 4. 5. 6. 7. 8.
Haddow, A. J., Davies, C. W., Walker, A. J. Trans. R. Soc. trop. Med. Hyg. 1960, 54, 517. Williams, M. C., Woodall, J. P. ibid. 1961, 55, 135. Shore, H. ibid. p. 361. Corbet, P. S., Williams, M. C., Gillett, J. D. ibid. p. 463. Porterfield, J. S. Bull. Wld Hlth Org. 1961, 24, 735. Colonial Research 1960-61. Cmnd 1584. H.M. Stationery Office, 1961. Pp. 353. 18s. Ross, R. W. J. Hyg., Camb. 1956, 54, 177. Osterrieth, P., Deleplanque-Liegeois, P., Blanes-Ridaura, G. Ann. Soc. belge Méd. trop. 1960, 40, 199.
training in the provinces ". In promoting these reforms, certainly it would be wrong to divert large resources from the undergraduate medical schools, in which the foundations of a lifelong ability to learn must be laid. Still less should we accept any distinction between undergraduate medical teachers " and " postgraduate medical teachers ": any good teacher can and should do both, and be the better for doing so. Just as trainees in regional hospitals can benefit from access to the facilities of the teaching centre, so medical students can learn a great deal from the rich practice of regional hospitals; and there is a good case for some concentration of special facilities in a hospital group adjacent to the university. But can we really be content with medical education until every hospital in the land is in some sense " a teaching hospital " ? "
Hyaline-membrane
Formation in the
Adult Lung HYALINE-MEMBRANE formation in the lung has
lately regarded as a prominent feature of the respiratory-distress syndrome in the newborn.12 It is also sometimes a complicating factor in some severe illnesses in older children and adults. Hyaline membranes were seen in the lungs of patients dying during the great influenza epidemic of 1919 and were described in detail by WOLBACH3 and others.45 In acute rheumatism some patients have pulmonary complications, with cough, dyspnoea, and a bloody sputum 6; and lung changes were outlined by HADFIELD.7 The primary lesion is a widespread fibrinous alveolitis with mononuclear-cell infiltration and hyaline-pseudomembrane come to
be
formation in most of the alveolar ducts. EpSTEIN and GREENSPANdescribed a similar picture of rheumatic pneumonia in the lungs of 16 out of 45 patients with rheumatic fever, and they thought the membrane was the result of damaged capillaries and increased permeability to plasma-proteins. NEUBERGER et awl. found 8 patients with distinctive pulmonary changes among 63 consecutive cases of active and quiescent rheumatic fever in older children and young adults between 12 and 22 years of age. In 5 of the 8 patients hyaline membranes were found in the lungs at necropsy. Histologically, in addition to the membrane formation, there was a fibrinous alveolar exudate composed of polymorphonuclear leucocytes, lymphocytes, and red cells, fibrinoid necrosis of the alveolar walls, fibrinoid swelling of pulmonary arterioles, and distinctive granulomatous lesions in the lumen of alveoli and alveolar ducts (Masson bodies). Hyaline-membrane formation has also been seen in the lungs of patients dying from pneumonic plague 10 and in lungs damaged by mustard gas.l1 Less commonly, hyaline membranes have been noted 1. Lancet, 1958, ii, 945. 2. ibid. 1960, ii, 1014. 3. Wolbach, S. B. Bull. Johns Hopk. Hosp. 1919, 30, 104. 4. Le Count, E. R. J. Amer. med. Ass. 1919, 72, 650. 5. Bruman, D., Goodpasture, E. W. Arch. intern. Med. 1924, 34, 739. 6. Masson, P., Rispelle, J. L., Martin, P. Ann. anat. path. 1937, 14, 359. 7. Hadfield, G. Lancet, 1938, ii, 710. 8. Epstein, E. C., Greenspan, E. B. Arch. intern. Med. 1941, 68, 1074. 9. Neuberger, K. T., Greeves, E. F., Rutledge, E. K. Arch. path. 1944, 37, 1. 10. Johnson, W. C. Proc. N.Y. path. Soc. 1923, 23, 138. 11. Kuczinski, M. H., Wolff, E. K. Ergebn. allg. Path. path. nat. 1921, 19, 947.
