Correspondence
354
Table 1. Clinical and biochemical data in four patients with early acute hepatitis A.
Patient,' age (gender) 1, 27 (F) 2, 21 (M) 3, 44 (F) 4, 35 (F) NOTE.
Symptoms, duration Fever, 3 d Icterus, malaise, fever, 2 d Malaise, 1 d Arthralgias, 1 d
Alanine Aspartate aminoaminotransferase transferase (units/l) (units/l)
Bilirubin (mg/dl)
366 2900
272 2600
0.8 6.5
77 605
109 500
1.0 1.0
All patients were negative for anti-HAV IgM but seroconverted later.
Numbness and Tingling of Fingers Associated with Parvovirus B19 Infection COLLEAGUES - Fifth disease or erythema infectiosum is a communicable disease that most often occurs in children aged 2-12 years and is characterized by an intense erythematous blush over the cheeks, a macular-papular eruption on the extremities that becomes an evanescent reticulated rash, and a general lack of constitutional symptoms
Reprints and correspondence: Dr. Howard Faden, Division of Infectious Diseases, Department of Pediatrics, Children's Hospital of Buffalo,219 Bryant St., Buffalo, NY 14222. The Journal of Infectious Diseases, 1990;161:354-355 © 1990 by The University of Chicago. All rights reserved. 0022-1899/90/6102-003$01.00
One unit is equivalent to about one reference unit of the WHO human leukocyte reference interferon IFN B 69/19. Serum interferon was demonstrable in patient 3 (40 units); the others were negative. Second, the activity of the IFN-regulated enzyme 2-5 A synthetase was determined by the radiobinding method [4] in the celllysate of 5 x lQ6 peripheral blood mononuclear cells of patient 4 for whom heparinized blood was available. A markedly elevated 2-5 A synthetase level (870 pmol/lQ6 cells/h) was found in this patient (normal values, 74 ± 40 pmol/lQ6 cells/h, mean ± SD). In a larger series of patients positive for anti-HAY IgM, 2-5 A synthetase levels were invariably increased in the lysate of peripheral blood mononuclear cells (296 ± 155 pmol/lQ6 cells/h, mean ± SD) (unpublished results). Thus, we found evidence of activation of the interferon system in two patients in the very early phase of acute hepatitis A before the appearance of specific antibodies.
R. Zachoval, M. Kroener, M. Brommer, and F. Deinhardt Medizinische Klinik II, Klinikum Gro,Phadem, Max von Pettenkofer-Institute, University of Munich, Stadusches Krankenhaus Schwabing, Munich, Federal Republic of Germany
References 1. Froesner GG, Deinhardt F, RoggendorfM, Scheid R, Bayed B, Zachoval R. Laboratory diagnosis of hepatitis A infection. In: Bianchi L, Gerok W, Sickinger K, Stalder GA, eds. Virus and the liver. Lancaster, PA: MTP Press, 1980:17-26 2. Davis GL, Hoofnagle JH, Waggoner JG. Acute type A hepatitis during chronic hepatitis B virus infection: association of depressed hepatitis B virus replication with appearance of endogenous alpha interferon. J Med Virol 1984;14:141-147 3. Zachoval R, Abb J, Zachoval V, Deinhardt F. Circulating interferon in patients with acute hepatitis A. J Infect Dis 1986;153:1174-1175 4. Silverman RH, Krause P. Analysis of anti-viral mechanisms: interferon regulated 2'5'oligoadenylate and protein kinase systems. In: Clemens MJ, Morris AG, Gearing AlH, eds. Lymphokines and interferons. Oxford, UK: IRL Press, 1987:149-193
