Acta med. scand. Vol. 199, pp. 147-149, 1976
The Nitroblue Tetrazolium (NBT) Test in Endemic Benign (Epidemic) Nephropathy Bengt Bjorksten, Kurt Nystrom and Bengt Lindqvist From the Depurtments of Paediatrics and Internal Medicine, Umed University, Umed, Sweden
ABSTRACT. NBT test values in blood samples from 25 cases of endemic benign (epidemic) nephropathy (EBN) were high, i.e. more than 19% NBT-positive neutrophils, in 22 (88%) of the patients, intermediate, i.e. 13-19 %, in two (8 %) and normal in one patient (4 %); in eight patients (32 %) the NBT test values were 50% or more. The test values remained elevated, i.e. 13% or more, for more than one month after the onset of illness in three of ten patients on whom serial tests were performed. Among 18 patients with kidney diseases other than EBN and 16 wlth kidney transplant, high NBT test values, 20 and 22%, respectively, were found in two (5.9%), intermediate values in two and normal test values in 30 patients (88.2 %). This paper is the first published report on NBT test values in cases of EBN. The test was rated to be of diagnostic value in patients in whom EBN might be suspected, highly elevated test values ( H O % NBT-positive neutrophils) lending support to the diagnosis. Applying the Nitroblue tetrazolium (NBT) test, introduced by Park et al. in 1%8 (IS), neutrophilic granulocytes may be divided into NBT-positive and NBT-negative, depending on whether or not they reduce NBT to nitroblue formazan. In patients with untreated bacterial. fungal or parasitic infections, the proportion of NBT-positive neutrophils was found to be raised (7, I I , 15), whereas in patients with viral infections, test values were normal. The test was recommended for routine use in the differentiation of various kinds of infections ( 5 , 8 ) , but in subsequent papers (2,9) the advantage of this practice has been questioned. Although the etiology of endemic benign (epidemic) nephropathy (EBN) remains undetermined, the symptoms of the disease are compatible with those of an acute infection. The diagnosis
remains a clinical one as long as no (laboratory) tests of a discriminating character have been found associated with the condition. The findings of elevated NBT test values in cases of EBN are therefore of interest. MATERIAL AND METHODS Twenty-five patients with EBN, 17 males and 8 females, aged 17-58 years (mean 36), 18 with kidney diseases other than EBN and 16 with kidney transplants, were studied. The cases of EBN were diagnosed using common clinical criteria (13): sudden onset of illness with elevated body temperature, ache or pain in the back and in the abdomen and gastrointestinal symptoms; in a majority of the patients a period of oliguria lasting a few days was followed by polyuria for about a week. Laboratory findings on admission invariably included proteinuria and elevated non-protein serum creatinine. None of the patients had a bacterial urinary infection at the time of investigation; ten were treated with antimicrobial drugs (penicillin, sulfonamides or nitrofurantoin). The disease was selflimiting and all the patients recovered within less than 10 weeks. A detailed account of the disease is given in papers on epidemic nephropathy (10, 12, 14, 17). The NBT tests were performed on venous blood samples employing a strictly standardized technique ( I ) . Test values of less than 13% NBT-positive neutrophilic granulocytes were considered to be normal (4); values above that were rated as elevated, 13-19% being considered intermediate and more than 19% high. To check the ability of the neutrophils to reduce NBT, blood samples from all patients were incubated for 10 min with 10 p g endotoxin (E. coli 0 : 11 I lipopolysaccharide, Difco Laboratories, Detroit, Mich., USA), whereafter the NBT test was repeated.
