1023
disease results from local cromoglycate, a drug which staallergy. bilises the mast-cell membrane, has been a major advance in the management of allergic disease of the respiratory tract. This drug is not absorbed, but an oral preparation has been used with some success in a small number of infants with cow’s milk allergy29 30 and also in a few patients with proctitis.31 Allergy alone is unlikely to be the cause of ulcerative proctocolitis and an antiallergic drug will not be a panacea for inflammatory diseases of the gastrointestinal tract. However, on theoretical grounds the possibility that local allergy is one of the causes of abdominal pain, mucosal inflammation, and gastrointestinal motility disorders is certainly worth pursuing. vide evidence that
a
Disodium
Pneumocystis carinii Pneumonitis WITHIN the past decade the
prevalence
of Pneu-
mocystis carinii pneumonitis (P.c.P.) has increased sharply in North America. Particularly susceptible are children and adults on immunosuppressive drugs (for organ transplantation or treatment of cancer) and those with immune deficiency disorders. The "epidemic" form of P.c.p., encountered primarily as interstitial plasma-cell pneumonitis in European infants, seems to have declined gradually since about 1960.32 The increase in number of American cases may be attributable to wider use of immunosuppressive therapy and prolonged survival of patients with compromised resistance to infection ; whereas the decline in European cases has been associated with socioeconomic recovery after the 1939-45 war. 32 During the past two years, P.c.p. has been diagnosed in malnourished orphans in Saigon and in Vietnamese refugees in the United States.’3 The mode of transmission and natural habitat of P. carinii are unknown. A few case-reports with circumstantial evidence of contagion,34 plus the epidemic pattern of infections in nursling homes, justify isolation of active cases from other patients who are at risk. Nevertheless, man-to-man transmission has not been proven. Like other organisms, such as cytomegalovirus, Herpesvirus hominas (simplex), Toxoplasma gondii, Candida albicans, and Aspergillus that cause serious infections in susceptible patients, P. carinii may also be a latent opportunist that is activated when host defences are impaired. This hypothesis is supported by experiments in which P.c.P. was provoked in animals solely by administration of immuno29 Freier, S., Berger, H. ibid 1973, i, 913. 30 Kuzemo, J. A., Simpson, K. R. ibid. 1975, 31. Heatley, R. V., Calcraft, B. J., Rhodes,
i, 337. J., Owen, E, Evans, B K Gut,
1975, 16, 559. 32 Dutz, W. Pathobiol. Ann. 1970, 5, 309. 33 Redman, J. C. J. Am med. Ass. 1975, 231, 1190 34 Yates, J. W., Ellison, R. R., Plager, J Lancet, Sept.
27 1975, p 610.
suppressive drugs or by induction of severe protein-energy malnutrition.36 Remarkably, with rare exceptions the disease and the organisms remain localised to the lungs even iri fatal cases. For definitive diagnosis P. carinii must be seen in lung tissue. On occasion the organism is detectable in sputum, pharyngeal smears, gastroc aspirates, and tracheal aspirates, but these are not sufficiently reliable to exclude the diagnosis if no organisms are found. Of the invasive techniques, open lung biopsy provides the most representative specimen and indicates the extent of disease. Disadvantages are the need for general anaesthesia (usually with intubation) and the time taken to process the specimen. Percutaneous needle biopsy of the lung is generally too hazardous. Percutaneous transthoracic needle aspiration of the lung is reasonably accurate and simple; but the specimen is suitable only for identification of organisms, not for histopathological examination. Some investigators have employed an endobronchial brush technique but this has the same disadvantages as the needle aspiration method. Pneumothorax is the main complication of all the invasive methods. With Gomori’s methenaminic silver nitrate and the toluidine-blue-0 stains P. carinii cysts are easily recognised; the sporozoite and trophozoite forms need Giemsa, Gram-Weigert, or polychrome methylene-blue.Neither the complement-fixation test nor immunofluorescence methods for humoral-antibody determination are diagnostically precise in immunosuppressed children and adults with P.C.P.,37 38 though hightitre complement-fixing antibodies may help in the diagnosis of interstitial plasma-cell pneumonitis in
infants. 39
respiratory alkalosis are usual in patient needs carefully monitored therapy, judiciously avoiding oxygen toxi-
Hypoxia r.c.r.
