- Email: [email protected]
LITHIUM THERAPY IN CONGENITAL NEUTROPENIA
1357
thyrotoxicosis the serum-T4 is a more sensitive indicator of hypothyroidism thatn the serum-T.s.H. level. Presumably as the thyrotrophs recovered from their previous suppression and the T.S.H. level rose in response to the low serum-T4, the thyroid responded to the increased stimulation by secreting more T3 and T4’ This patient may get permanent hypothyroidism in the future. Transient hypothyroidism after 1251 therapy for thyrotoxicosis has been reported.2 Theoretically 1311 therapy should be less likely to produce transient hypothyroidism than 1251 therapy,3 but, in practice, it does so.
S. M. SHALET I. A. MACFARLANE C. G. BEARDWELL
Christie Hospital and Holt Radium Institute, Wittington, Manchester M20 9BX
IMMUNE RESPONSES IN CHILDREN WITH CONGENITAL CYTOMEGALOVIRUS AND THEIR MOTHERS
SIR,-The report by
Dr Gehrz and his
colleagues (Oct. 22, defect to cytomegalovirus
specific cell-mediated in infants with active c.M.v. infection and their mothers interested us because we have recently done similar studies. Immune responses to c.M.v. were examined in four children with congenital infection, demonstrated by positive urine cultures during the first week of life, and in their mothers. Lymphocyte blastogenesis and interferon production were measured in leucocyte cultures stimulated with purified C.M.v. (Towne strain) or control antigens. 844) (c.M.v.)
p.
on a
IMMUNOLOGICAL RESPONSES AND VIRUS EXCRETION IN CHILDREN WITH CONGENITAL C.M.V. INFECTION AND THEIR MOTHERS
and their mothers have diminished blastogenic responses to purified c.M.v. antigen. In addition our data indicate that c.M.v. stimulated interferon production is impaired, that immune defects can be detected even when the infection is asymptomatic, and that in older children immune responses to c.t.v. may be present. Further studies to elucidate the role of cell-mediated immune responses to c.M.v. in the pathogenesis of congenital infection are in progress. University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, U.S.A. Medical College of Pennsylvania, Philadelphia
STUART E. STARR MARK D. TOLPIN HARVEY M. FRIEDMAN STANLEY A. PLOTKIN KURT PAUCKER
LITHIUM THERAPY IN CONGENITAL NEUTROPENIA
SIR,-Stimulation of neutrophil granulopoiesis by lithium has been described in normal subjects, patients with malignancy or acute myeloid leukaemia following chemotherapy, in Felty’s syndrome, and in a patient with Fanconi-type aplastic3 anaemia.1.2 We have confirmed the finding of Harker et awl. that lithium stimulates normal monocytes to produce granulocyte colony-stimulating factor and we have investigated the invitro effect of lithium on mononuclear leucocytes from two patients with congenital neutropenia. Patient 1 was a 23-month-old girl with severe recurrent skin and pulmonary infection, who had no blood neutrophils, increased blood monocytes (2xl0’’/l) and eosinophils (1 x 109;1), and normal hsemoglobin. The bone marrow had 20-25% granulocyte pre1. 2.
Tisman, G., Show-Jen G. W. Lancet, 1977, ii, 251. Barrett, A. J., Hugh Jones, K., Newton, K., Watson, J. G. Lancet, 1977, i,
202. 3. Harker, W. G., and others Blood, 1977, 49, 263.
* Mean counts/min. t Stimulation index in counts/min.Interferon titre (units/ml).
=
c.M.v.
Ag/control Ag, both
Three of the four children, including two infants aged 4 and 7 months (nos. 1 and 2), with typical symptoms of cytomegalic inclusion disease and an 8-month-old infant (no. 3) who was small for gestational age but otherwise symptom-free failed to respond in the blastogenesis assay. All were excreting C.M.v. in the urine at the time of testing. Their mothers had diminished blastogenic responses compared with seropositive adult controls (s.1. 16-69). Interferon could not be detected in the c.M.v.-stimulated leucocyte cultures of any of these infants or their mothers. In contrast, patient no. 4, a 9-year-old with severe cytomegalic inclusion disease who was no longer excreting the virus, had a low but definite response in the blastogenesis assay and produced interferon. His mother’s leucocytes demonstrated a normal blastogenic response and also produced interferon in a titre comparable with that detected in c.M.v.-stimulated leucocyte cultures of seropositive adult controls (200-300 units/ml). Preliminary studies indicate that the interferon produced in these cultures is immune interferon.1 Our findings thus accord with those of Gehrz et al.namely, that young infants with congenital c.M.v. infection 1.
