Journal of the Royal Society of Medicine Volume 72 February 1979
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hepatojejunostomy has been performed within the regenerated left lobe of the liver. While there is a limited place for Longmire's operation, this case emphasizes the valuable role that it may play in certain defined situations where other approaches to the intrahepatic biliary tree are precluded. Acknowledgments: We are most grateful for the expert assistance of all those concerned in this patient's care, to Dr F Paradinas for the histopathology reports and to the Medical Illustration Department, Charing Cross Hospital, for the figures. References Blumgart L H (1978) American Journal of Surgery 135, 19-31 Longniire WP jr & Sandford M C (1949) Annals of Surgery 130, 455-460 Longmire W P jr & Lippman H N (1956) Surgical Clinics of North America 36, 849-863 Sedgwick C E, Poulantzas J K & Kune G A (1966) Annals of Surgery 163, 949-953
Chronic granulomatous disease in an adult' D A Burns MRCP I Sarkany FRCP Royal Free Hospital, London NW3 2QG In 1954 at the age of 3 years, F C (male, now aged 26) developed bilateral cervical lymphadenopathy. The adenopathy regressed spontaneously and he was well until three years later when the cervical nodes again became enlarged. Tonsillectomy was performed, and no further problems occurred until 1961 when he was admitted to hospital with suppurative cervical adenitis. Abscesses formed, and subsequently drained spontaneously. In 1965 he was again hospitalized for therapy of a pulmonary 'abscess'. This was initially thought to be tuberculous, but acid-fast bacilli were not demonstrated in his sputum and there was no confirmatory evidence of a tuberculous aetiology. He was, however, treated with streptomycin and Pasinah-D (sodium aminosalicylate and isoniazid), and the lesion resolved. At the age of 18 a right perinephric abscess was drained surgically and Staphylococcus aureus was isolated on cluture. He then remained well until he presented to us in September 1976 with a history of pustular lesions on the trunk and superficial pyoderma affecting both axillae and the suprapubic region for several weeks. He had received treatment with several oral antibiotics without improvement. There was no family history of recurrent sepsis and there were no siblings. On examination: He had bilateral purulent conjunctivitis. There were multiple pustules scattered over the trunk (Figure 1) and areas of superficial pyoderma in both axillae (Figure 2) and in the suprapubic region. The remainder of the physical examination was normal.
Investigations: Haemoglobin 16.4 g/dl; WBC 9900/mm3. Normal morphology. Electrolytes and urea, liver function tests, serum calcium, phosphate and alkaline phosphatase, and random blood sugar were all normal. Rose Waaler, antinuclear factor, Australia antigen and treponemal haemagglutination test were all negative. Chest X-ray showed apical pleural thickening, but was otherwise normal. Swabs from pustules on the trunk, areas of pyoderma, external nares, urethra and conjunctivae all grew Staphylococcus aureus on culture. Serum complement C3, C4: normal. Immunoglobulins: IgG 17 g/l, IgA 3.75 g/l, IgM 1.35 g/l. Mantoux test 1: 1000, negative; 1: 100, positive. Intradermal tests with mumps antigen and Candida antigen were positive; lymphocyte transformation with phytohaemagglutinin: ' Case presented to Section of Dermatology, 16 June 1977. Accepted 21 November 1977
0 141-0768/79/020139-04/$O 1.00/0
Ir"
1979 The Royal Society of Medicine
140
Journal of the Royal Society off Medicine Volume 72 February 1979
Figure 1. Pustules on the trunk
Figure 2. Pyoderma in the left axilla
normal. Bone marrow examination showed an active marrow with sea-blue histiocytes which gave a positive periodic acid-Schiff reaction. Skin biopsy from the suprapubic region: 'Mild acanthosis of the epidermis. The dermis contains a mixed chronic inflammatory infiltrate, and there is scarring around hair follicles. The appearances are non-specific'. Results of the granulocyte function tests are shown in Table 1. Table 1. Results of tests on granulocyte function
Nylon column NBT reduction:0 (Segal & Peters 1975) (nmol/106 phagocytes) Staphylococcal killing: (Biggar 1975) (residual living bacteria %) Hexose monophosphate shunt activation: (Klebanoff & Pincus 1971) (nmol/107 phagocytes) Granulocyte morphology: normal Myeloperoxidase: normal
