- Email: [email protected]
Human parvovirus B19-associatedarthritis in children
ORIGINAL ARTICLES
Human parvovirus B'19-associated arthritis in children James J. N o c t o n , MD, Laurie C. Miller, MD, Lori B. Tucker, MD, a n d Jane G. Schaller, MD From the Divisionof Pediatric Rheumatology, Floating Hospital for Infants and Children, New England Medical Center and Tufts UniversitySchool of Medicine, Boston, Massachusetts
Human parvovirus B49 (HPV B19) infection has been associated with chronic joint complaints in adult patients. We now report 22 children with Joint complaints associated with recent HPV B19 Infection. These children had either erylhema In~ fectiosum or serologic evidence of recent infection. Twenty children had arthritis; two had arthralgias. Eleven children had associated constitutional symptoms. Laboratory findings were generally normal. The duration of Joint symptoms was less than 4 months in 44 children; however, six children have had persistent arthritis for 2 to 43 months, which would fulfill criteria for the diagnosis of Juvenile rheumatoid arthritis. Although HPV B19 Is usually associated with acute arthritis of brief duration, in some children infection with HPV B49 may be associated with the development of chronic arthritis. (J PEDIAI'R4993;122:186-90)
Infection with human parvovirus BI9 is common among children and young adults) "3 This virus is associated with several clinical syndromes, including erythema in fectiosum, hydrops fetalis, and aplastic crises in patients with chronic hemolytic anemia) s Joint symptoms occur in approximately 80% of adults with erythema,infectiosum. 9 The incidence of joint symptoms in children with erythema infectiosum has been approximately 8%.9 However, HPV BI9 infection can occur without classic symptoms and signs of erythema infectiosum, and the true incidence of arthritis in those infected with the virus is unknown. A recent review t~ of adult patients emphasized the similarity between IIPV'B19 arthropathy and seronegative rheumatoid arthritis. We then began to consider the diagnosis of tlPV BI9 infection in children referred to our pediatric rheumatology clinic for evaluation of joint complaints. We report here the clinical characteristics of 22 children with joint complaints and evidence of recent HPV Bi9 infection.
Submitted for publication Aug. 14, 1992; accepted Sept. 29, 1992. Reprint requests: James J. Nocton, b,ID, Box 286, New England Medical Center, 750 Washington St., Boston, MA 0211 I. Copyright 9 1993 by Mosby-Year Book, Inc. 0022-3476/93/$1.00 + .10 9/20/43055 186
METHODS One hundred four children initially seen in the pediatric rheumatology clinic of the Floating Hospital for Infants and Children, Boston, Mass., between February 1991 and April 1992 were screened for antibodies to IIPV BI9 because the acute onset of joint symptoms, associated constitutional symptoms, or exposure to viral illness raised the suspicion ANA ELISA HPV BI9 JRA
Antinuelear antibody Enzyme-linked immunosorbent assay tluman parvovirus BI9 Juvenile rheumatoid arthritis
of recent viral infection. Twenty of these children had detectable lgM anti-llPV BI9 antibodies and are included in this report. An additional two patients are included who did not have IgM anti-HPV BI9 antibodies but who had clinical findings consistent with erythema infectiosum at the time of onset of their symptoms. These patients were seen in November 1990 and August 1991, respectively. Serum from one of these patients was tested, and IgM anti-HPV BI9 antibodies were not detected. Serum from the other patient was not tested. The presence or absence of IgM and IgG anti-HPV B19 antibodies was determined by enzyme-linked immunosorbent assay (16 patients) or Western blot (four patients)
The Journal of Pediatrics Volume 122, Number 2
(Microbiology Reference Laboratory, Cypress, Calif.). The ELISA results were reported as an index, calculated as the ratio of the optical density of the test serum to the optical density of a serum with confirmed positivity. An index of >__0.8 was established by the reference laboratory to indicate a borderline antibody level, and an index of >__1.2 was established to indicate an unequivocally elevated antibody level. The patients included in this report had either (1) an lgM index of 1.2 or greater, (2) the combination of an IgM index of 0.8 to 1.2 initially, an IgG index greater than 1.2, and a fall in the IgM index on a second serum sample, or (3) a positive lgM Western blot. Each of these results was considered indicative of recent infection with HPV BI9 on the basis of the previous demonstration that lgM and lgG antibodies both appear early after infection, and that IgM antibodies then decrease, generally within a few months. It Data collected included age, gender, history of joint pain, warmth, erythema or swelling, evidence