Valle, M. J., Jordan, G. W., Haahr, S., Merigan, T. C. J. Immun. 1975, 115, 230.
Effect of lithium
on
colony-stimulating activity.
C=Control; l=patient 1; 2=patient . With lithium (2 mmol/1).
2.
0
Without lithium,
1358 cursors
with
the
an arrest at
promyelocyte stage,
no
mature
and an increased proportion of eosinophils. Patient 2 was a 14-month-old girl with recurrent skin abscesses and pneumonia, no blood neutrophils, and increased blood eosinophils (075x109/1), and platemonocytes (>2.5x10/1), lets (7x 10"/1). The bone-marrow had a diminished proportion of neutrophil precursors (10%), no mature neutrophils, and increased proportion of eosinophils (10-20%). Both an patients had subnormal numbers of colony-forming cells in the bone marrow and peripheral blood. The colony-stimulating activity of their blood mononuclear cells was compared with that of two normal controls. Bone marrow mononuclear cells (2 x 105) from the patients and controls were used as a source of colony-forming cells. The feeder cells were incorporated into soft agar at 2, 6, and 10 x 105 cells/ml with and without lithium (2 mmol/1 final concentration). Cells from the patients, despite having an increased proportion of monocytes, had a reduced ability to stimulate colony-formation by normal and by autologous marrow cells (see figure). With colony-forming cells from both sources, lithium increased the colony-stimulating activity of blood mononuclear cells from patients and controls but was less effective with normal cells. Both patients were given oral lithium carbonate and serumlithium was maintained around 1 mmol/ml over a 4 week trial period. Patient 1 developed tubular nephropathy and treatment was stopped after 21 days. 1 week later the neutrophil count rose to 2 x 109/ml and remained high for a further week. The pulmonary infection also cleared during this time. Patient 2 did not show any beneficial response. Lithium treatment may have brought about the maturation of abnormal stem cells in the patients by inducing monocytes to produce more colony-stimulating factor. Patient 2 may have failed to respond to lithium treatment because neutrophil precursors were absent rather than arrested during maturation as in patient 1. These results encourage further exploration of lithium treatment for congenital neutropenia with defective col-
neutrophils,
ony-stimulating activity. A.
Royal
J. B.
was
Marsden
supported by
the Leukaemia Research Fund.
Hospital,
Sutton, Surrey
Groupe de Recherches d’Immunologie
A. J. BARRETT
et Rheumatologie Pediatriques, Hôpital des Enfants Malades, Paris
C. GRISCELLI D. BURIOT
Institut de Recherches sur les Leucemies et les Maladies du Sang, Hôpital Saint-Louis, Paris
A. FAILLE
TREATMENT OF RECURRENT FURUNCULOSIS WITH ORAL ZINC
SIR,-The treatment of recurrent furunculosis is usually concentrated on active lesions, managed by incision and local and systemic antibiotics. In most cases in otherwise healthy people no causative factor can be convincingly incriminated.’1 In fifteen patients aged 24-50 I found low serum-zinc values ranging between 7.5S and 9.00 mol/1 (normal range 11-0—17-0). Serum-albumin values were normal (40-55 g/1). The patients had had recurrent furunculosis for 3-10 years, with boils appearing one or more times a month. The affected sites were groin, thigh, buttocks, abdomen, breasts, face, and neck. Furuncles frequently developed where clothing (e.g., a collar) had rubbed against the skin. In four males and three females the furuncles were incised and antibiotics were prescribed. These patients were followed up for 3 months, during which time new boils appeared, some requiring incision. Their serum-zinc values were consistently low. The other eight patients (four males and four females) took oral zinc sulphate as the only treatment over the whole 1. Rook, A., Roberts, S. O. B. in Textbook of Dermatology (edited D S. Wilkinson, and F. J. G. Ebling); p. 487. Oxford, 1972.