RESULTS The NBT test values were high (Fig. I ) in 22 (88 %) and intermediate in two (8%)of the patients with EBN. A normal test value was found in only one Acta med. scand. 199
B. Bjorkste'n et al.
148
patient (4%); when stimulated with endotoxin, 82 % of her neutrophils were NBT-positive, indicating that they were capable of reducing NBT. There was no difference in the distribution of NBT test values between patients treated and those not treated with antimicrobial drugs, nor did the mean of the maximum leukocyte count and of serum creatinine level differ between these groups (Wilcoxon's t-test for non-parametric observations). In kidney diseases with an acute onset other than EBN (Table I), high NBT test values, 22 and 20%, respectively, were found in one patient of two with acute tubular necrosis and in one of three with interstitial nephritis; intermediate test values were obtained in one patient with proliferative glo-
-.-
50
-
40
-
n
E
0
c L
m
c
..-c
30-
n
a I-
z 20-
1
plant. In the remaining 15 patients with a kidney dis100
lo
0
90
1st
2nd
3rd
4th
5th
6th
7th
Week a f t e r onset of disease
Fig. 2. Mean valuesfS.E.M. of weekly determinations
of NBT test values in 25 cases of EBN. - - - =upper limit for normal test values.
80
m
-.-c I
ease other than EBN and in 15 with kidney transplant (88.2%), NE3T test values were normal. Serial tests were pekormed in 10 patients with EBN and high NBT test values (Fig. 1). In four patients the NBT test values were normal after 4-5 weeks and in two after 6 and 12 weeks, respectively. In four patients the NBT test values were still elevated after 3-7 weeks. Fig. 2 presents the mean values of 40 NBT tests in 25 cases of EBN, excluding one normal value obtained on the 85th day after the onset of disease. The test values remained high up to the fifth week and were still intermediate seven weeks after the tient had contracted the disease.
60
0
L
c 3
:50
.-c>0 .LO
k
'
30
20
10
4 t-I
0 1st
2nd
Acfa med. scand. 199
3rd 4th 5th 6th 7th Week after o n s e t o f d i s e a s e
NBT test values in 25 cases of EBN and results of serial determinations. ---=upper limit for normal test values.
Fig. f. initial
I
13th
NBT test in endemic nephropathy DISCUSSION
The proportion of patients with high NBT test values was greater in EBN than in infectious diseases of known etiology and previously investigated (2). Very high test values, i.e. 50% NBT-positive neutrophils or more, were found in eight of the patients (31.3%); in conditions with an infectious etiology, test values of such a magnitude were obtained only occasionally, e.g. in cases of acute osteomyelitis (unpublished observations). The high NBT test values associated with EBN are interesting, since they are most commonly found during the acute phase of the disease. Uraemia does not give rise t o high N B T test values if the patients are free from infection (16). Th e etiology of the disease is undertermined but several authors consider it viral (10, 12, 14). High NBT test values are, however, usually not found in viral infections (5, 8) and in another study (2) elevated test values were found in only 14% of blood samples from patients with viroses. On the other hand, NBT test values are often high in mycoplasmal infections (2, 6). Assuming that EBN is caused by an as yet unidentified mycoplasma1 species, this might explain the high NB T test values found in patients with this disease. Although the mechanisms underlying the NBT test are only partially known, this study indicates that the test may b e rated as a valuable aid in the diagnosis of EBN, normal test values speaking against the disease and very high test values lending support t o the diagnosis. As the N B T test values in
Table I. Distribution of NBT test values in cases of kidney disease other than EBN and in patients with kidney transplant No. of cases with NBT test value (%) of Clinical diagnosis Glomerulonephritis, acute and proliferative Acute tubular necrosis Polycystic kidneys, interstitial nephritis, chronic pyelonephritis Collagenic disorders with renal involvement Kidney transplant Total
s12
3 I
13-19
1
I
7 4 I5 30
219
I 1
2
2
149
some cases remained elevated for several weeks after the onset of disease and the subsidence of azotaemia, the test might also be of use as a diagnostic aid even if a case of suspected EBN is not seen until late i n the course of the disease.