of arthritis on physical examination, number of joints affected, history of fever, rash, anorexia, malaise or fatigue, and history of parvovirus exposure. In addition to results of anti-HPV BI9 antibody screening (21 patients), laboratory data collected included complete blood cell count and erythrocyte sedimentation rate (all patients), antinuclear antibody titer (21 patients), ELI.SA for antibody to Borrelia burgdorferi (19 patients), rheumatoid factor (10 patients), total hemolytic complement (CHs0) (6 patients), and joint radiograph or ultrasonogram (10 patients). Patients were followed until resolution of their symptoms. Those with persistent symptoms continue to be followed. All patient s were examined by one of us. Except for anti-HPV BI9 antibody testing, 21 patients had laboratory testing performed at the clinical laboratory of New England Medical Center, Boston, Mass., and one at Beverly Hospital Laboratory, Beverly, Mass. All radiographs were obtained in the department of radiology of New England Medical Center, and interpreted by a staff radiologist. RESULTS
Serologic testing for HPV B19. The IgM anti-HPV B19 antibody titer was significantly elevated in 20 children; 16 had IgM antibody by ELISA, and four patients had IgM antibody by Western blot. Of the 16 patients in whom antibody was detected by ELISA, 14 patients had an IgM index > !.2 (range 1.52 to > 10). Of these 16 patients, two had equivocal lgM indexes initially (0.90, 1.19); when convalescent serum was tested 2 weeks to 3 months later, these two patients had decreased lgM indexes, and lgG indexes > I0. The two patients who did not fulfill serologic criteria for recent HPV BI9 infection had an illness consistent with erythema infectiosum at the time of onset of joint complaints, and one of them first had serum tested for anti-HPV antibodies 4 months after the onset of symptoms, when IgM
Nocton et al.
187
antibody may no longer be present. This patient had an IgG index of 7.54, indicating past infection. Timing of serologic testing for HPV BI9. Of the 22 patients, 18 were examined within I0 weeks of the onset of joint symptoms, when IgM antibody titers would be expected to be highest 3. II and therefore readily detectable. The remaining four patients were examined and tested 4 to 12 months after the onset of joint symptoms (patients 6, 8, 9, and 16). The patient tested at 7 months had increased IgM anti-HPV BI9 antibody. This patient had an increase in the severity of his joint complaints 2 months before serologic testing. The patient tested 12 months after the onset of symptoms had a slowly evolving symmetric polyarthrifts, and also had increased IgM anti-HPV B 19 antibody. One patient initially did not have detectable IgM antibody by Western blot 1 week after the onset of his symptoms; additional testing 4 months later revealed IgM and IgG. Seven patients had paired serum samples tested by ELISA. All seven had a decrease in IgM index on the second sample. The change in IgG index from the first to second serum was variable. Clinical manifestations. Sixteen patients are female and six male. Age range is 2 to 19 years and median age is 7.5 years. Only three patients had known HPV BI9 exposure shortly before the onset of symptoms. Eleven of the patients had constitutional symptoms, defined as fever, anorexia, malaise, or fatigue. Only seven had a history of rash (four patients) or had rash at the time of examination (three p~tients). Four patients had erythematous patches on the cheeks and extremities. One patient had a history of a peteehial rash on his lower extremities that lasted only 24 hours. One patient had erythematous papules on the face and one leg, and one patient had a remote history of urticaria. Joint symptoms. Arthritis occurred in 20 patients; two patients had arthralgias only. Two patterns of arthritis or arthralgia were evident. In 10 patients, arthritis or arthralgia was polyarticular, affecting >__5joints; in 12 patients the pattern was pauciarticular, affecting four or fewer joints. Two patients had monoarticular arthritis. Ofthe 12 patients with a pauciarticular pattern, two had a migratory component to their complaints and one had hip arthralgias only. Large joints were affected more often than small joints (Figure). The knee was the most common joint affected (82%). The duration of joint symptoms was generally brief, with complete resolution within 6 weeks in l l children and within 4 months in three additional children. Eight children continue to have persistent joint symptoms (six arthritis, two arthralgia) 2 to 13 months after onset of their complaints. Those with symptoms 2 months (two patients), 2'/2 months, 5 months, I 1 months, and 13 months in duration have arthritis and fulfill criteria for the diagnosis of juvenile rheumatoid arthritis (Table I). 12
18 8
Nocton et al.