by A. Rook,
period of observation. They (Tika, Sweden) every day (45
took three tablets ’Solvezink’ mg Zn2+ per tablet). Seven patients were followed for 3 months and one patient for 7 months after the start of zinc therapy. In all eight patients the serumzinc value rose to normal within a month, active lesions regressed, and no fresh boils appeared. Department of Dermatology, General Hospital, S-631 88 Eskilstuna, Sweden
ISSER BRODY
&agr;1-ANTITRYPSIN PHENOTYPES IN RHEUMATOID ARTHRITIS AND ANKYLOSING SPONDYLITIS
SIR,-The distribution of IXcantitrypsin (IXCA.T.) phenotypes, genetically controlled by the Pi system, is controversial in the context of rheumatoid arthritis. Cox and Huber1 reported an increased frequency of o-A.T. phenotypes which include the Pi Z allele, but their statistical analysis has been questioned.2 Sjoblom and Wollheim3 found a not very striking increase in frequency of the Pi Z allele in rheumatoid patients. Dr Geddes and his colleagues (Nov. 19, p. 1049) found significant increases for Pi MZ and all non-MM phenotypes, but only in R.A. patients with fibrosing alveolitis and patients with fibrosing alveolitis but not R.A.; the difference in patients with R.A. alone was not significant. We have studied sera from 94 patients with R.A. and 175 with ankylosing spondylitis and compared their o-A.T. phenotypes with those of 200 controls and with Cook’s large control series.4 None of the patients or controls were related. All were seen consecutively at an arthritis clinic in South-East England. Pi typing was done by acid starch-gel electrophoresis,5 as modified by Cook.4 All non-Pi MM sera were incubated with mercaptoethanol and retestedand non-MM heterozygotes were retested by isoelectric focusing.6 The Pi phenotypes are summarised in the table. Among the R.A. patients there was an increased frequency of MZ heterozygotes and decreased frequency of MS heterozygotes. The Pi phenotypes in ankylosing spondylitis showed an increase in the Z allele, mainly due to Pi ZZ homozygotes. The increased frequency of the Pi Z allele in R.A. confirms the finding of Cox and Huber.’ However, interpretation of this finding is difficult. The Pi Z allele may represent a factor which can delay the healing of synovium and encourage chronicity in various forms of inflammatory joint disease. In keeping with this is the excess of Z alleles in both R.A. and ankylosing spondylitis, diseases which differ substantially and in which there is no evidence of a genetic link. Proteinase inhibitors can inactivate synovial-cell enzymes and so limit their inflammatory actionso A.T. deficiency ought to facilitate the development of inflammatory joint disease or delay its resolution. That this has not been observed in A.T.-deficient patients with emphysema and liver disease requires explanation but, as with platelet defects in IXCA.T. deficiency8 and renal disease in Pi Z individuals,9 disease associations may be being missed. Patients with MS phenotypes have a reduction in o-A.T. similar to that seen in MZ phenotypes; but in our series and othersl.3 there seemed to be a deficit of MS phenotype among R.A. patients. If this finding is confirmed, a simple reduction in total anti-tryptic activity would not explain the increased susceptibility to R.A. which accompanies the MZ allele. It is unlikely that a particular Pi type is the direct cause of Cox, D. W., Huber, O. Lancet, 1976, i, 1216. Benn, R. T., Wood, P. H. N. ibid. 1976, ii, 147. 3. Sjöblom, K. G., Wolheim, F. A. ibid 1977, ii, 41. 4. Cook, P. J. L. Ann. hum. Genet. 1975, 38, 275. 1. 2.
5.
Fagerhol, M. K. in Pulmonary Emphysema and Proteolysis (edited by Mittman); p. 145. London, 1972. Pierce, J. A., Jeppsson, J, Laurell C. Analyt. Biochem. 1976, 74, 227.