[1]. Adults become more ill, develop significant joint disturbances, and exhibit a rash on their extremities [1]. Recent studies identified parvovirus B19 as the cause of fifth disease [2-4]. Viral particles and viral DNA fragments have been identified in serum, urine, and throat washes [3]. Immunoglobulin M-specific antibody is characteristically present during acute infection, rapidly falls off at 2 months, but may remain detectable for 4 months or longer [2, 3, 5, 6]. Immunoglobulin M-specific antibody is not observed in the normal population. In contrast, IgGspecific antibody is commonly measured in the general population; the prevalence of antibody-positive individuals increases from 12 % in 5- to 9-year-olds to 55% in adults >30 years [6]. From 1 April through 31 August 1987, an outbreak of fifth disease occurred in the Buffalo, NY, area, including cases among employees at a children's hospital. A survey of 47 nurses in the intensive care unit (ICU) revealed 11 with symptoms consistent with fifth disease. Each of the nurses with apparent fifth disease had serum tested
Downloaded from http://jid.oxfordjournals.org/ at Freie Universitaet Berlin on July 4, 2015
results for IgM antibodies to the hepatitis B core antigen (CORAB M; Abbott), to cytomegalovirus (Behring AG, Marburg, FRG), and to Epstein-Barr virus viral capsid antigen. All four had seroconverted and were positive for anti-HAY IgM (HAVAB-Menzyme immunoassay; Abbott) when second serum samples were collected 5-11 days later. The three patients with normal bilirubin values (patients 1, 3, and 4) at the outset became icteric later. All four patients had uncomplicated clinical courses of disease with full recovery; there were no apparent cellular or humoral immune defects. We conclude that, although demonstration of anti-HAY IgM in a single serum sample is the usual method to diagnose acute HAV infection, in rare instances production of specific antibodies is delayed in patients with acute hepatitis without any evidence of immunodeficiency. It is suggested, therefore, that in suspected cases of HAV infection with a negative anti-HAY IgM, a second serum sample be obtained a few days after the first. As the interferon (lFN) system is thought to be an early defense " mechanism in HAV infection [2,3], we used two methods to investigate IFN action in the same four patients. First, antiviral activity was determined in serial twofold dilutions of serum by measuring the inhibition of the cytopathic effect (CPE) of vesicular stomatitis virus on bovine kidney cells (MDBK). Antiviral units were calculated as the reciprocal of the highest dilution inhibiting 50% ofCPE.
JID 1990;161 (February)
Correspondence
JID 1990;161 (February)
Table 1. Clinical features of nurses with fifth disease. Subject 1 2 3 4 5 6 7 8 9 10 11
12 13 NOTE.
Fever
Facial rash
+ +
+
Extremity rash
Numbness/ tingling
+ + + + + +
+ +
+ +
+ +
+ + + +
Subjects 1-11 had joint symptoms. +, symptoms; -, no symptoms.
Thus, 13 of 47 nurses in the ICU developedfifth disease: 7 experienced numbness and tingling of fingers; in 2 the only sign of the parvovirus infection was the numbness and tingling. Infection with parvovirusBI9 was confirmed by the presence of IgM-specificantibodyin everysymptomatic subject.Controlsubjectsuniformly lacked IgM-specific antibody. IgO-specific antibody was present in all of the ill nurses and in 82 % of the controls. The mechanism of numbness and tingling was not established. Some data suggestedthat the symptomswere the result of a peripheral neuropathy; however, neurologic complications in fifth disease are uncommon. Twocases of encephalitishave been described previously [8, 9]. Possibly, some of the symptomatologyseen in parvovirus BI9 infection may be due to an unusualimmunologic resonse; however, in several large studies of parvovirus-associatedarthropathy, evaluations of immune complexesand rheumatoid factor proved negative [5, 10]. The evidencein our study suggested that parvovirusBI9 maycause numbnessand tingling of the peripheral extremities. Even in the absence of an illness consistent with fifth disease, parvovirus BI9 infection should be considered in the differential diagnosis of such symptoms.