The Journal of Pediatrics February 1993
knee allkle
wrist em
elbow neck
hand/foot
~1
hip shoulde~ s-clav 0
5
10
15
20
# of patients Figure. Distribution of affected joints in children with ttPV B19-associated joint complaints. Handffoot, Small joints of the hands and feet; S-clay, sternoclavicular joint. Laboratory results (Table II). Hematocrit values were ~_0.35 (35%) in 12 patients, but no patient had a hematocrit <0.31 (31%). Leukocyte counts were normal (4.5 to 10.0 • 109/L [4500 to 10,000/mm3]) in 16 patients; no patient had a leukocyte count >15.0 • 109/L (15,000/ mm3). Likewise, the erythrocyte sedimentation rate was usually normal. Antinuclear antibodies were detected in 7 of 21 patients. Three sera had ANA titers of 1:40 in a speckled pattern, one had an ANA titer of 1:320 speckled, and one had an ANA titer of 1:640 in a mixed speckled and diffuse pattern. In the other two sera, diffuse pattern ANA in titers of 1:40 and 1:160 were detected. One patient had a mild elevation of serum aminotransferase values (<3 times normal); values returned to normal as his symptoms (fever, malaise, rashr arthralgias) resolved. Rheumatoid factor was absent in all 10 patients tested. Total hemolytic complement (CHs0) was found to be decreased in three of six patients tested. Radiography or ultrasonography was performed in 10 patients, and results were abnormal in eight. Joint effusions were seen in five patients, and synovial thickening was detected by ultrasonography in one patient. An additional two patients' radiographs revealed soft tissue swelling with osteopenia. Each of these patients with abnormal radiographs had arthritis by examination. DISCUSSION In a 1962 epidemic, 9 nearly 80% of adults with erythema infectiosum had joint symptoms, but fewer than 8% of those
less than 20 years of age had joint symptoms. With the availability of serologic testing for HPV BI9, it became possible to diagnose acute infection in the absence of typical symptoms associated with erythema infectiosum. In 1985, two reports emphasized the association of HPV BI9 with an arthropathy that in some patients can appear similar to rheumatoid arthritis. 13, t4 Most patients bad joint symptoms in the absence of rash or prodromal illness. Only three children were described in detail. All had rash and an asymmetric arthritis involving small and large joints. One of these children had persistent arthritis lasting longer than 7 months, ta More recently, Naides et al. t~ reported 21 adult patients with serologic evidence of recent HPV BI9 infection, 20 of whom had polyarthralgia or polyarthritis and three of whom had joint symptoms for longer than 2 years. In two of these three patients with chronic symptoms, HPV B19 DNA has been detected in synovial tissue by polymerase chain reaction, ts Our experience suggests that recent HPV BI9 infection is associated with the onset of arthritis in children more frequently than has been previously recognized. Although we did not test all children with recent-onset arthritis, 19% (20/104) of the children with recent joint complaints who were tested for lgM anti-HPV B19 were found to have antibody in amounts consistent with recently acquired infection. In adult patients with HPV Bl9-associated arthritis, the arthritis is typically polyarticular and symmetric and has
The Journal o f Pediatrics Volume 122, Number 2
Nocton et al.
1g 9
Table I. Patients with chronic joint symptoms Patient No.