in the lungs of patients dying of uraemia. In an intensive study 12 of 107 such cases, 66 (62%) showed changes indicative of " uraemic pneumonitis ". The lungs were increased in weight and had a diffuse rubbery consistence. The cut surface was pale red, and a fibrinous pleurisy was often present. Microscopically the alveoli contained a granular protein precipitate which was sometimes arranged in a fine network, and at other times in dense hyaline masses, or was adherent to the alveolar walls in the form of a hyaline membrane. A cellular exudate was present in some alveoli but consisted largely of macrophages. No granulocytes were seen except in zones of actual bronchopneumonic consolidation, which was found in 38 of the 66 affected lungs. More recently, CAPERS 13 has found hyaline membranes in the lungs of adults who had died from a wide variety of conditions. He studied all lungs examined at necropsy at Dallas Veterans Administration Hospital in 1960, and 10 examples of hyaline-membrane formation emerged from 352 cases. 8 further examples were discovered among patients dying in the three previous years, and there were another 19 cases of slight membrane formation, giving a total of 37. In 18 patients the lesion was bilateral, in 10 it was unilateral, and in 9 the distribution was unknown. 13 patients had neoplastic disease, and 6 of these had lung cancer. The other neoplasms were malignant melanoma, carcinomas of larynx, hypopharynx, adrenal gland, and kidney, and Hodgkin’s disease; and 1 patient had a thymoma. There were 3 cases of chronic liver disease, 3 of arteriosclerotic heart-disease, and 6 of coronary thrombosis. Other conditions included rheumatoid arthritis, interstitial
pneumonitis, pulmonary tuberculosis, nephrosclerosis, uraemia, diabetes mellitus, and acute pancreatitis. The patients’ ages ranged from 31 to 80 years, and the average was 54 years. There seemed to be no association between the presence of pulmonary oedema and hyalinemembrane formation in the affected lungs, but nearly half the patients had had blood-transfusion shortly before they died. A patient with aplastic anaemia had needed 192 transfusions over a long period and the hyaline membranes gave a strongly positive reaction for iron. It is thus possible that circulatory overload associated with blood-transfusion may be a factor in the development of a hyaline membrane in the adult lung. Hyaline membrane has been seen after radiotherapy 14 and total-body irradiation 15; but only 3 patients in CAPERS’ series had had radiotherapy. The gross pulmonary changes in the adult closely resemble those in the newborn infant.16 Histologically, the membrane in both adult and infant is composed of layers of strongly eosinophilic material, presumably mainly fibrin. The walls of both alveolar ducts and alveoli may be lined with this material, and the ducts are often the commoner site in the adult7 as in the infant,16 Here, as is to be expected, the resemblance between the Hopps, H. C., Wissler, R. W. Amer. J. Path. 1955, 31, 261. Capers, T. H. Amer. J. Med. 1961, 31, 701. Warren, S., Gates, O. Arch. path. 1940, 30, 440. Fleming, W. H., Szabacs, J. E., Hartney, T. C., King, E. R. Lancet, 1960, ii, 1010. 16. ibid. 1959, i, 1234.
12. 13. 14. 15.
363
conditions ends. In the infant lung the picture is that of a severe diffuse atelectasis, which is very rare in the adult.12 Any atelectasis there may be in the adult two
usually very patchy. (Edema is also fairly common in the lungs of newborn infants with membrane lung
is
formation, but it is seldom found in the adult, and the large pools17 of protein seen in pulmonary alveolar proteinosis are not usually accompanied by membrane formation. Pulmonary congestion is more constantly associated with membrane formation in the infant lung. The adult and infant hyaline membranes react similarly to special stains. They both give positive results with the periodic-acid/ Schiff stain and both are largely devoid of fat. The adult membranes may give a positive stain for fibrin, whereas the infant membranes are usually negative. Careful study of membranes in both adults and infants suggests that they are very similar and that fibrin is one of the chief components. This seems to indicate that the membrane is formed by the escape of protein from the pulmonary vascular bed into the air spaces. The presence of iron in the hyaline membrane of the patient who had had many bloodtransfusions supports this view. The cause of the transudate into the lung is very variable. Sometimes, as in influenza and acute rheumatism, an inflammatory reaction is responsible. Or an irritant such as mustard gas may be implicated. Hyaline membranes can also be produced experimentally by oxygen poisoning,18 and, in 14 out of 18 severe cases reported by CAPERS, oxygen had been inhaled, with or without positive-pressure breathing. In the newborn, the cause of membrane formation is complex. It is probably associated with changes in the alveolar surface tension 19 and in the hxmodynamics of the pulmonary circulation immediately after birth. It has been suggested that deficiency of lung fibrinolysin 20 may also play a part in membrane formation in the newborn lung. It is not yet known whether fibrinolysin is similarly lacking in the lungs of adults with membrane formation. Both the adult and the newborn infant suffer much respiratory embarrassment when hyaline membrane forms, and there seems little doubt that the membrane, when widespread, seriously interferes with gaseous exchange in the lungs. It is of some clinical interest that membrane is now known to form in many different conditions in the adult and not merely in association with inflammatory lesions.