Howard Faden, G. William Gary, Jr., and Michael Korman Departments of Pediatrics and Neurology, State University of New lVrk at Buffalo, School of Medicine, and Children's Hospital, Buffalo; and Division of Viral Diseases, Center for Infectious Diseases, Centers for Disease Control, Atlanta, Georgia
References 1. Balfour H. Erythema infectiosum (fifth disease): clinical review and descriptionof91 casesseen in an epidemic. Clio Pediatr1969;8:721-727 2. Okabe N, Koboyashi S, Thtsuzawa 0, Mortimer PP. Detection of antibody to human parvovirus in erythema infectiosum (fifth disease). Arch Dis Child 1984;59:1016-1019 3. Chorba T, Coccia P, Holman RC, Tattersall P, Anderson U, Sudman J, Young NS, Kurczynski E, Sarrinen UM, Moir R, Lawrence DN, Jason JM, Evatt B. The role of parvovirus B19 in aplastic crisis and erythema infectiosum (fifth disease). J Infect Dis 1986;154:383-392 4. Anderson MJ, Higgins PG, Davis LR, WllimanJS, Jones SE, Kidd 1M, Pattison JR, Tyrrell DAJ. Experimental parvoviral infection in humans. J Infect Dis 1985;152:257-265 5. Reid OM, Reid TMS, Brown T, Rennie JAN, Eastmond CJ. Human parvovirus-associatedarthritis: a clinical and laboratory description. Lancet 1985;1:422-425 6. NunoueT, Okochi K, Mortimer PP, Cohen BJ. Human parvovirus(B19) and erythema infectiosum. J Pediatr 1985;107:38-40 7. Anderson U, Tsou C, Parker RA, Chorba TL, Wulff H, Tattersall P, Mortimer PP. Detection of antibodies and antigens of human parvovirus B19by enzyme-linkedimmunosorbent assay. J Clio Microbiol 1986;24:522-526 8. Hall CB, Homer FA. Encephalopathy with erythema infectiosum. Am J Dis Child 1977;131:65-67 9. Balfour HH, Schiff GM, Bloom JE. Encephalitis associated with erythema infectiosum. J Pediatr 19;,);77:133-136 10. White DG, Woolf AD, Mortimer PP, Cohen BJ, Blake DR, Bacon PA. Human parvovirus arthropathy. Lancet 1981;1:419-421
Downloaded from http://jid.oxfordjournals.org/ at Freie Universitaet Berlin on July 4, 2015
for IgM and IgO antibody against parvovirus BI9 in the laboratory of Dr. W. Oary (Centers for Disease Control, Atlanta, OA), using an IgO and IgM capture ELISA[7]. Serum specimenswereobtained within 2 months of the onset of symptoms. A group of eight asymptomatic nurses who worked in the same unit were screened at the same time to detect asymptomatic infection. A secondcontrol group of nine asymptomaticindividuals who worked in the Division of Infectious Diseases was screened to assess the background frequency of past infection with parvovirus BI9. Subjects 1-11 were readily diagnosed because they exhibited features consistent with fifth disease (table 1). Numbness and tingling of the fingersoccurred in five nurses with classic fifth disease. One also complained of numbness and tingling in her toes. The neurologic examination in 4 subjects was normal except for mildly decreased sensationto lighttouchoverthe involved areas. In 2 subjects, the signs disappeared completely within 2 months; however, in 3, the numbness and tingling recurred intermittently over 1 year. One nurse exhibited more significant disease: progressive weakness of one arm involving wrist, finger, and thumb extension and numbness of the forearm. She had normal muscle mass and tone; however, strengthwas mildlyreducedin the triceps,wrist, and fingers. Sensation remained intact; reflexes were normal. Subsequently, she developed mild numbness in the toes of both feet. Electrodiagnostic studies showedmild slowingof nerve conduction velocitiesand decreased amplitudes of motor and sensory potentials. Twoother nurses withoutthe typical featuresof fifth di-sease complainedof numbnessand tinglingin their fingers duringthe outbreak. Because the onset of their symptoms and the similarity of the features coincided with those previouslydescribed, parvovirusBI9 was presumed to be the cause of the disease in these subjects and the other cases. Each of the nurses with fifth disease and the two with numbness and tingling alone possessedboth IgM- and IgO-specificparvovirus antibody. In contrast, none of 17 asymptomatic controls had IgM antibody to parvovirus BI9, although 14 had IgO-specificantibody.