oxygen city. In
and
The
assistance with a continuousnegative-pressure system, as in respiratory-distress syndrome of newborns, has been successful. 40 Extrapulmonary oxygenation, with a membrane lung as prepulmonary oxygenator, has been employed in four very ill patients and one recovered.41 The drug of choice has been pentamidine isothionate, but lately the combination of trimethoprim and sulphamethoxazole (TMP-SMZ) has proved effective in P.C.P.—dosage, 20 mg TMP, 100 mg SMZ per kg severe cases
body-weight per day.42 Similarly pyrimethamine a sulphonamide has been given to adults and
with
35. Frenkel, J. K., Good, J. T., Schultz, J. A. Lab. Invest. 1966, 15, 1559. 36. Hughes, W. T., Price, R. A., Sisko, F., Havron, S., Kafatos, A. G., Schonland, M., Smythe, P. M. Am. J. Dis. Child. 1974, 128, 44 37. Norman, L., Kagan, I. G. Infect. Immun, 1973, 8, 317. 38. Rifkind, D., Faris, T. D., Hill, R. B. Ann. intern. Med 1966, 65, 943. 39. Vivell, O., Buhn, W. H. Lips, G. Z. Kinderheilk, 1956, 78, 653. 40 Sanyal, S. K., Mitchell, C., Hughes, W. T., Feldman, S., Caces, J. Chest, 1975, 68, 143. 41 Geelhoed, G. W., Corso, P., Joseph, W. B. J. thorac. cardiovac. Surg. 1974, 42
68, 802. Hughes, W. T., Feldman, S., Sanyal, S. K. Can. med. Ass J. 1975, 112, 47S.
1024
infants38 43 44but no firm conclusions
can
be drawn.
Comparisons with pentamidine are necessary before a drug can be accepted as alternative treatment. In animals, immunisation, pentamidine, pyrimethamine and sulpha, rifampicin, and clindamycin give no protection; yet TMP-SMZ has been successful in preventing the infection." Sulphadoxine plus pyrimethamine reduced the incidence of P.c.p. in an infected orphanage in Shiraz. " Although drug prophylaxis may be a means to prevention of P.C.P. in highly susceptible patients, 46
work is needed before recommendations be made. Where malnutrition is the cause of ceptibility, special diets are prophylactic. more
can sus-
COT DEATH EVERY year in the United Kingdom, about 2000-3000 babies between 1 month and 2 years of age are found dead unexpectedly, in the sense that preceding signs of illness were either absent or apparently trivial. At the necropsy ordered by the coroner about half are found to have macroscopic disease sufficient to account for death. This usually takes the form of bronchitis or pneumonia. A proportion of the remainder have histological abnormality, again usually in the respiratory tract. The others have no discoverable lesion.48 In view of this hetero geneity it is understandable that there should be confusion about terminology. Some workers concerned with the problem use the term cot death, or its more respectable synonym sudden infant death, only for cases with no disease detectable either macroscopically or microscopically. Others include all babies dying suddenly and unexpectedly, whatever the pathological findings. Others yet follow tradition and confine the term to deaths where naked-eye pathological examination is negative, whatever the histological findings. Definition at present is entirely a matter of personal predilection, and decisions about significant macroscopic or microscopic abnormality are subjective and not necessarily uncontroversial. These problems of definition have made epidemiological studies more difficult. They emerged particularly well in the investigation by Froggatt and his colleagues,49 who concluded that the only epidemiological feature of cot death not shared by known causes of death in infancy, and especially respiratory infection, was its peculiar age incidence, peaking at 2-4 months. The epidemiological features in question consist of such well-known indices as low income, bottle-feeding, and low birth-weight. They are sufficiently consistent to have been used by Carpenter and ErneryS° as predictive factors in selecting babies particularly at risk of sudden unexpected death who could be monitored and possibly pro43.