6. 7. Lancet, 1977, 8. Miale, T. D.,
C.
i, 1190. Lawson, D. L., Demian, S., Teague, P. O. Wolfson, S. L. ibid. 1977, ii, 93. 9. Milford Ward, A., Pickering, J. D., Shortland J. R. Inst. natn. Santé Reche. méd. 1975, 40, 131.
thyrotoxicosis the serum-T4 is a more sensitive indicator of hypothyroidism thatn the serum-T.s.H. level. Presumably as the thyrotrophs recovered from their previous suppression and the T.S.H. level rose in response to the low serum-T4, the thyroid responded to the increased stimulation by secreting more T3 and T4’ This patient may get permanent hypothyroidism in the future. Transient hypothyroidism after 1251 therapy for thyrotoxicosis has been reported.2 Theoretically 1311 therapy should be less likely to produce transient hypothyroidism than 1251 therapy,3 but, in practice, it does so.
S. M. SHALET I. A. MACFARLANE C. G. BEARDWELL
Christie Hospital and Holt Radium Institute, Wittington, Manchester M20 9BX
IMMUNE RESPONSES IN CHILDREN WITH CONGENITAL CYTOMEGALOVIRUS AND THEIR MOTHERS
SIR,-The report by
Dr Gehrz and his
colleagues (Oct. 22, defect to cytomegalovirus
specific cell-mediated in infants with active c.M.v. infection and their mothers interested us because we have recently done similar studies. Immune responses to c.M.v. were examined in four children with congenital infection, demonstrated by positive urine cultures during the first week of life, and in their mothers. Lymphocyte blastogenesis and interferon production were measured in leucocyte cultures stimulated with purified C.M.v. (Towne strain) or control antigens. 844) (c.M.v.)
p.
on a
IMMUNOLOGICAL RESPONSES AND VIRUS EXCRETION IN CHILDREN WITH CONGENITAL C.M.V. INFECTION AND THEIR MOTHERS
and their mothers have diminished blastogenic responses to purified c.M.v. antigen. In addition our data indicate that c.M.v. stimulated interferon production is impaired, that immune defects can be detected even when the infection is asymptomatic, and that in older children immune responses to c.t.v. may be present. Further studies to elucidate the role of cell-mediated immune responses to c.M.v. in the pathogenesis of congenital infection are in progress. University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, U.S.A. Medical College of Pennsylvania, Philadelphia
STUART E. STARR MARK D. TOLPIN HARVEY M. FRIEDMAN STANLEY A. PLOTKIN KURT PAUCKER
LITHIUM THERAPY IN CONGENITAL NEUTROPENIA
SIR,-Stimulation of neutrophil granulopoiesis by lithium has been described in normal subjects, patients with malignancy or acute myeloid leukaemia following chemotherapy, in Felty’s syndrome, and in a patient with Fanconi-type aplastic3 anaemia.1.2 We have confirmed the finding of Harker et awl. that lithium stimulates normal monocytes to produce granulocyte colony-stimulating factor and we have investigated the invitro effect of lithium on mononuclear leucocytes from two patients with congenital neutropenia. Patient 1 was a 23-month-old girl with severe recurrent skin and pulmonary infection, who had no blood neutrophils, increased blood monocytes (2xl0’’/l) and eosinophils (1 x 109;1), and normal hsemoglobin. The bone marrow had 20-25% granulocyte pre1. 2.
Tisman, G., Show-Jen G. W. Lancet, 1977, ii, 251. Barrett, A. J., Hugh Jones, K., Newton, K., Watson, J. G. Lancet, 1977, i,
202. 3. Harker, W. G., and others Blood, 1977, 49, 263.
* Mean counts/min. t Stimulation index in counts/min.Interferon titre (units/ml).
=
c.M.v.
Ag/control Ag, both
Three of the four children, including two infants aged 4 and 7 months (nos. 1 and 2), with typical symptoms of cytomegalic inclusion disease and an 8-month-old infant (no. 3) who was small for gestational age but otherwise symptom-free failed to respond in the blastogenesis assay. All were excreting C.M.v. in the urine at the time of testing. Their mothers had diminished blastogenic responses compared with seropositive adult controls (s.1. 16-69). Interferon could not be detected in the c.M.v.-stimulated leucocyte cultures of any of these infants or their mothers. In contrast, patient no. 4, a 9-year-old with severe cytomegalic inclusion disease who was no longer excreting the virus, had a low but definite response in the blastogenesis assay and produced interferon. His mother’s leucocytes demonstrated a normal blastogenic response and also produced interferon in a titre comparable with that detected in c.M.v.-stimulated leucocyte cultures of seropositive adult controls (200-300 units/ml). Preliminary studies indicate that the interferon produced in these cultures is immune interferon.1 Our findings thus accord with those of Gehrz et al.namely, that young infants with congenital c.M.v. infection 1.