355
354
Table 1. Clinical and biochemical data in four patients with early acute hepatitis A.
Patient,' age (gender) 1, 27 (F) 2, 21 (M) 3, 44 (F) 4, 35 (F) NOTE.
Symptoms, duration Fever, 3 d Icterus, malaise, fever, 2 d Malaise, 1 d Arthralgias, 1 d
Alanine Aspartate aminoaminotransferase transferase (units/l) (units/l)
Bilirubin (mg/dl)
366 2900
272 2600
0.8 6.5
77 605
109 500
1.0 1.0
All patients were negative for anti-HAV IgM but seroconverted later.
Numbness and Tingling of Fingers Associated with Parvovirus B19 Infection COLLEAGUES - Fifth disease or erythema infectiosum is a communicable disease that most often occurs in children aged 2-12 years and is characterized by an intense erythematous blush over the cheeks, a macular-papular eruption on the extremities that becomes an evanescent reticulated rash, and a general lack of constitutional symptoms
Reprints and correspondence: Dr. Howard Faden, Division of Infectious Diseases, Department of Pediatrics, Children's Hospital of Buffalo,219 Bryant St., Buffalo, NY 14222. The Journal of Infectious Diseases, 1990;161:354-355 © 1990 by The University of Chicago. All rights reserved. 0022-1899/90/6102-003$01.00
One unit is equivalent to about one reference unit of the WHO human leukocyte reference interferon IFN B 69/19. Serum interferon was demonstrable in patient 3 (40 units); the others were negative. Second, the activity of the IFN-regulated enzyme 2-5 A synthetase was determined by the radiobinding method [4] in the celllysate of 5 x lQ6 peripheral blood mononuclear cells of patient 4 for whom heparinized blood was available. A markedly elevated 2-5 A synthetase level (870 pmol/lQ6 cells/h) was found in this patient (normal values, 74 ± 40 pmol/lQ6 cells/h, mean ± SD). In a larger series of patients positive for anti-HAY IgM, 2-5 A synthetase levels were invariably increased in the lysate of peripheral blood mononuclear cells (296 ± 155 pmol/lQ6 cells/h, mean ± SD) (unpublished results). Thus, we found evidence of activation of the interferon system in two patients in the very early phase of acute hepatitis A before the appearance of specific antibodies.
R. Zachoval, M. Kroener, M. Brommer, and F. Deinhardt Medizinische Klinik II, Klinikum Gro,Phadem, Max von Pettenkofer-Institute, University of Munich, Stadusches Krankenhaus Schwabing, Munich, Federal Republic of Germany
References 1. Froesner GG, Deinhardt F, RoggendorfM, Scheid R, Bayed B, Zachoval R. Laboratory diagnosis of hepatitis A infection. In: Bianchi L, Gerok W, Sickinger K, Stalder GA, eds. Virus and the liver. Lancaster, PA: MTP Press, 1980:17-26 2. Davis GL, Hoofnagle JH, Waggoner JG. Acute type A hepatitis during chronic hepatitis B virus infection: association of depressed hepatitis B virus replication with appearance of endogenous alpha interferon. J Med Virol 1984;14:141-147 3. Zachoval R, Abb J, Zachoval V, Deinhardt F. Circulating interferon in patients with acute hepatitis A. J Infect Dis 1986;153:1174-1175 4. Silverman RH, Krause P. Analysis of anti-viral mechanisms: interferon regulated 2'5'oligoadenylate and protein kinase systems. In: Clemens MJ, Morris AG, Gearing AlH, eds. Lymphokines and interferons. Oxford, UK: IRL Press, 1987:149-193