Kirby,
H.
B., Kenamore, B., Guckian, J G. Ann.
intern.
Med 1971,
75,
505. 44. 45. 46. 47.
Ruskin, J., Remington, V. S. Antimicrob. Agents Chemother 1967, 7, 70. Hughes, W. T., Kim, H. K., Price, R. A., Miller, C Curr Ther. Res 1973, 15, 581. Hughes, W. T., McNabb, P. C., Makres, T D., Feldman, S. Antimicrob Agents Chemother. 1974, 5, 289. Post, C., Fakouhi, T., Dutz, W., Bandarizadeh, B , Kohout, E. Curv. Ther.
Res. 1971, 13, 273. 48. Protestos, C. D., Carpenter, R. G., McWeeney, P. M, Emery, I I. Archs Dis. Childh. 1973, 48, 835 49. Froggatt, P., Lynas, A., Mackenzie, G. Br. J. prev soc. Med. 1971, 25, 119. 50. Carpenter, R. G., Emery, J.L. Nature, 1974, 250, 729
tected. Nevertheless, this set of socio-medical characteristics makes a sharp contrast with the classic picture of the cherished healthy child whose sudden death comes as a stunning blow to its devoted parents. Could we be dealing with two separate diseases or a whole range of diseases all lumped together as cot death? The question has been given a new dimension by publication of the results of a fruitful collaboration, sponsored by the Foundation for the Study of Infant Deaths, between a forensic pathologist (J. M. Cameron) and a sociologist (Elizabeth Watson).5’ All cases of sudden infant death (excluding violence) notified to the coroner, occurring in inner North London over a 2-year period, were scrutinised. The necropsy was performed, a diagnosis of "known cause" or "cot death" was made, and the sections were put away. The household was visited quickly and a full interview obtained with the mother by the deputy medical officer of health using a
questionnaire based on market-research techniquesnot, in fact, very different from a skilfully taken medical history. To everybody’s surprise a very high proportion of the cases with or without macroscopic disease were found to have a history of clinical illness in the period before death. A disturbingly high number of these babies seemed to have received suboptimal medical care for this illness, with no difference between the known-cause and the cot-death groups. With all the interviews completed and analysed the pathologist examined his sections and found only a handful of babies without microscopical abnormality sufficient to cause death, the lesion being usually in the lungs. In other words, the great majority of cot deaths had either clinical illness before death, or a discernible pathological cause of death, or both. McWeeny and Emery52 have obtained essentially similar findings by a different route. Apparently, therefore, cot death is a heterogeneous phenomenon attributable to both social and bodily ills. At one end of the spectrum we have a baby receiving less than its proper requirement of care and attention, falling through the holes in the health and welfare net, and succumbing to undiagnosed pneumonia. At the other end is the well-tended baby dying in totally mysterious fashion. In the middle are the snuffly babies who die quickly instead of getting better. In all three situations the problem is, why did this baby die when others in the same category (even ill-cared-for babies) survive? There is no answer as yet, but several fruitful hypotheses are being pursued.53 Some babies may be allergic to microbial or dietary antigens or may lack resistance to certain infective agents. Some babies may be less competent than others to breathe through their mouths when their noses are blocked by secretion. Some babies may die of reflex apncea because of stimulation of the recently discovered postlaryngeal receptors which can distinguish between fluids of differing composition, including milk from different sources. The role of defective conduction of cardiac impulses has not yet been disproved. Dehydration, azotxmia, and hypernatrxmia due partly to faulty artificial feeding may be a precipitating factor. There are many possibilities but the work of Cameron and Watson and of Emery and Carpenter has undoubt51. Cameron, J. M., Watson, E. J. Path. 1975, 117, 55 52. McWeeny, P. M., Emery, J. L. Archs Dis. Childh. 1975, 50, 191 53 S. I. D. S. Canadian Foundation for the Study of Infant Deaths, Toronto, 1974.