Valle, M. J., Jordan, G. W., Haahr, S., Merigan, T. C. J. Immun. 1975, 115, 230.
Effect of lithium
on
colony-stimulating activity.
C=Control; l=patient 1; 2=patient . With lithium (2 mmol/1).
2.
0
Without lithium,
1358 cursors
with
the
an arrest at
promyelocyte stage,
no
mature
and an increased proportion of eosinophils. Patient 2 was a 14-month-old girl with recurrent skin abscesses and pneumonia, no blood neutrophils, and increased blood eosinophils (075x109/1), and platemonocytes (>2.5x10/1), lets (7x 10"/1). The bone-marrow had a diminished proportion of neutrophil precursors (10%), no mature neutrophils, and increased proportion of eosinophils (10-20%). Both an patients had subnormal numbers of colony-forming cells in the bone marrow and peripheral blood. The colony-stimulating activity of their blood mononuclear cells was compared with that of two normal controls. Bone marrow mononuclear cells (2 x 105) from the patients and controls were used as a source of colony-forming cells. The feeder cells were incorporated into soft agar at 2, 6, and 10 x 105 cells/ml with and without lithium (2 mmol/1 final concentration). Cells from the patients, despite having an increased proportion of monocytes, had a reduced ability to stimulate colony-formation by normal and by autologous marrow cells (see figure). With colony-forming cells from both sources, lithium increased the colony-stimulating activity of blood mononuclear cells from patients and controls but was less effective with normal cells. Both patients were given oral lithium carbonate and serumlithium was maintained around 1 mmol/ml over a 4 week trial period. Patient 1 developed tubular nephropathy and treatment was stopped after 21 days. 1 week later the neutrophil count rose to 2 x 109/ml and remained high for a further week. The pulmonary infection also cleared during this time. Patient 2 did not show any beneficial response. Lithium treatment may have brought about the maturation of abnormal stem cells in the patients by inducing monocytes to produce more colony-stimulating factor. Patient 2 may have failed to respond to lithium treatment because neutrophil precursors were absent rather than arrested during maturation as in patient 1. These results encourage further exploration of lithium treatment for congenital neutropenia with defective col-
neutrophils,
ony-stimulating activity. A.
Royal
J. B.
was
Marsden
supported by
the Leukaemia Research Fund.
Hospital,
Sutton, Surrey
Groupe de Recherches d’Immunologie
A. J. BARRETT
et Rheumatologie Pediatriques, Hôpital des Enfants Malades, Paris
C. GRISCELLI D. BURIOT
Institut de Recherches sur les Leucemies et les Maladies du Sang, Hôpital Saint-Louis, Paris
A. FAILLE
TREATMENT OF RECURRENT FURUNCULOSIS WITH ORAL ZINC
SIR,-The treatment of recurrent furunculosis is usually concentrated on active lesions, managed by incision and local and systemic antibiotics. In most cases in otherwise healthy people no causative factor can be convincingly incriminated.’1 In fifteen patients aged 24-50 I found low serum-zinc values ranging between 7.5S and 9.00 mol/1 (normal range 11-0—17-0). Serum-albumin values were normal (40-55 g/1). The patients had had recurrent furunculosis for 3-10 years, with boils appearing one or more times a month. The affected sites were groin, thigh, buttocks, abdomen, breasts, face, and neck. Furuncles frequently developed where clothing (e.g., a collar) had rubbed against the skin. In four males and three females the furuncles were incised and antibiotics were prescribed. These patients were followed up for 3 months, during which time new boils appeared, some requiring incision. Their serum-zinc values were consistently low. The other eight patients (four males and four females) took oral zinc sulphate as the only treatment over the whole 1. Rook, A., Roberts, S. O. B. in Textbook of Dermatology (edited D S. Wilkinson, and F. J. G. Ebling); p. 487. Oxford, 1972.