Sex
Age (yr)
ANA
Duration (me)
Joint signs and symptoms
6
M
7
Neg
11
7
F
12
1:320
289
8
F
12
Neg
13
9
F
3
1:40
7
I0
F
2
Neg
2
13
F
2
1:160
2
16
M
9
Neg
5
20
F
16
Neg
3
Initially, right wrist pain, swelling;then bilateral wrist and finger PIP joint swelling, loss of range of motion Monoarticular knee arthritis with mild swelling and pain Symmetric, mild swelling, and gradual loss of range of motion of shoulders, elbows, wrists, hips, knees, and ankles Bilateral knee arthritis that resolved within 2 me; recurrent arthralgia of one knee for an additional 5 me Monoarticular knee arthritis with swelling, mild stiffness Swelling of one knee, one finger PIP joint, one toe PIP joint, with knee and finger stiffness Initially, bilateral index finger PIP joint and right knee swelling with bilateral MCP pain; all resolved except right index finger PIP swelling Intermittent, symmetric arthralgias of knees, wrists after initial polyarthralgia
Neg, Negative;PIP, proximalinterphalangeal;MCP, metacarpalphalangeal.
been described as evolving to a form that is often indistinguishable from rheumatoid arthritis) e, 13, 14, 16 Some of our patients had polyartieular and symmetric symptoms, but 12 had symptoms in fewer than five joints. These patients had an illness similar to early pauciarticular JRA. Constitutional symptoms Were not consistently present, and therefore fever, rash, malaise, or other viral symptoms cannot be viewed as reliable clues to distinguish HPV BI9 infection from the onset of pauciarticular JRA. As in reports of adult patients, l~ ~3, 14most ofour patients had a brief period of illness with complete resolution of their symptoms. Eight of our patients, however, have had ongoing complaints for 2 months or longer. Six of these eight patients have arthritis and ffould meet diagnostic criteria for JRA. There were no clinical or laboratory findings that distinguished the patients with chronic symptoms; they ineluded several young girls with signs and symptoms consistent with pauciarticular JRA, as well as some older children with varying joint signs and symptoms. Six of the eight patients with chronic symptoms are female, a ratio similar to that seen in adults with chronic joint symptoms associated with HPV BI9 infection,l~ All but two of these patients have been examined by an ophthalmologist, and none has iritis. With each of these patients, we cannot exclude the possibility that ttPV BI9 infection was coincidental and that the presence of IgM anti-llPV BI9 antibodies reflects re-
T a b l e II. Laboratory characteristics Hematocrit 0.31-0.35 0.36-0.40 Leukocyte count 4.5-10.0 • 109/L 10.1-14.4 X 109/L ESR _<25 >25 ANA >_1:40 RF negative Low CHs0 Lyme serologic findings negative X-ray or ultrasound studies abnormal (effusion, synovial thickening, or soft tissue swelling)
12/22 10/22 16/22 6/22 17/22 5/22 7/21 10/10 3/6 19/19 8/10
ESR, Erythrocytesedimentationrate; RF, rheumatoidfactor; Cit5o, total
hemolyticcomplement.
cent asymptomatic infection unrelated to the joint complaints. In particular, we cannot exclude the finding that the two patients tested 7 and 12 months after the onset of their symptoms had acute HPV BI9 infection superimposed on a preexisting chronic arthritis. However, we speculate that these patients may have had a prolonged lgM response to an acute infection at the time of onset of their joint symptoms, similar to the prolonged lgM antibody response seen in some patients with Lyme arthritis. 17 It is also possible
19 0
Nocton et aL
that antibodies detected in the serum are part of a nonspecific anamnestic response from a stimulated immune system and are not related to an acute infection. The presence of IgM antibodies, however, indicates specific anti-HPV BI9 antibody production as a result of recent infection with H P V . B I 9 . II Three of the six patients tested had low levels of total hemolyiic complement (CHso), a finding described in adult patients with HPV BI9 infection. 13 The association of a recent H P V BI9 infection with a low complement level suggests that immune complexes may play a role in the pathogenesis of joint complaints in these patients. Previous studies in which complement and immune complexes have been measured 13 have found evidence of complement consumption and an increase in circulating immune complexes in H P V BI9 infection, providing support for this mechanism of pathogenesis. A t present, the relationship of HPV B19 infection to the development of chronic arthritis remains unclear. Further advances in the ability to diagnose acute HPV BI9 infection accurately, such as the development of culture and D N A amplification techniques, and further study of synovial tissue and fluid in these patients will help clarify this relationship. REFERENCES I. Smith CA, Woolf AD, Lenci M. Parvoviruses: infections and arthropatbies. Rheum Dis Clin North Am 1987;13:249-63. 2. Anderson LJ. Role of parvovirus BI9 in human disease. Pediatr Infect Dis J 1987;6:711-8. 3. Anderson LJ. Human parvoviruses. J Infect Dis 1990; 161:603-8.