disease results from local cromoglycate, a drug which staallergy. bilises the mast-cell membrane, has been a major advance in the management of allergic disease of the respiratory tract. This drug is not absorbed, but an oral preparation has been used with some success in a small number of infants with cow’s milk allergy29 30 and also in a few patients with proctitis.31 Allergy alone is unlikely to be the cause of ulcerative proctocolitis and an antiallergic drug will not be a panacea for inflammatory diseases of the gastrointestinal tract. However, on theoretical grounds the possibility that local allergy is one of the causes of abdominal pain, mucosal inflammation, and gastrointestinal motility disorders is certainly worth pursuing. vide evidence that
a
Disodium
Pneumocystis carinii Pneumonitis WITHIN the past decade the
prevalence
of Pneu-
mocystis carinii pneumonitis (P.c.P.) has increased sharply in North America. Particularly susceptible are children and adults on immunosuppressive drugs (for organ transplantation or treatment of cancer) and those with immune deficiency disorders. The "epidemic" form of P.c.p., encountered primarily as interstitial plasma-cell pneumonitis in European infants, seems to have declined gradually since about 1960.32 The increase in number of American cases may be attributable to wider use of immunosuppressive therapy and prolonged survival of patients with compromised resistance to infection ; whereas the decline in European cases has been associated with socioeconomic recovery after the 1939-45 war. 32 During the past two years, P.c.p. has been diagnosed in malnourished orphans in Saigon and in Vietnamese refugees in the United States.’3 The mode of transmission and natural habitat of P. carinii are unknown. A few case-reports with circumstantial evidence of contagion,34 plus the epidemic pattern of infections in nursling homes, justify isolation of active cases from other patients who are at risk. Nevertheless, man-to-man transmission has not been proven. Like other organisms, such as cytomegalovirus, Herpesvirus hominas (simplex), Toxoplasma gondii, Candida albicans, and Aspergillus that cause serious infections in susceptible patients, P. carinii may also be a latent opportunist that is activated when host defences are impaired. This hypothesis is supported by experiments in which P.c.P. was provoked in animals solely by administration of immuno29 Freier, S., Berger, H. ibid 1973, i, 913. 30 Kuzemo, J. A., Simpson, K. R. ibid. 1975, 31. Heatley, R. V., Calcraft, B. J., Rhodes,
i, 337. J., Owen, E, Evans, B K Gut,
1975, 16, 559. 32 Dutz, W. Pathobiol. Ann. 1970, 5, 309. 33 Redman, J. C. J. Am med. Ass. 1975, 231, 1190 34 Yates, J. W., Ellison, R. R., Plager, J Lancet, Sept.
27 1975, p 610.
suppressive drugs or by induction of severe protein-energy malnutrition.36 Remarkably, with rare exceptions the disease and the organisms remain localised to the lungs even iri fatal cases. For definitive diagnosis P. carinii must be seen in lung tissue. On occasion the organism is detectable in sputum, pharyngeal smears, gastroc aspirates, and tracheal aspirates, but these are not sufficiently reliable to exclude the diagnosis if no organisms are found. Of the invasive techniques, open lung biopsy provides the most representative specimen and indicates the extent of disease. Disadvantages are the need for general anaesthesia (usually with intubation) and the time taken to process the specimen. Percutaneous needle biopsy of the lung is generally too hazardous. Percutaneous transthoracic needle aspiration of the lung is reasonably accurate and simple; but the specimen is suitable only for identification of organisms, not for histopathological examination. Some investigators have employed an endobronchial brush technique but this has the same disadvantages as the needle aspiration method. Pneumothorax is the main complication of all the invasive methods. With Gomori’s methenaminic silver nitrate and the toluidine-blue-0 stains P. carinii cysts are easily recognised; the sporozoite and trophozoite forms need Giemsa, Gram-Weigert, or polychrome methylene-blue.Neither the complement-fixation test nor immunofluorescence methods for humoral-antibody determination are diagnostically precise in immunosuppressed children and adults with P.C.P.,37 38 though hightitre complement-fixing antibodies may help in the diagnosis of interstitial plasma-cell pneumonitis in
infants. 39
respiratory alkalosis are usual in patient needs carefully monitored therapy, judiciously avoiding oxygen toxi-
Hypoxia r.c.r.