Date
Patient
Control
8.2.77 16.2.77 16.2.77 22.2.77
0.3 0.2 1.25 2.5 5.1
5.3 3.7 0.47 0.56 49.0
G6PD screen: normal * Parents: father, 6.3; mother, 5. 1; control, 8.5
Treatment andprogress: Parenteral therapy with flucloxacillin 2 gm daily produced resolution of the cutaneous lesions. Subsequently prophylactic antibiotic therapy with Septrin (cotrimoxazole) two tablets twice daily was commenced, and there has been no recurrence of his lesions to date. Discussion History and investigations suggest that this patient is an example of chronic granulomatous disease, a well recognized neutrophil dysfunction syndrome. In this condition, granulocytes capable of normal phagocytosis are unable to kill certain ingested organisms. Originally
Journal of the Royal Society of Medicine Volume 72 February 1979
141
referred to as fatal chronic granulomatous disease of childhood, this condition was reported as presenting in male infants as an X-linked characteristic. Many of the affected individuals died in infancy from overwhelming infection unresponsive to antibiotic therapy. More recently, however, clinical and genetic heterogeneity has been recognized, and several adult cases have been described in whom a less severe form of the condition appears to exist (Biggar et al. 1976, Chusid et al. 1975, Godtfredsen & Koch 1972, Kontras et al. 1972). The dermatological aspects of this condition appear to have been somewhat neglected in the literature, although many of the reported cases have, at some time, manifest cutaneous abnormality in the form of pyoderma (Bass et al. 1972). Normal phagocyte function has several components: random movement (non-directional), chemotaxis (directional), attachment to the organism, ingestion of the organism, activation of the phagocyte, and bacterial killing (Weston 1976). The basic abnormality in chronic granulomatous disease lies in the processes of phagocyte activation and bacterial killing. In normal phagocytes, ingestion of bacteria is followed by a burst of metabolic activity known as the respiratory burst, in which there is activation of the hexose monophosphate shunt pathway and production of hydrogen peroxide and superoxide anion. Several enzymes are involved in the proper functioning of this system. These products of the respiratory burst, in combination with myeloperoxidase and a halide, constitute the main mechanism of bacterial killing. The adequacy of the system may be assessed by the nitroblue tetrazolium (NBT) test in which NBT is reduced to the blue dye formazan by normal phagocytes. The nylon column dye test utilizes this phenomenon and is a useful screening test (Segal & Peters 1975). In chronic granulomatous disease the normal respiratory burst following phagocytosis of bacteria does not occur, and phagocytes do not reduce NBT. In the majority of cases the condition is inherited as an X-linked recessive characteristic presenting in male infants. Female carriers have been shown to have a dual population of phagocytes - 50% normal, and 50% with defective bacterial killing - a situation explained by the Lyon hypothesis. Interestingly, several female carriers have been reported who developed cutaneous lesions resembling discoid lupus erythematosus (Schaller 1972, Humbert et al. 1976), but this phenomenon remains unexplained. However, cases with a presumed autosomal recessive inheritance, in whom phagocyte function in both parents is normal, have been reported (Kontras et al. 1972, Chusid et al. 1975) and our patient is most probably in this group. As there are several enzymes responsible for the respiratory burst, defective bacterial killing may be a manifestation of an abnormality of any one or more of these enzymes. In confirmation of this, several groups of workers have reported cases in which specific enzyme defects could be demonstrated, and these findings have established the heterogeneity of the condition. The organisms responsible for infections in this disorder - e.g. Staphylococcus aureus, Escherichia coli, Serratia marcescens, nocardia, aspergillus - are in the main catalase-positive, and are not killed following phagocytosis. Catalase-negative organisms - e.g. Streptococcus pyogenes, pneumococcus - are usually killed effectively. The term