- Email: [email protected]
PENICILLIN AND MENINGOCOCCI
702 SM, LaVelle M, Pesick SD, Ridella SA Are pregnant teenagers still m rapid growth? Am J Dis Child 1984; 138: 32-34. 4. Sukanich AC, Rogers KD, McDonald HM. Physical maturity and outcome of pregnancy in primiparae younger than 16 years. Pediatrics 1986, 78: 31-36. 5. Interscience Development Associates (3508 Market Street, Suite 212, Philadelphia, PA 19104, USA). 6. Valk IM, Chabloz A, Langout A, et al. Accurate measurements of the lower leg length and its application m short term growth measurement. Growth 1983; 47: 53-66. 7. Cronk CE, Widdoes HD, Spender QW, et al. Measurement of short term growth with a knee height measuring device. 13th annual meeting of Human Biology Council (1988); abstr. 8. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985; 312: 82-90. 9. Naeye RL. Teenaged and pre-teenaged pregnancies: Consequencs of the fetalmaternal competition for nutrients. Pediatrics 1981; 67: 146-50. 3. Garn
NEOPTERIN IN CLINICAL MEDICINE
SIR,-Your March 5 editorial (p 509) dwells at length on the well-established place of neopterin in the differential diagnosis of atypical phenylketonuria (PKU), which is diagnosed in 1 per million newborn babies-and only a subgroup of these children has very high concentrations of neopterins (namely, those with deficient 6-pyruvoyl-5,6,7,8-tetrahydropterin synthetasel). Most recent developments in neopterin research have been achieved in an immunological context, increased concentrations of Derythroneopterin being reported in body fluids. Yet only a minor part of the editorial focuses on this aspect of
"pteridinology";
require correction. You state that accurate measurement of one single pterin species is difficult because these compounds are so susceptible to oxidative breakdown. This is certainly true for reduced species. Thus, measurement of total neopterins including NH2 after oxidationz can only lead to results comparable to direct neopterin measurement when samples are adequately handled. However, the precautions necessary do limit the routine use of such testing. In contrast, fully oxidised neopterin is stable, and direct measurement is possible in clinical settings without special collection of samples at the bedside furthermore, some
or
statements
addition of antioxidants. It is
true
that the relation between
neopterin and NH2 varies between different body fluids but in a certain body fluid it is fairly constant. Measurement of total neopterin, including NH,, therefore, offers no advantage. Neopterin represents about one-third of total neopterins in serum. The urine of healthy males contains 110 (SD 30) pmol neopterin/ mol creatinine and of healthy females 140 (35), figures lower than those stated by The Lancet. There is no potential for biopterin in evaluating cellular immunity, as proposed in the editorial. In vitro, only neopterins are released from macrophages on stimulation with interferongamma.3 In patients, during immunostimulatory treatment only the concentration of neopterin increases significantly. In diseases involving cellular immune activation accompanied by very high neopterin levels no change in biopterin was observed.2 Obviously, the enzymes for further conversion to biopterins are not active in stimulated macrophages. Your editorial states that various stimuli may induce increased neopterin. However, no other inducer of macrophage activity than interferon-gamma leads to significant release of neopterin in vitro.3.4 Of course, immunostimulators that activate T-lymphocytes to release interferon gamma, in turn evoke increase of neopterin in vivo. Concentrations of neopterin in body fluids (eg, urine, blood, cerebrospinal or synovial fluid) provide a sensitive insight into cellular immune status directly in vivo just by measurement of concentrations, and this is why neopterin has been proposed for use in clinical practice. Neopterin levels do not merely correlate with other indices of disease activity, as your editorial suggests, although this finding is itself important. Many studies have shown, by multivariate analysis, that neopterin carries independent information and that, in certain situations, it might be used as a valid alternative for single or combined conventional tests. Neopterin levels are already influencing clinical decisions. Increasing neopterin levels indicate immunological complications in allograft recipients,s and in several European transplant centres patients are monitored daily. In HIV infection neopterin levels are of particular value in defining the patient’s status.6 Further