by A. Rook,
period of observation. They (Tika, Sweden) every day (45
took three tablets ’Solvezink’ mg Zn2+ per tablet). Seven patients were followed for 3 months and one patient for 7 months after the start of zinc therapy. In all eight patients the serumzinc value rose to normal within a month, active lesions regressed, and no fresh boils appeared. Department of Dermatology, General Hospital, S-631 88 Eskilstuna, Sweden
ISSER BRODY
&agr;1-ANTITRYPSIN PHENOTYPES IN RHEUMATOID ARTHRITIS AND ANKYLOSING SPONDYLITIS
SIR,-The distribution of IXcantitrypsin (IXCA.T.) phenotypes, genetically controlled by the Pi system, is controversial in the context of rheumatoid arthritis. Cox and Huber1 reported an increased frequency of o-A.T. phenotypes which include the Pi Z allele, but their statistical analysis has been questioned.2 Sjoblom and Wollheim3 found a not very striking increase in frequency of the Pi Z allele in rheumatoid patients. Dr Geddes and his colleagues (Nov. 19, p. 1049) found significant increases for Pi MZ and all non-MM phenotypes, but only in R.A. patients with fibrosing alveolitis and patients with fibrosing alveolitis but not R.A.; the difference in patients with R.A. alone was not significant. We have studied sera from 94 patients with R.A. and 175 with ankylosing spondylitis and compared their o-A.T. phenotypes with those of 200 controls and with Cook’s large control series.4 None of the patients or controls were related. All were seen consecutively at an arthritis clinic in South-East England. Pi typing was done by acid starch-gel electrophoresis,5 as modified by Cook.4 All non-Pi MM sera were incubated with mercaptoethanol and retestedand non-MM heterozygotes were retested by isoelectric focusing.6 The Pi phenotypes are summarised in the table. Among the R.A. patients there was an increased frequency of MZ heterozygotes and decreased frequency of MS heterozygotes. The Pi phenotypes in ankylosing spondylitis showed an increase in the Z allele, mainly due to Pi ZZ homozygotes. The increased frequency of the Pi Z allele in R.A. confirms the finding of Cox and Huber.’ However, interpretation of this finding is difficult. The Pi Z allele may represent a factor which can delay the healing of synovium and encourage chronicity in various forms of inflammatory joint disease. In keeping with this is the excess of Z alleles in both R.A. and ankylosing spondylitis, diseases which differ substantially and in which there is no evidence of a genetic link. Proteinase inhibitors can inactivate synovial-cell enzymes and so limit their inflammatory actionso A.T. deficiency ought to facilitate the development of inflammatory joint disease or delay its resolution. That this has not been observed in A.T.-deficient patients with emphysema and liver disease requires explanation but, as with platelet defects in IXCA.T. deficiency8 and renal disease in Pi Z individuals,9 disease associations may be being missed. Patients with MS phenotypes have a reduction in o-A.T. similar to that seen in MZ phenotypes; but in our series and othersl.3 there seemed to be a deficit of MS phenotype among R.A. patients. If this finding is confirmed, a simple reduction in total anti-tryptic activity would not explain the increased susceptibility to R.A. which accompanies the MZ allele. It is unlikely that a particular Pi type is the direct cause of Cox, D. W., Huber, O. Lancet, 1976, i, 1216. Benn, R. T., Wood, P. H. N. ibid. 1976, ii, 147. 3. Sjöblom, K. G., Wolheim, F. A. ibid 1977, ii, 41. 4. Cook, P. J. L. Ann. hum. Genet. 1975, 38, 275. 1. 2.
5.
Fagerhol, M. K. in Pulmonary Emphysema and Proteolysis (edited by Mittman); p. 145. London, 1972. Pierce, J. A., Jeppsson, J, Laurell C. Analyt. Biochem. 1976, 74, 227.
6. 7. Lancet, 1977, 8. Miale, T. D.,
C.
i, 1190. Lawson, D. L., Demian, S., Teague, P. O. Wolfson, S. L. ibid. 1977, ii, 93. 9. Milford Ward, A., Pickering, J. D., Shortland J. R. Inst. natn. Santé Reche. méd. 1975, 40, 131.