granulomatous in the designation of this disease refers to the formation of granulomas provoked by the presence of viable organisms within phagocytes. There is a wide spectrum of organ involvement. Suppurative cervical adenitis is common, and osteomyelitis, liver abscesses and bronchopneumonia are frequent manifestations. The pneumonia often has a peculiarly localized appearance on chest X-ray which has been termed encapsulating pneumonia. Diarrhoea, perianal abscesses and fistulae have been reported in some 20% of cases (Johnston & Baehner 1971), and histology of rectal biopsies often shows a granulomatous reaction with many large pigmented, lipid-laden histiocytes. Similar histiocytes may be demonstrated in the lamina propria in small bowel biopsy material. Destructive chorioretinal lesions have also been described recently (Lischner & Martyn 1975). Treatment is difficult because standard antibacterial agents are relatively ineffective against bacteria within phagocytes. This has prompted trials of therapy with rifampicin (Ezer & Soothill 1974), clofazimine (McCrae & Raeburn 1972), or isoniazid (Sanders et al. 1972), which have demonstrable intracellular bactericidal activity in vitro. In vivo, however, therapy with these agents has proved disappointing. Attempts to stimulate hexose monophosphate shunt
142
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activity with methylene blue have proved equally ineffective in vivo. Long-term antibiotic prophylaxis is probably the most effective method of treatment. An interesting additional finding in this patient was the presence of many sea-blue histiocytes in the bone marrow. These large histiocytes contain lipofuscin-like material thought to represent lipid breakdown products. They are found in a number of other conditions (Table 2). Their presence in the marrow in chronic granulomatous disease has been reported Table 2. Conditions in which sea-blue histiocytes have been described
Chronic myeloid leukaemia Hodgkin's disease Hurler's syndrome Type V hyperlipidaemia Multiple myeloma Polycythaemia rubra vera Rheumatoid arthritis Sickle cell anaemia Thrombocytopenic purpura Lecithin: cholesterol acyltransferase deficiency Niemann-Pick disease Chronic granulomatous disease
previously (Lischner & Martyn 1975), but their exact function is not known. It may be that they contain undigested bacterial or cellular debris carried from a distant site of infection. Further investigation of this patient is in progress in an attempt to characterize the enzyme defect responsible for his phagocyte malfunction. Acknowledgments: We are most grateful to Dr J M Goldman, Hammersmith Hospital, for the neutrophil function studies, and to Professor J F Soothill who provided valuable advice on therapy. References Bass L J, Voorhees J J, Dubin H V & Tanner M H (1972) Archives of Dermatology 106, 68-71 Biggar W D (1975) Lancet i, 991-994 Biggar W D, Buron S & Holmes B (1976) Journal of Pediatrics 88, 63-70 Chusid M J, Parr;llo J E & Fauci A S (1975) Journal of the American Medical Association 233, 1295-1296 Ezer G & Soothill J F (1974) Archives of Disease in Childhood 49, 463-466 Godtfredson J & Koch C (1972) Scandinavian Journal of Infectious Diseases 4, 259-264 Humbert J R, Fishman C B, Weston W L, DeArmey P A & Thoren C H (1976) Clinical Genetics 10, 16-20 Johnston R B & Baehner R L (1971) Pediatrics 48, 730-739 Klebanoff S J & Pincus S H (1971) Journal of Clinical Investigation 50, 2226-2229 Kontras S B, Bodenbender J G & Liden C B (1972) In: Birth Defects: Original Article Series VIII, No. 3. Liss, New York; pp 83-98 Lischner H W & Martyn L J (1975) In: Birth Defects: Original Article Series XI, No. 1. Liss, New York; pp 73-76 McCrae W M & Raeburn J A (1972) Lancet i, 1370-1371 Sanders D Y, Cooper M R, McCall C E & DeChatelet L R (1972) Journal of Pediatrics 80, 104-106 Schaller J (1972) Annals of Internal Medicine 76, 747-750 Segal A W & Peters T J (1975) Clinical Science and Molecular Medicine 49, 591-596 Weston W L (1976) Archives of Dermatology 112, 1589-1596
Dr R A J Eady: The various tests of phagocyte function you mention concern the neutrophil leukocyte. As you noticed sea-blue histiocytes in the marrow, did you investigate macrophage function in this patient? Dr D A Burns: Yes. We looked at monocyte function, and this was normal.