[1]. Adults become more ill, develop significant joint disturbances, and exhibit a rash on their extremities [1]. Recent studies identified parvovirus B19 as the cause of fifth disease [2-4]. Viral particles and viral DNA fragments have been identified in serum, urine, and throat washes [3]. Immunoglobulin M-specific antibody is characteristically present during acute infection, rapidly falls off at 2 months, but may remain detectable for 4 months or longer [2, 3, 5, 6]. Immunoglobulin M-specific antibody is not observed in the normal population. In contrast, IgGspecific antibody is commonly measured in the general population; the prevalence of antibody-positive individuals increases from 12 % in 5- to 9-year-olds to 55% in adults >30 years [6]. From 1 April through 31 August 1987, an outbreak of fifth disease occurred in the Buffalo, NY, area, including cases among employees at a children's hospital. A survey of 47 nurses in the intensive care unit (ICU) revealed 11 with symptoms consistent with fifth disease. Each of the nurses with apparent fifth disease had serum tested
Downloaded from http://jid.oxfordjournals.org/ at Freie Universitaet Berlin on July 4, 2015
results for IgM antibodies to the hepatitis B core antigen (CORAB M; Abbott), to cytomegalovirus (Behring AG, Marburg, FRG), and to Epstein-Barr virus viral capsid antigen. All four had seroconverted and were positive for anti-HAY IgM (HAVAB-Menzyme immunoassay; Abbott) when second serum samples were collected 5-11 days later. The three patients with normal bilirubin values (patients 1, 3, and 4) at the outset became icteric later. All four patients had uncomplicated clinical courses of disease with full recovery; there were no apparent cellular or humoral immune defects. We conclude that, although demonstration of anti-HAY IgM in a single serum sample is the usual method to diagnose acute HAV infection, in rare instances production of specific antibodies is delayed in patients with acute hepatitis without any evidence of immunodeficiency. It is suggested, therefore, that in suspected cases of HAV infection with a negative anti-HAY IgM, a second serum sample be obtained a few days after the first. As the interferon (lFN) system is thought to be an early defense " mechanism in HAV infection [2,3], we used two methods to investigate IFN action in the same four patients. First, antiviral activity was determined in serial twofold dilutions of serum by measuring the inhibition of the cytopathic effect (CPE) of vesicular stomatitis virus on bovine kidney cells (MDBK). Antiviral units were calculated as the reciprocal of the highest dilution inhibiting 50% ofCPE.
JID 1990;161 (February)
Correspondence
JID 1990;161 (February)
Table 1. Clinical features of nurses with fifth disease. Subject 1 2 3 4 5 6 7 8 9 10 11
12 13 NOTE.
Fever
Facial rash
+ +
+
Extremity rash
Numbness/ tingling
+ + + + + +
+ +
+ +
+ +
+ + + +
Subjects 1-11 had joint symptoms. +, symptoms; -, no symptoms.
Thus, 13 of 47 nurses in the ICU developedfifth disease: 7 experienced numbness and tingling of fingers; in 2 the only sign of the parvovirus infection was the numbness and tingling. Infection with parvovirusBI9 was confirmed by the presence of IgM-specificantibodyin everysymptomatic subject.Controlsubjectsuniformly lacked IgM-specific antibody. IgO-specific antibody was present in all of the ill nurses and in 82 % of the controls. The mechanism of numbness and tingling was not established. Some data suggestedthat the symptomswere the result of a peripheral neuropathy; however, neurologic complications in fifth disease are uncommon. Twocases of encephalitishave been described previously [8, 9]. Possibly, some of the symptomatologyseen in parvovirus BI9 infection may be due to an unusualimmunologic resonse; however, in several large studies of parvovirus-associatedarthropathy, evaluations of immune complexesand rheumatoid factor proved negative [5, 10]. The evidencein our study suggested that parvovirusBI9 maycause numbnessand tingling of the peripheral extremities. Even in the absence of an illness consistent with fifth disease, parvovirus BI9 infection should be considered in the differential diagnosis of such symptoms.