important clinical findings missed by predictive value of neopterin assessment
your editorial are the in sepsis’ and in certain
types of cancer. These studies were carefully designed and underline the potential of neopterin in clinical practice; of course, no laboratory test will replace the physician. Your criticism that clinically unimportant infections may disqualify the test is not justified-nor is the claimed high frequency of false positives and false negatives. Neopterin levels are well suited to support differential diagnosis in several clinical settings-eg, neopterin levels permit autoimmune rheumatoid arthritis to be distinguished from osteoarthrosis9 and fatty liver from chronic non-A, non-B hepatitis. 10’nere is only a small overlap of neopterin levels between controls and patients with diseases with a cellular
immunological background. We conclude that neopterin is a useful index in various clinical conditions. Measurement of neopterin provides insight into cellular immunology that is hard to obtain by other methods. The fact that a biological role for neopterin has not yet been established should not impede its use in clinical routine, and several groups are already exploiting this test. DIETMAR FUCHS ARNO HAUSEN Institute of Medical Chemistry and Biochemistry, University of Innsbruck, A-6020 Innsbruck, Austria
GILBERT REIBNEGGER ERNST R. WERNER HELMUT WACHTER
J, Fontana A, et al. Biosynthesis and metabolism of pterins in peripheral blood mononuclear cells and leukaemia lines of man and mouse. Eur J
1 Schoedon G, Troppmair
Biochem 1987; 166: 303-10. S, Kaufman S, Saimot G. Urinary neopterin and biopterin levels in patients with AIDS and AIDS related complex. Lancet 1985; ii: 51-52. Huber C, Batchelor JR, Fuchs D, et al. Immune response-associated production of neoptenn—Release from macrophages primarily under control of interferongamma. J Exp Med 1984; 160: 310-16 Nathan CF. Peroxide and ptendine a hypothesis of the regulation of macrophage antimicrobial activity by interferon-gamma. In: Gresser J, ed. Interferon 7. London: Academic Press, 1986: 125-43. Margreiter R, Fuchs D, Hausen A, et al. Neopterin as a new biochemical marker for diagnosis of allograft rejection. Transplantation 1983; 36: 650-53. Fuchs D, Hausen A, Reibnegger G, Wemer ER, Dierich MP, Wachter H. Neopterin as a marker for activated cell-mediated immunity: Use in HIV infection. Immunol
2. Abita JP, Cost H, Milstien 3.
4.
5.
6.
Today (in press). W, Redl H, Schlag G, Inthom D. D-erythroneopterin plasma levels in intensive care patients with and without septic complications. Crit Care Med 1987;
7. Strohmaier
15: 757-60. 8.
Reibnegger G, Fuchs D, Hausen A, Wemer ER, Wachter H. Activated macrophages and cancer. Lancet 1987; i; 1439.
et al Urinary neopterin reflects clinical activity in patients with rheumatoid arthritis. Arthr Rheum 1986; 29: 1063-70. 10. Pnor C, Fuchs E, Hausen A, et al. Potential of urinary neoptenn excretion in differentiating chronic non-A, non-B hepatitis from fatty liver. Lancet 1987; ii: 1235-37.
9.
Reibriegger G, Egg D, Fuchs D,
PENICILLIN AND MENINGOCOCCI
SIR,-Professor Geddes (Feb 6, p 286) suggests that penicillin is likely to be adequate for the treatment of meningococcal meningitis although there are some reports of diminished sensitivity. In Malawi, however, our experience is different. In January, 1988, at the end of our meningitis season, 6 of our 7 culture-proven meningococcal meningitis patients had organisms resistant to penicillin (’Mastring S’ discs, Mast Laboratories). In addition, resistance to other antibiotics was noted--sulphadiazine (4), streptomycin (2), and tetracycline (1). The clinical course in 4 of the patients was satisfactory on initial blind therapy with benzylpenicillin 18 megaunits daily and chloramphenicol 2 g daily; they recovered fully. The other 2 patients, however, had persistent fever and little clinical improvement for 6 days until addition of streptomycin or ampicillin led to recovery. Earlier in the season we had isolated 2 lots of meningococci resistant to both chloramphenicol and penicillin. Both patients died. We have therefore had to change our policy to include ampicillin therapy for patients with meningococcal or unidentified meninigitis who show no response after 48 h of conventional treatment. If the prevalence of the chloramphenicol-resistant strain increases then initial therapy will need
to
be altered as well.