139
hepatojejunostomy has been performed within the regenerated left lobe of the liver. While there is a limited place for Longmire's operation, this case emphasizes the valuable role that it may play in certain defined situations where other approaches to the intrahepatic biliary tree are precluded. Acknowledgments: We are most grateful for the expert assistance of all those concerned in this patient's care, to Dr F Paradinas for the histopathology reports and to the Medical Illustration Department, Charing Cross Hospital, for the figures. References Blumgart L H (1978) American Journal of Surgery 135, 19-31 Longniire WP jr & Sandford M C (1949) Annals of Surgery 130, 455-460 Longmire W P jr & Lippman H N (1956) Surgical Clinics of North America 36, 849-863 Sedgwick C E, Poulantzas J K & Kune G A (1966) Annals of Surgery 163, 949-953
Chronic granulomatous disease in an adult' D A Burns MRCP I Sarkany FRCP Royal Free Hospital, London NW3 2QG In 1954 at the age of 3 years, F C (male, now aged 26) developed bilateral cervical lymphadenopathy. The adenopathy regressed spontaneously and he was well until three years later when the cervical nodes again became enlarged. Tonsillectomy was performed, and no further problems occurred until 1961 when he was admitted to hospital with suppurative cervical adenitis. Abscesses formed, and subsequently drained spontaneously. In 1965 he was again hospitalized for therapy of a pulmonary 'abscess'. This was initially thought to be tuberculous, but acid-fast bacilli were not demonstrated in his sputum and there was no confirmatory evidence of a tuberculous aetiology. He was, however, treated with streptomycin and Pasinah-D (sodium aminosalicylate and isoniazid), and the lesion resolved. At the age of 18 a right perinephric abscess was drained surgically and Staphylococcus aureus was isolated on cluture. He then remained well until he presented to us in September 1976 with a history of pustular lesions on the trunk and superficial pyoderma affecting both axillae and the suprapubic region for several weeks. He had received treatment with several oral antibiotics without improvement. There was no family history of recurrent sepsis and there were no siblings. On examination: He had bilateral purulent conjunctivitis. There were multiple pustules scattered over the trunk (Figure 1) and areas of superficial pyoderma in both axillae (Figure 2) and in the suprapubic region. The remainder of the physical examination was normal.
Investigations: Haemoglobin 16.4 g/dl; WBC 9900/mm3. Normal morphology. Electrolytes and urea, liver function tests, serum calcium, phosphate and alkaline phosphatase, and random blood sugar were all normal. Rose Waaler, antinuclear factor, Australia antigen and treponemal haemagglutination test were all negative. Chest X-ray showed apical pleural thickening, but was otherwise normal. Swabs from pustules on the trunk, areas of pyoderma, external nares, urethra and conjunctivae all grew Staphylococcus aureus on culture. Serum complement C3, C4: normal. Immunoglobulins: IgG 17 g/l, IgA 3.75 g/l, IgM 1.35 g/l. Mantoux test 1: 1000, negative; 1: 100, positive. Intradermal tests with mumps antigen and Candida antigen were positive; lymphocyte transformation with phytohaemagglutinin: ' Case presented to Section of Dermatology, 16 June 1977. Accepted 21 November 1977
0 141-0768/79/020139-04/$O 1.00/0
Ir"
1979 The Royal Society of Medicine
140
Journal of the Royal Society off Medicine Volume 72 February 1979
Figure 1. Pustules on the trunk
Figure 2. Pyoderma in the left axilla
normal. Bone marrow examination showed an active marrow with sea-blue histiocytes which gave a positive periodic acid-Schiff reaction. Skin biopsy from the suprapubic region: 'Mild acanthosis of the epidermis. The dermis contains a mixed chronic inflammatory infiltrate, and there is scarring around hair follicles. The appearances are non-specific'. Results of the granulocyte function tests are shown in Table 1. Table 1. Results of tests on granulocyte function
Nylon column NBT reduction:0 (Segal & Peters 1975) (nmol/106 phagocytes) Staphylococcal killing: (Biggar 1975) (residual living bacteria %) Hexose monophosphate shunt activation: (Klebanoff & Pincus 1971) (nmol/107 phagocytes) Granulocyte morphology: normal Myeloperoxidase: normal