REFEREN CES 1. Bjorksten, B.: The influence of technical factors on
the NBT test. Scand. J. Haemat. 12:46, 1974. 2. - The Nitroblue tetrazolium (NBT) test. A methodological and clinical study. UmeA Univ. Medical Diss. IS, 1974. 3. BjorkstBn, B. & de Chateau, P.: Use of the Nitroblue tetrazolium (NBT) test in the differentiation of pyelonephritis from cystitis. Acta paediat. scand. 64: 182, 1975. 4. Bjorksten, B., Ekstrand, T., Gothefors, L. & Ostberg, Y.: The nitroblue tetrazolium (NBT) test and white blood cell count in acute throat infections. Scand. J. infect. Dis. 7: 45, 1975. 5 . Feigin, R. D.: NBT test in the diagnosis of febrile patients. New Engl. J. Med. 285:347, 1971. 6. Freeman, R. & King, B.: N.B.T. test and mycoplasma. Lancet 1:962, 1972. 7. Humbert, J. R., Marks, M. I., Hathaway, W. E. & Thoren, C. H.: The histochemical nitroblue tetrazolium reduction test in the differential diagnosis of acute infections. Pediatrics 48:259, 1971, 8. Leading article: Nitroblue tetrazolium: a Routine test? Lancet 2:909, 1971. 9. Another look at the N.B.T. test. Lancet 1:664, 1974. 10. Liihdevirta, J.: Nephropathia epidemica in Finland. A clinical, histological and epidemiological study. Ann. clin. Res., Suppl. 8, 1971. I I . Matula, G. & Paterson, P. Y.:Spontaneous in vitro reduction of nitroblue tetrazolium by neutrophils of adult patients with bacterial infection. New Engl. J. Med. 285:311, 1971. 12. Myhrman, G.: Nephropathia epidemica, a new infectious disease in Northern Scandinavia. Acta med. scand. 140:52, 1951. 13. Nystrom, K.: Incidence and prevalence of endemic benign (epidemic) nephropathy in AC county, Sweden, 1960 to 1974. To be published. 14. Ornstein, K. & Soderhjelm, L.: Nephropathia epidemica Symptome und Verlauf. Acta SOC.Med. upsalien. 68: 286, 1943. 15. Park,B. H., Fikrig, S. M. & Smithwick, E. M.: Infection and nitroblue-tetrazolium reduction by neutrophils. A diagnostic aid. Lancet 2: 532, 1968. 16. Wollman, M. R . , David, D. S . , Breman, B. L., Lewy, J. E., Stenzel, K. H., Rubin, A. L. & Miiller, D. R.: The Nitroblue-Tetrazolium test. Usefulness in detecting bacterial infections in uraemic and immunosuppressed renal transplant patients. Lancet 2: 289, 1972. 17. Zetterholm, S . G.: Akuta nefnter simulemnde akuta bukfall. Lakartidningen 31: 425, 1934.
-
-
Acta med. scand. 199
The very journals for you! Acta Chirurgica Scandinavica Editor: L. T h o r h 8 issues per volume. Free supplements. Including free subscriptions to the Scandinavian Journal of Plastic and Reconstructive Surgery (without suppl.), the Scandinavian Journal of Thoracic and Cardiovascular Surgery (without suppl.) and the Scandinavian Journal of Urology and Nephrology (without suppl.). Current volume 142/1976. Sw. kr. 300 per year, incl. postage
Acta Dermato-Venereologica Editor: Nils Thyresson 6 issues per volume. Free supplements. Current volume 56/1976. Sw. kr. 140 per year, incl. postage
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Editor: Bengt Johanson 3 issues per volume. Free supplements. Current volume 10/1976. Sw. kr. 120 per year, incl. postage
4 issues per volume. Free supplements. Current volume 5/1976. Sw. kr. 125 per year, incl. postage
Acta Oto-Laryngologica
Editor: R. Zetterstrom
Scandinavian Journal of Plastic and Reconstructive Surgery
Scandinavian Journal of Psychology
Acta Medica Scandinavica
6 issues per volume. Free supplements. Current volume 65/1976 Sw. kr. 175 per year, incl. postage
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Editor: J. Waldenstrom 6 issues per volume. Free supplements. Current volumes 199-200/1976. Sw. kr. 275 per year (two volumes), incl. postage
Acta Paediatrica Scandinavica
Scandinavian Journal of Infectious Diseases
Scandinavian Journal of Social Medicine Editor: Gunnar Inghe 3 issues per volume. Free supplements. Current volume 4/1976. Sw. kr. 115 per year, incl. postage