O’nyong-nyong THE story of O’nyong-nyong fever is as fascinating as its name, which means " the joint breaker " in the tribal language of the Acholi district of Northern Uganda. The villagers first affected were unfamiliar with the condition and invented a name to describe it. Laboratory tests showed that the virus fell into the broad category of the arthropod-borne viruses, and within the serological group A, although O’nyong-nyong virus was clearly 17. Rosen,
S., Castleman, B., Liebow, A. A. New Engl. J. Med. 1958, 258, 1123. 18. Bruns, P. D., Shields, L. V. Amer. J. Obstet. Gynec. 1951, 61, 953. 19. Pattle, R. E. J. Path. Bact. 1961, 82, 333. 20. Lieberman, J. New Engl. J. Med. 1959, 260, 619; see also J. S. Crawford and P. E. G. Mitchell, Lancet, Feb. 3, 1962, p. 250.
distinct from any other group-A virus. Entomological studies indicated that the virus was carried by anopheles mosquitoes-agents which, though important vectors of malaria, have never before been shown to spread an epidemic virus disease of man. These findings, described in a series of papers, 1-5 are summarised in the latest report on Colonial Research.6 The disease is characterised by fever, headache, joint pains which are often crippling, an itching rash, and, in many cases, painful lymphadenopathy. The first cases were recognised in the north-western region of Uganda in February, 1959. From this focus the epidemic spread southeastward at a rate of 1.7 miles per day during the first eight months. All age-groups were affected, and attack-rates of 50-75% of the total population were general. It is estimated that there have been about a million cases in two years, and the condition is apparently still active in the southern parts of Uganda around the shores of Lake Victoria. No deaths directly attributable to the disease have been reported, but the epidemic was certainly a notable one in the public-health records of East Africa. The fever was thought to be probably of viral origin, and the Uganda Medical Department called on the staff of the Virus Research Institute in Entebbe to investigate its xtiology. Dengue or chikungunya viruses were suspected-particularly the latter since this virus had been isolated from clinically similar cases in Tanganyikain the Congo,and also in Uganda itself. This view was strengthened when serum from 9 of 11 convalescent patients was found to contain neutralising antibodies against chikungunya virus. Attempts to isolate virus from human material and from mosquito suspensions were at first unsuccessful, although no such difficulties had been experienced in earlier studies on chikungunya virus. Successful results were later achieved by the use of day-old mice, a curious patchy alopecia being used as evidence of infection in these animals. Two strains which were adapted to kill baby mice were sent to the National Institute for Medical Research, London, where they were tested against a battery of antisera, by means of tissue-culture methods instead of injection into mice. It was established that O’nyong-nyong was related to chikungunya, and that the virus was to some extent neutralised by chikungunya antiserum (the converse did not hold). O’nyong-nyong was clearly distinct from fourteen other group-A arthropod-borne viruses isolated in Africa, North and South America, and Asia. Meanwhile, entomological studies in Uganda had shown that O’nyong-nyong was almost certainly being spread by anopheles mosquitoes. This finding cuts right across all previous vector studies with arthropod-borne viruses. Different viruses have occasionally been 1.
2. 3. 4. 5. 6. 7. 8.
Haddow, A. J., Davies, C. W., Walker, A. J. Trans. R. Soc. trop. Med. Hyg. 1960, 54, 517. Williams, M. C., Woodall, J. P. ibid. 1961, 55, 135. Shore, H. ibid. p. 361. Corbet, P. S., Williams, M. C., Gillett, J. D. ibid. p. 463. Porterfield, J. S. Bull. Wld Hlth Org. 1961, 24, 735. Colonial Research 1960-61. Cmnd 1584. H.M. Stationery Office, 1961. Pp. 353. 18s. Ross, R. W. J. Hyg., Camb. 1956, 54, 177. Osterrieth, P., Deleplanque-Liegeois, P., Blanes-Ridaura, G. Ann. Soc. belge Méd. trop. 1960, 40, 199.