Date
Patient
Control
8.2.77 16.2.77 16.2.77 22.2.77
0.3 0.2 1.25 2.5 5.1
5.3 3.7 0.47 0.56 49.0
G6PD screen: normal * Parents: father, 6.3; mother, 5. 1; control, 8.5
Treatment andprogress: Parenteral therapy with flucloxacillin 2 gm daily produced resolution of the cutaneous lesions. Subsequently prophylactic antibiotic therapy with Septrin (cotrimoxazole) two tablets twice daily was commenced, and there has been no recurrence of his lesions to date. Discussion History and investigations suggest that this patient is an example of chronic granulomatous disease, a well recognized neutrophil dysfunction syndrome. In this condition, granulocytes capable of normal phagocytosis are unable to kill certain ingested organisms. Originally
Journal of the Royal Society of Medicine Volume 72 February 1979
141
referred to as fatal chronic granulomatous disease of childhood, this condition was reported as presenting in male infants as an X-linked characteristic. Many of the affected individuals died in infancy from overwhelming infection unresponsive to antibiotic therapy. More recently, however, clinical and genetic heterogeneity has been recognized, and several adult cases have been described in whom a less severe form of the condition appears to exist (Biggar et al. 1976, Chusid et al. 1975, Godtfredsen & Koch 1972, Kontras et al. 1972). The dermatological aspects of this condition appear to have been somewhat neglected in the literature, although many of the reported cases have, at some time, manifest cutaneous abnormality in the form of pyoderma (Bass et al. 1972). Normal phagocyte function has several components: random movement (non-directional), chemotaxis (directional), attachment to the organism, ingestion of the organism, activation of the phagocyte, and bacterial killing (Weston 1976). The basic abnormality in chronic granulomatous disease lies in the processes of phagocyte activation and bacterial killing. In normal phagocytes, ingestion of bacteria is followed by a burst of metabolic activity known as the respiratory burst, in which there is activation of the hexose monophosphate shunt pathway and production of hydrogen peroxide and superoxide anion. Several enzymes are involved in the proper functioning of this system. These products of the respiratory burst, in combination with myeloperoxidase and a halide, constitute the main mechanism of bacterial killing. The adequacy of the system may be assessed by the nitroblue tetrazolium (NBT) test in which NBT is reduced to the blue dye formazan by normal phagocytes. The nylon column dye test utilizes this phenomenon and is a useful screening test (Segal & Peters 1975). In chronic granulomatous disease the normal respiratory burst following phagocytosis of bacteria does not occur, and phagocytes do not reduce NBT. In the majority of cases the condition is inherited as an X-linked recessive characteristic presenting in male infants. Female carriers have been shown to have a dual population of phagocytes - 50% normal, and 50% with defective bacterial killing - a situation explained by the Lyon hypothesis. Interestingly, several female carriers have been reported who developed cutaneous lesions resembling discoid lupus erythematosus (Schaller 1972, Humbert et al. 1976), but this phenomenon remains unexplained. However, cases with a presumed autosomal recessive inheritance, in whom phagocyte function in both parents is normal, have been reported (Kontras et al. 1972, Chusid et al. 1975) and our patient is most probably in this group. As there are several enzymes responsible for the respiratory burst, defective bacterial killing may be a manifestation of an abnormality of any one or more of these enzymes. In confirmation of this, several groups of workers have reported cases in which specific enzyme defects could be demonstrated, and these findings have established the heterogeneity of the condition. The organisms responsible for infections in this disorder - e.g. Staphylococcus aureus, Escherichia coli, Serratia marcescens, nocardia, aspergillus - are in the main catalase-positive, and are not killed following phagocytosis. Catalase-negative organisms - e.g. Streptococcus pyogenes, pneumococcus - are usually killed effectively. The term granulomatous in the designation of this