oxygen city. In
and
The
assistance with a continuousnegative-pressure system, as in respiratory-distress syndrome of newborns, has been successful. 40 Extrapulmonary oxygenation, with a membrane lung as prepulmonary oxygenator, has been employed in four very ill patients and one recovered.41 The drug of choice has been pentamidine isothionate, but lately the combination of trimethoprim and sulphamethoxazole (TMP-SMZ) has proved effective in P.C.P.—dosage, 20 mg TMP, 100 mg SMZ per kg severe cases
body-weight per day.42 Similarly pyrimethamine a sulphonamide has been given to adults and
with
35. Frenkel, J. K., Good, J. T., Schultz, J. A. Lab. Invest. 1966, 15, 1559. 36. Hughes, W. T., Price, R. A., Sisko, F., Havron, S., Kafatos, A. G., Schonland, M., Smythe, P. M. Am. J. Dis. Child. 1974, 128, 44 37. Norman, L., Kagan, I. G. Infect. Immun, 1973, 8, 317. 38. Rifkind, D., Faris, T. D., Hill, R. B. Ann. intern. Med 1966, 65, 943. 39. Vivell, O., Buhn, W. H. Lips, G. Z. Kinderheilk, 1956, 78, 653. 40 Sanyal, S. K., Mitchell, C., Hughes, W. T., Feldman, S., Caces, J. Chest, 1975, 68, 143. 41 Geelhoed, G. W., Corso, P., Joseph, W. B. J. thorac. cardiovac. Surg. 1974, 42
68, 802. Hughes, W. T., Feldman, S., Sanyal, S. K. Can. med. Ass J. 1975, 112, 47S.
1024
infants38 43 44but no firm conclusions
can
be drawn.
Comparisons with pentamidine are necessary before a drug can be accepted as alternative treatment. In animals, immunisation, pentamidine, pyrimethamine and sulpha, rifampicin, and clindamycin give no protection; yet TMP-SMZ has been successful in preventing the infection." Sulphadoxine plus pyrimethamine reduced the incidence of P.c.p. in an infected orphanage in Shiraz. " Although drug prophylaxis may be a means to prevention of P.C.P. in highly susceptible patients, 46
work is needed before recommendations be made. Where malnutrition is the cause of ceptibility, special diets are prophylactic. more
can sus-
COT DEATH EVERY year in the United Kingdom, about 2000-3000 babies between 1 month and 2 years of age are found dead unexpectedly, in the sense that preceding signs of illness were either absent or apparently trivial. At the necropsy ordered by the coroner about half are found to have macroscopic disease sufficient to account for death. This usually takes the form of bronchitis or pneumonia. A proportion of the remainder have histological abnormality, again usually in the respiratory tract. The others have no discoverable lesion.48 In view of this hetero geneity it is understandable that there should be confusion about terminology. Some workers concerned with the problem use the term cot death, or its more respectable synonym sudden infant death, only for cases with no disease detectable either macroscopically or microscopically. Others include all babies dying suddenly and unexpectedly, whatever the pathological findings. Others yet follow tradition and confine the term to deaths where naked-eye pathological examination is negative, whatever the histological findings. Definition at present is entirely a matter of personal predilection, and decisions about significant macroscopic or microscopic abnormality are subjective and not necessarily uncontroversial. These problems of definition have made epidemiological studies more difficult. They emerged particularly well in the investigation by Froggatt and his colleagues,49 who concluded that the only epidemiological feature of cot death not shared by known causes of death in infancy, and especially respiratory infection, was its peculiar age incidence, peaking at 2-4 months. The epidemiological features in question consist of such well-known indices as low income, bottle-feeding, and low birth-weight. They are sufficiently consistent to have been used by Carpenter and ErneryS° as predictive factors in selecting babies particularly at risk of sudden unexpected death who could be monitored and possibly pro43.