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Free inspection copies on request-write
to
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The Nitroblue Tetrazolium (NBT) Test in Endemic Benign (Epidemic) Nephropathy Bengt Bjorksten, Kurt Nystrom and Bengt Lindqvist From the Depurtments of Paediatrics and Internal Medicine, Umed University, Umed, Sweden
ABSTRACT. NBT test values in blood samples from 25 cases of endemic benign (epidemic) nephropathy (EBN) were high, i.e. more than 19% NBT-positive neutrophils, in 22 (88%) of the patients, intermediate, i.e. 13-19 %, in two (8 %) and normal in one patient (4 %); in eight patients (32 %) the NBT test values were 50% or more. The test values remained elevated, i.e. 13% or more, for more than one month after the onset of illness in three of ten patients on whom serial tests were performed. Among 18 patients with kidney diseases other than EBN and 16 wlth kidney transplant, high NBT test values, 20 and 22%, respectively, were found in two (5.9%), intermediate values in two and normal test values in 30 patients (88.2 %). This paper is the first published report on NBT test values in cases of EBN. The test was rated to be of diagnostic value in patients in whom EBN might be suspected, highly elevated test values ( H O % NBT-positive neutrophils) lending support to the diagnosis. Applying the Nitroblue tetrazolium (NBT) test, introduced by Park et al. in 1%8 (IS), neutrophilic granulocytes may be divided into NBT-positive and NBT-negative, depending on whether or not they reduce NBT to nitroblue formazan. In patients with untreated bacterial. fungal or parasitic infections, the proportion of NBT-positive neutrophils was found to be raised (7, I I , 15), whereas in patients with viral infections, test values were normal. The test was recommended for routine use in the differentiation of various kinds of infections ( 5 , 8 ) , but in subsequent papers (2,9) the advantage of this practice has been questioned. Although the etiology of endemic benign (epidemic) nephropathy (EBN) remains undetermined, the symptoms of the disease are compatible with those of an acute infection. The diagnosis
remains a clinical one as long as no (laboratory) tests of a discriminating character have been found associated with the condition. The findings of elevated NBT test values in cases of EBN are therefore of interest. MATERIAL AND METHODS Twenty-five patients with EBN, 17 males and 8 females, aged 17-58 years (mean 36), 18 with kidney diseases other than EBN and 16 with kidney transplants, were studied. The cases of EBN were diagnosed using common clinical criteria (13): sudden onset of illness with elevated body temperature, ache or pain in the back and in the abdomen and gastrointestinal symptoms; in a majority of the patients a period of oliguria lasting a few days was followed by polyuria for about a week. Laboratory findings on admission invariably included proteinuria and elevated non-protein serum creatinine. None of the patients had a bacterial urinary infection at the time of investigation; ten were treated with antimicrobial drugs (penicillin, sulfonamides or nitrofurantoin). The disease was selflimiting and all the patients recovered within less than 10 weeks. A detailed account of the disease is given in papers on epidemic nephropathy (10, 12, 14, 17). The NBT tests were performed on venous blood samples employing a strictly standardized technique ( I ) . Test values of less than 13% NBT-positive neutrophilic granulocytes were considered to be normal (4); values above that were rated as elevated, 13-19% being considered intermediate and more than 19% high. To check the ability of the neutrophils to reduce NBT, blood samples from all patients were incubated for 10 min with 10 p g endotoxin (E. coli 0 : 11 I lipopolysaccharide, Difco Laboratories, Detroit, Mich., USA), whereafter the NBT test was repeated.