Howard Faden, G. William Gary, Jr., and Michael Korman Departments of Pediatrics and Neurology, State University of New lVrk at Buffalo, School of Medicine, and Children's Hospital, Buffalo; and Division of Viral Diseases, Center for Infectious Diseases, Centers for Disease Control, Atlanta, Georgia
References 1. Balfour H. Erythema infectiosum (fifth disease): clinical review and descriptionof91 casesseen in an epidemic. Clio Pediatr1969;8:721-727 2. Okabe N, Koboyashi S, Thtsuzawa 0, Mortimer PP. Detection of antibody to human parvovirus in erythema infectiosum (fifth disease). Arch Dis Child 1984;59:1016-1019 3. Chorba T, Coccia P, Holman RC, Tattersall P, Anderson U, Sudman J, Young NS, Kurczynski E, Sarrinen UM, Moir R, Lawrence DN, Jason JM, Evatt B. The role of parvovirus B19 in aplastic crisis and erythema infectiosum (fifth disease). J Infect Dis 1986;154:383-392 4. Anderson MJ, Higgins PG, Davis LR, WllimanJS, Jones SE, Kidd 1M, Pattison JR, Tyrrell DAJ. Experimental parvoviral infection in humans. J Infect Dis 1985;152:257-265 5. Reid OM, Reid TMS, Brown T, Rennie JAN, Eastmond CJ. Human parvovirus-associatedarthritis: a clinical and laboratory description. Lancet 1985;1:422-425 6. NunoueT, Okochi K, Mortimer PP, Cohen BJ. Human parvovirus(B19) and erythema infectiosum. J Pediatr 1985;107:38-40 7. Anderson U, Tsou C, Parker RA, Chorba TL, Wulff H, Tattersall P, Mortimer PP. Detection of antibodies and antigens of human parvovirus B19by enzyme-linkedimmunosorbent assay. J Clio Microbiol 1986;24:522-526 8. Hall CB, Homer FA. Encephalopathy with erythema infectiosum. Am J Dis Child 1977;131:65-67 9. Balfour HH, Schiff GM, Bloom JE. Encephalitis associated with erythema infectiosum. J Pediatr 19;,);77:133-136 10. White DG, Woolf AD, Mortimer PP, Cohen BJ, Blake DR, Bacon PA. Human parvovirus arthropathy. Lancet 1981;1:419-421
Downloaded from http://jid.oxfordjournals.org/ at Freie Universitaet Berlin on July 4, 2015
for IgM and IgO antibody against parvovirus BI9 in the laboratory of Dr. W. Oary (Centers for Disease Control, Atlanta, OA), using an IgO and IgM capture ELISA[7]. Serum specimenswereobtained within 2 months of the onset of symptoms. A group of eight asymptomatic nurses who worked in the same unit were screened at the same time to detect asymptomatic infection. A secondcontrol group of nine asymptomaticindividuals who worked in the Division of Infectious Diseases was screened to assess the background frequency of past infection with parvovirus BI9. Subjects 1-11 were readily diagnosed because they exhibited features consistent with fifth disease (table 1). Numbness and tingling of the fingersoccurred in five nurses with classic fifth disease. One also complained of numbness and tingling in her toes. The neurologic examination in 4 subjects was normal except for mildly decreased sensationto lighttouchoverthe involved areas. In 2 subjects, the signs disappeared completely within 2 months; however, in 3, the numbness and tingling recurred intermittently over 1 year. One nurse exhibited more significant disease: progressive weakness of one arm involving wrist, finger, and thumb extension and numbness of the forearm. She had normal muscle mass and tone; however, strengthwas mildlyreducedin the triceps,wrist, and fingers. Sensation remained intact; reflexes were normal. Subsequently, she developed mild numbness in the toes of both feet. Electrodiagnostic studies showedmild slowingof nerve conduction velocitiesand decreased amplitudes of motor and sensory potentials. Twoother nurses withoutthe typical featuresof fifth di-sease complainedof numbnessand tinglingin their fingers duringthe outbreak. Because the onset of their symptoms and the similarity of the features coincided with those previouslydescribed, parvovirusBI9 was presumed to be the cause of the disease in these subjects and the other cases. Each of the nurses with fifth disease and the two with numbness and tingling alone possessedboth IgM- and IgO-specificparvovirus antibody. In contrast, none of 17 asymptomatic controls had IgM antibody to parvovirus BI9, although 14 had IgO-specificantibody.
355