Department of Medicine, Queen Elizabeth Central Hospital, Blantyre, Malawi
ALISON ROUND WILLIAM HAMILTON
NEOPTERIN IN CLINICAL MEDICINE
SIR,-Your March 5 editorial (p 509) dwells at length on the well-established place of neopterin in the differential diagnosis of atypical phenylketonuria (PKU), which is diagnosed in 1 per million newborn babies-and only a subgroup of these children has very high concentrations of neopterins (namely, those with deficient 6-pyruvoyl-5,6,7,8-tetrahydropterin synthetasel). Most recent developments in neopterin research have been achieved in an immunological context, increased concentrations of Derythroneopterin being reported in body fluids. Yet only a minor part of the editorial focuses on this aspect of
"pteridinology";
require correction. You state that accurate measurement of one single pterin species is difficult because these compounds are so susceptible to oxidative breakdown. This is certainly true for reduced species. Thus, measurement of total neopterins including NH2 after oxidationz can only lead to results comparable to direct neopterin measurement when samples are adequately handled. However, the precautions necessary do limit the routine use of such testing. In contrast, fully oxidised neopterin is stable, and direct measurement is possible in clinical settings without special collection of samples at the bedside furthermore, some
or
statements
addition of antioxidants. It is
true
that the relation between
neopterin and NH2 varies between different body fluids but in a certain body fluid it is fairly constant. Measurement of total neopterin, including NH,, therefore, offers no advantage. Neopterin represents about one-third of total neopterins in serum. The urine of healthy males contains 110 (SD 30) pmol neopterin/ mol creatinine and of healthy females 140 (35), figures lower than those stated by The Lancet. There is no potential for biopterin in evaluating cellular immunity, as proposed in the editorial. In vitro, only neopterins are released from macrophages on stimulation with interferongamma.3 In patients, during immunostimulatory treatment only the concentration of neopterin increases significantly. In diseases involving cellular immune activation accompanied by very high neopterin levels no change in biopterin was observed.2 Obviously, the enzymes for further conversion to biopterins are not active in stimulated macrophages. Your editorial states that various stimuli may induce increased neopterin. However, no other inducer of macrophage activity than interferon-gamma leads to significant release of neopterin in vitro.3.4 Of course, immunostimulators that activate T-lymphocytes to release interferon gamma, in turn evoke increase of neopterin in vivo. Concentrations of neopterin in body fluids (eg, urine, blood, cerebrospinal or synovial fluid) provide a sensitive insight into cellular immune status directly in vivo just by measurement of concentrations, and this is why neopterin has been proposed for use in clinical practice. Neopterin levels do not merely correlate with other indices of disease activity, as your editorial suggests, although this finding is itself important. Many studies have shown, by multivariate analysis, that neopterin carries independent information and that, in certain situations, it might be used as a valid alternative for single or combined conventional tests. Neopterin levels are already influencing clinical decisions. Increasing neopterin levels indicate immunological complications in allograft recipients,s and in several European transplant centres patients are monitored daily. In HIV infection neopterin levels are of particular value in defining the patient’s status.6 Further
important clinical findings missed by predictive value of neopterin assessment
your editorial are the in sepsis’ and in certain