RESULTS The NBT test values were high (Fig. I ) in 22 (88 %) and intermediate in two (8%)of the patients with EBN. A normal test value was found in only one Acta med. scand. 199
B. Bjorkste'n et al.
148
patient (4%); when stimulated with endotoxin, 82 % of her neutrophils were NBT-positive, indicating that they were capable of reducing NBT. There was no difference in the distribution of NBT test values between patients treated and those not treated with antimicrobial drugs, nor did the mean of the maximum leukocyte count and of serum creatinine level differ between these groups (Wilcoxon's t-test for non-parametric observations). In kidney diseases with an acute onset other than EBN (Table I), high NBT test values, 22 and 20%, respectively, were found in one patient of two with acute tubular necrosis and in one of three with interstitial nephritis; intermediate test values were obtained in one patient with proliferative glo-
-.-
50
-
40
-
n
E
0
c L
m
c
..-c
30-
n
a I-
z 20-
1
plant. In the remaining 15 patients with a kidney dis100
lo
0
90
1st
2nd
3rd
4th
5th
6th
7th
Week a f t e r onset of disease
Fig. 2. Mean valuesfS.E.M. of weekly determinations
of NBT test values in 25 cases of EBN. - - - =upper limit for normal test values.
80
m
-.-c I
ease other than EBN and in 15 with kidney transplant (88.2%), NE3T test values were normal. Serial tests were pekormed in 10 patients with EBN and high NBT test values (Fig. 1). In four patients the NBT test values were normal after 4-5 weeks and in two after 6 and 12 weeks, respectively. In four patients the NBT test values were still elevated after 3-7 weeks. Fig. 2 presents the mean values of 40 NBT tests in 25 cases of EBN, excluding one normal value obtained on the 85th day after the onset of disease. The test values remained high up to the fifth week and were still intermediate seven weeks after the tient had contracted the disease.
60
0
L
c 3
:50
.-c>0 .LO
k
'
30
20
10
4 t-I
0 1st
2nd
Acfa med. scand. 199
3rd 4th 5th 6th 7th Week after o n s e t o f d i s e a s e
NBT test values in 25 cases of EBN and results of serial determinations. ---=upper limit for normal test values.
Fig. f. initial
I
13th
NBT test in endemic nephropathy DISCUSSION
The proportion of patients with high NBT test values was greater in EBN than in infectious diseases of known etiology and previously investigated (2). Very high test values, i.e. 50% NBT-positive neutrophils or more, were found in eight of the patients (31.3%); in conditions with an infectious etiology, test values of such a magnitude were obtained only occasionally, e.g. in cases of acute osteomyelitis (unpublished observations). The high NBT test values associated with EBN are interesting, since they are most commonly found during the acute phase of the disease. Uraemia does not give rise t o high N B T test values if the patients are free from infection (16). Th e etiology of the disease is undertermined but several authors consider it viral (10, 12, 14). High NBT test values are, however, usually not found in viral infections (5, 8) and in another study (2) elevated test values were found in only 14% of blood samples from patients with viroses. On the other hand, NBT test values are often high in mycoplasmal infections (2, 6). Assuming that EBN is caused by an as yet unidentified mycoplasma1 species, this might explain the high NB T test values found in patients with this disease. Although the mechanisms underlying the NBT test are only partially known, this study indicates that the test may b e rated as a valuable aid in the diagnosis of EBN, normal test values speaking against the disease and very high test values lending support t o the diagnosis. As the N B T test values in
Table I. Distribution of NBT test values in cases of kidney disease other than EBN and in patients with kidney transplant No. of cases with NBT test value (%) of Clinical diagnosis Glomerulonephritis, acute and proliferative Acute tubular necrosis Polycystic kidneys, interstitial nephritis, chronic pyelonephritis Collagenic disorders with renal involvement Kidney transplant Total
s12
3 I
13-19
1
I
7 4 I5 30
219
I 1
2
2
149
some cases remained elevated for several weeks after the onset of disease and the subsidence of azotaemia, the test might also be of use as a diagnostic aid even if a case of suspected EBN is not seen until late i n the course of the disease.