Kirby,
H.
B., Kenamore, B., Guckian, J G. Ann.
intern.
Med 1971,
75,
505. 44. 45. 46. 47.
Ruskin, J., Remington, V. S. Antimicrob. Agents Chemother 1967, 7, 70. Hughes, W. T., Kim, H. K., Price, R. A., Miller, C Curr Ther. Res 1973, 15, 581. Hughes, W. T., McNabb, P. C., Makres, T D., Feldman, S. Antimicrob Agents Chemother. 1974, 5, 289. Post, C., Fakouhi, T., Dutz, W., Bandarizadeh, B , Kohout, E. Curv. Ther.
Res. 1971, 13, 273. 48. Protestos, C. D., Carpenter, R. G., McWeeney, P. M, Emery, I I. Archs Dis. Childh. 1973, 48, 835 49. Froggatt, P., Lynas, A., Mackenzie, G. Br. J. prev soc. Med. 1971, 25, 119. 50. Carpenter, R. G., Emery, J.L. Nature, 1974, 250, 729
tected. Nevertheless, this set of socio-medical characteristics makes a sharp contrast with the classic picture of the cherished healthy child whose sudden death comes as a stunning blow to its devoted parents. Could we be dealing with two separate diseases or a whole range of diseases all lumped together as cot death? The question has been given a new dimension by publication of the results of a fruitful collaboration, sponsored by the Foundation for the Study of Infant Deaths, between a forensic pathologist (J. M. Cameron) and a sociologist (Elizabeth Watson).5’ All cases of sudden infant death (excluding violence) notified to the coroner, occurring in inner North London over a 2-year period, were scrutinised. The necropsy was performed, a diagnosis of "known cause" or "cot death" was made, and the sections were put away. The household was visited quickly and a full interview obtained with the mother by the deputy medical officer of health using a
questionnaire based on market-research techniquesnot, in fact, very different from a skilfully taken medical history. To everybody’s surprise a very high proportion of the cases with or without macroscopic disease were found to have a history of clinical illness in the period before death. A disturbingly high number of these babies seemed to have received suboptimal medical care for this illness, with no difference between the known-cause and the cot-death groups. With all the interviews completed and analysed the pathologist examined his sections and found only a handful of babies without microscopical abnormality sufficient to cause death, the lesion being usually in the lungs. In other words, the great majority of cot deaths had either clinical illness before death, or a discernible pathological cause of death, or both. McWeeny and Emery52 have obtained essentially similar findings by a different route. Apparently, therefore, cot death is a heterogeneous phenomenon attributable to both social and bodily ills. At one end of the spectrum we have a baby receiving less than its proper requirement of care and attention, falling through the holes in the health and welfare net, and succumbing to undiagnosed pneumonia. At the other end is the well-tended baby dying in totally mysterious fashion. In the middle are the snuffly babies who die quickly instead of getting better. In all three situations the problem is, why did this baby die when others in the same category (even ill-cared-for babies) survive? There is no answer as yet, but several fruitful hypotheses are being pursued.53 Some babies may be allergic to microbial or dietary antigens or may lack resistance to certain infective agents. Some babies may be less competent than others to breathe through their mouths when their noses are blocked by secretion. Some babies may die of reflex apncea because of stimulation of the recently discovered postlaryngeal receptors which can distinguish between fluids of differing composition, including milk from different sources. The role of defective conduction of cardiac impulses has not yet been disproved. Dehydration, azotxmia, and hypernatrxmia due partly to faulty artificial feeding may be a precipitating factor. There are many possibilities but the work of Cameron and Watson and of Emery and Carpenter has undoubt51. Cameron, J. M., Watson, E. J. Path. 1975, 117, 55 52. McWeeny, P. M., Emery, J. L. Archs Dis. Childh. 1975, 50, 191 53 S. I. D. S. Canadian Foundation for the Study of Infant Deaths, Toronto, 1974.