types of cancer. These studies were carefully designed and underline the potential of neopterin in clinical practice; of course, no laboratory test will replace the physician. Your criticism that clinically unimportant infections may disqualify the test is not justified-nor is the claimed high frequency of false positives and false negatives. Neopterin levels are well suited to support differential diagnosis in several clinical settings-eg, neopterin levels permit autoimmune rheumatoid arthritis to be distinguished from osteoarthrosis9 and fatty liver from chronic non-A, non-B hepatitis. 10’nere is only a small overlap of neopterin levels between controls and patients with diseases with a cellular
immunological background. We conclude that neopterin is a useful index in various clinical conditions. Measurement of neopterin provides insight into cellular immunology that is hard to obtain by other methods. The fact that a biological role for neopterin has not yet been established should not impede its use in clinical routine, and several groups are already exploiting this test. DIETMAR FUCHS ARNO HAUSEN Institute of Medical Chemistry and Biochemistry, University of Innsbruck, A-6020 Innsbruck, Austria
GILBERT REIBNEGGER ERNST R. WERNER HELMUT WACHTER
J, Fontana A, et al. Biosynthesis and metabolism of pterins in peripheral blood mononuclear cells and leukaemia lines of man and mouse. Eur J
1 Schoedon G, Troppmair
Biochem 1987; 166: 303-10. S, Kaufman S, Saimot G. Urinary neopterin and biopterin levels in patients with AIDS and AIDS related complex. Lancet 1985; ii: 51-52. Huber C, Batchelor JR, Fuchs D, et al. Immune response-associated production of neoptenn—Release from macrophages primarily under control of interferongamma. J Exp Med 1984; 160: 310-16 Nathan CF. Peroxide and ptendine a hypothesis of the regulation of macrophage antimicrobial activity by interferon-gamma. In: Gresser J, ed. Interferon 7. London: Academic Press, 1986: 125-43. Margreiter R, Fuchs D, Hausen A, et al. Neopterin as a new biochemical marker for diagnosis of allograft rejection. Transplantation 1983; 36: 650-53. Fuchs D, Hausen A, Reibnegger G, Wemer ER, Dierich MP, Wachter H. Neopterin as a marker for activated cell-mediated immunity: Use in HIV infection. Immunol
2. Abita JP, Cost H, Milstien 3.
4.
5.
6.
Today (in press). W, Redl H, Schlag G, Inthom D. D-erythroneopterin plasma levels in intensive care patients with and without septic complications. Crit Care Med 1987;
7. Strohmaier
15: 757-60. 8.
Reibnegger G, Fuchs D, Hausen A, Wemer ER, Wachter H. Activated macrophages and cancer. Lancet 1987; i; 1439.
et al Urinary neopterin reflects clinical activity in patients with rheumatoid arthritis. Arthr Rheum 1986; 29: 1063-70. 10. Pnor C, Fuchs E, Hausen A, et al. Potential of urinary neoptenn excretion in differentiating chronic non-A, non-B hepatitis from fatty liver. Lancet 1987; ii: 1235-37.
9.
Reibriegger G, Egg D, Fuchs D,
PENICILLIN AND MENINGOCOCCI
SIR,-Professor Geddes (Feb 6, p 286) suggests that penicillin is likely to be adequate for the treatment of meningococcal meningitis although there are some reports of diminished sensitivity. In Malawi, however, our experience is different. In January, 1988, at the end of our meningitis season, 6 of our 7 culture-proven meningococcal meningitis patients had organisms resistant to penicillin (’Mastring S’ discs, Mast Laboratories). In addition, resistance to other antibiotics was noted--sulphadiazine (4), streptomycin (2), and tetracycline (1). The clinical course in 4 of the patients was satisfactory on initial blind therapy with benzylpenicillin 18 megaunits daily and chloramphenicol 2 g daily; they recovered fully. The other 2 patients, however, had persistent fever and little clinical improvement for 6 days until addition of streptomycin or ampicillin led to recovery. Earlier in the season we had isolated 2 lots of meningococci resistant to both chloramphenicol and penicillin. Both patients died. We have therefore had to change our policy to include ampicillin therapy for patients with meningococcal or unidentified meninigitis who show no response after 48 h of conventional treatment. If the prevalence of the chloramphenicol-resistant strain increases then initial therapy will need
to
be altered as well.
Department of Medicine, Queen Elizabeth Central Hospital, Blantyre, Malawi
ALISON ROUND WILLIAM HAMILTON