REFEREN CES 1. Bjorksten, B.: The influence of technical factors on
the NBT test. Scand. J. Haemat. 12:46, 1974. 2. - The Nitroblue tetrazolium (NBT) test. A methodological and clinical study. UmeA Univ. Medical Diss. IS, 1974. 3. BjorkstBn, B. & de Chateau, P.: Use of the Nitroblue tetrazolium (NBT) test in the differentiation of pyelonephritis from cystitis. Acta paediat. scand. 64: 182, 1975. 4. Bjorksten, B., Ekstrand, T., Gothefors, L. & Ostberg, Y.: The nitroblue tetrazolium (NBT) test and white blood cell count in acute throat infections. Scand. J. infect. Dis. 7: 45, 1975. 5 . Feigin, R. D.: NBT test in the diagnosis of febrile patients. New Engl. J. Med. 285:347, 1971. 6. Freeman, R. & King, B.: N.B.T. test and mycoplasma. Lancet 1:962, 1972. 7. Humbert, J. R., Marks, M. I., Hathaway, W. E. & Thoren, C. H.: The histochemical nitroblue tetrazolium reduction test in the differential diagnosis of acute infections. Pediatrics 48:259, 1971, 8. Leading article: Nitroblue tetrazolium: a Routine test? Lancet 2:909, 1971. 9. Another look at the N.B.T. test. Lancet 1:664, 1974. 10. Liihdevirta, J.: Nephropathia epidemica in Finland. A clinical, histological and epidemiological study. Ann. clin. Res., Suppl. 8, 1971. I I . Matula, G. & Paterson, P. Y.:Spontaneous in vitro reduction of nitroblue tetrazolium by neutrophils of adult patients with bacterial infection. New Engl. J. Med. 285:311, 1971. 12. Myhrman, G.: Nephropathia epidemica, a new infectious disease in Northern Scandinavia. Acta med. scand. 140:52, 1951. 13. Nystrom, K.: Incidence and prevalence of endemic benign (epidemic) nephropathy in AC county, Sweden, 1960 to 1974. To be published. 14. Ornstein, K. & Soderhjelm, L.: Nephropathia epidemica Symptome und Verlauf. Acta SOC.Med. upsalien. 68: 286, 1943. 15. Park,B. H., Fikrig, S. M. & Smithwick, E. M.: Infection and nitroblue-tetrazolium reduction by neutrophils. A diagnostic aid. Lancet 2: 532, 1968. 16. Wollman, M. R . , David, D. S . , Breman, B. L., Lewy, J. E., Stenzel, K. H., Rubin, A. L. & Miiller, D. R.: The Nitroblue-Tetrazolium test. Usefulness in detecting bacterial infections in uraemic and immunosuppressed renal transplant patients. Lancet 2: 289, 1972. 17. Zetterholm, S . G.: Akuta nefnter simulemnde akuta bukfall. Lakartidningen 31: 425, 1934.
-
-
Acta med. scand. 199
The very journals for you! Acta Chirurgica Scandinavica Editor: L. T h o r h 8 issues per volume. Free supplements. Including free subscriptions to the Scandinavian Journal of Plastic and Reconstructive Surgery (without suppl.), the Scandinavian Journal of Thoracic and Cardiovascular Surgery (without suppl.) and the Scandinavian Journal of Urology and Nephrology (without suppl.). Current volume 142/1976. Sw. kr. 300 per year, incl. postage
Acta Dermato-Venereologica Editor: Nils Thyresson 6 issues per volume. Free supplements. Current volume 56/1976. Sw. kr. 140 per year, incl. postage
Acta Obstetricia et Gynecologica Scandinavica Editor: Axel Ingelman-Sundberg 5 issues per volume. Free supplements. Current volume 55/1976 Sw. kr. 175 per year, incl. postage
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Acta Oto-Laryngologica
Editor: R. Zetterstrom
Scandinavian Journal of Plastic and Reconstructive Surgery
Scandinavian Journal of Psychology
Acta Medica Scandinavica
6 issues per volume. Free supplements. Current volume 65/1976 Sw. kr. 175 per year, incl. postage
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Editor: J. Waldenstrom 6 issues per volume. Free supplements. Current volumes 199-200/1976. Sw. kr. 275 per year (two volumes), incl. postage
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Scandinavian Journal of Social Medicine Editor: Gunnar Inghe 3 issues per volume. Free supplements. Current volume 4/1976. Sw. kr. 115 per year, incl. postage
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to
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