disease refers to the formation of granulomas provoked by the presence of viable organisms within phagocytes. There is a wide spectrum of organ involvement. Suppurative cervical adenitis is common, and osteomyelitis, liver abscesses and bronchopneumonia are frequent manifestations. The pneumonia often has a peculiarly localized appearance on chest X-ray which has been termed encapsulating pneumonia. Diarrhoea, perianal abscesses and fistulae have been reported in some 20% of cases (Johnston & Baehner 1971), and histology of rectal biopsies often shows a granulomatous reaction with many large pigmented, lipid-laden histiocytes. Similar histiocytes may be demonstrated in the lamina propria in small bowel biopsy material. Destructive chorioretinal lesions have also been described recently (Lischner & Martyn 1975). Treatment is difficult because standard antibacterial agents are relatively ineffective against bacteria within phagocytes. This has prompted trials of therapy with rifampicin (Ezer & Soothill 1974), clofazimine (McCrae & Raeburn 1972), or isoniazid (Sanders et al. 1972), which have demonstrable intracellular bactericidal activity in vitro. In vivo, however, therapy with these agents has proved disappointing. Attempts to stimulate hexose monophosphate shunt
142
Journal of the Royal Society of Medicine Volume 72 February 1979
activity with methylene blue have proved equally ineffective in vivo. Long-term antibiotic prophylaxis is probably the most effective method of treatment. An interesting additional finding in this patient was the presence of many sea-blue histiocytes in the bone marrow. These large histiocytes contain lipofuscin-like material thought to represent lipid breakdown products. They are found in a number of other conditions (Table 2). Their presence in the marrow in chronic granulomatous disease has been reported Table 2. Conditions in which sea-blue histiocytes have been described
Chronic myeloid leukaemia Hodgkin's disease Hurler's syndrome Type V hyperlipidaemia Multiple myeloma Polycythaemia rubra vera Rheumatoid arthritis Sickle cell anaemia Thrombocytopenic purpura Lecithin: cholesterol acyltransferase deficiency Niemann-Pick disease Chronic granulomatous disease
previously (Lischner & Martyn 1975), but their exact function is not known. It may be that they contain undigested bacterial or cellular debris carried from a distant site of infection. Further investigation of this patient is in progress in an attempt to characterize the enzyme defect responsible for his phagocyte malfunction. Acknowledgments: We are most grateful to Dr J M Goldman, Hammersmith Hospital, for the neutrophil function studies, and to Professor J F Soothill who provided valuable advice on therapy. References Bass L J, Voorhees J J, Dubin H V & Tanner M H (1972) Archives of Dermatology 106, 68-71 Biggar W D (1975) Lancet i, 991-994 Biggar W D, Buron S & Holmes B (1976) Journal of Pediatrics 88, 63-70 Chusid M J, Parr;llo J E & Fauci A S (1975) Journal of the American Medical Association 233, 1295-1296 Ezer G & Soothill J F (1974) Archives of Disease in Childhood 49, 463-466 Godtfredson J & Koch C (1972) Scandinavian Journal of Infectious Diseases 4, 259-264 Humbert J R, Fishman C B, Weston W L, DeArmey P A & Thoren C H (1976) Clinical Genetics 10, 16-20 Johnston R B & Baehner R L (1971) Pediatrics 48, 730-739 Klebanoff S J & Pincus S H (1971) Journal of Clinical Investigation 50, 2226-2229 Kontras S B, Bodenbender J G & Liden C B (1972) In: Birth Defects: Original Article Series VIII, No. 3. Liss, New York; pp 83-98 Lischner H W & Martyn L J (1975) In: Birth Defects: Original Article Series XI, No. 1. Liss, New York; pp 73-76 McCrae W M & Raeburn J A (1972) Lancet i, 1370-1371 Sanders D Y, Cooper M R, McCall C E & DeChatelet L R (1972) Journal of Pediatrics 80, 104-106 Schaller J (1972) Annals of Internal Medicine 76, 747-750 Segal A W & Peters T J (1975) Clinical Science and Molecular Medicine 49, 591-596 Weston W L (1976) Archives of Dermatology 112, 1589-1596
Dr R A J Eady: The various tests of phagocyte function you mention concern the neutrophil leukocyte. As you noticed sea-blue histiocytes in the marrow, did you investigate macrophage function in this patient? Dr D A Burns: Yes. We looked at monocyte function, and this was normal.