The Journal of Pediatrics February 1993
4. Ware RW. Human parvovirus infection. J PEDIATR 1989; 114:343-7.
5. Nunoue T, Okochi K, Mortimer PP, Cohen BJ. tluman parvovirus (BI9) and erythema infectiosum. J PEmA'rg 1985; 107:138-40.
6..Serjeant GR, Topley JM, Mason K, et al. Outbreak of aplastic crises in sickle cell anaemia associated with parvovirus-like agent. Lancet 1981;2:595-7. 7. Kelleher JF, Luban NLC, Cohen BJ, Mortimer PP. ttuman serum parvovirus as the cause of aplastic crisis in sickle cell disease. Am J Dis Child 1984;138:401-3. 8. Anand A, Gray E, Brown T, Clewley JP, Cohen BJ. Human parvovirus infection in pregnancy and hydrops fetalis. N Engl J Med 1987;316:183-6. 9. Ager EA, Chin TDY, Poland JD. Epidemic erythema infectiosum. N Engl J Med 1966;275:1326-31. 10. Naides S J, Scharosch LL, Foto F, Howard EJ. Rheumatologic manifestations of human parvovirus BI9 infection in adults. Arthritis Rheum 1990;33:1297-309. I I. Anderson L J, Tsou C, Parker RA, et al. Detection of antibodies and antigens of human parvovirus BI9 by enzyme-linked immunosorbent assay. J Clin Microbiol 1986;24:522-6. 12. Brewer E J, Bass J, Baum J, et al. Current proposed revision of JRA criteria. Arthritis Rheum 1977;20(suppl 2):195-9. 13. White DG, Mortimer PP, Blake DR, Woolf AD, Cohen BJ, Bacon PA. Human parvovirus arthropathy. Lancet 1985;I :41921. 14. Reid DM, Brown T, Reid TMS, Rennie JAN, Eastmond CJ. Human parvovirus-associated arthritis: a clinical and laboratory description. Lancet 1985;1:422-5. 15. Foto F, Marsh JL, Scharosch LL, Howard EJ, Naides SJ. Synovialiissue analysis in patients with chronic parvovirus BI 9 arthropathy [Abstract]. Arthritis Rheum 1991 ;34(suppl):103. 16. Naides S J, Field EM. Transient rheumatoid factor positivity in acute human parvovirus BI9 infection. Arch Intern Med 1988;148:2587-9. 17. Steere AC. Lyme disease. N Engl J Med 1989;321:586-96.
Human parvovirus B'19-associated arthritis in children James J. N o c t o n , MD, Laurie C. Miller, MD, Lori B. Tucker, MD, a n d Jane G. Schaller, MD From the Divisionof Pediatric Rheumatology, Floating Hospital for Infants and Children, New England Medical Center and Tufts UniversitySchool of Medicine, Boston, Massachusetts
Human parvovirus B49 (HPV B19) infection has been associated with chronic joint complaints in adult patients. We now report 22 children with Joint complaints associated with recent HPV B19 Infection. These children had either erylhema In~ fectiosum or serologic evidence of recent infection. Twenty children had arthritis; two had arthralgias. Eleven children had associated constitutional symptoms. Laboratory findings were generally normal. The duration of Joint symptoms was less than 4 months in 44 children; however, six children have had persistent arthritis for 2 to 43 months, which would fulfill criteria for the diagnosis of Juvenile rheumatoid arthritis. Although HPV B19 Is usually associated with acute arthritis of brief duration, in some children infection with HPV B49 may be associated with the development of chronic arthritis. (J PEDIAI'R4993;122:186-90)
Infection with human parvovirus BI9 is common among children and young adults) "3 This virus is associated with several clinical syndromes, including erythema in fectiosum, hydrops fetalis, and aplastic crises in patients with chronic hemolytic anemia) s Joint symptoms occur in approximately 80% of adults with erythema,infectiosum. 9 The incidence of joint symptoms in children with erythema infectiosum has been approximately 8%.9 However, HPV BI9 infection can occur without classic symptoms and signs of erythema infectiosum, and the true incidence of arthritis in those infected with the virus is unknown. A recent review t~ of adult patients emphasized the similarity between IIPV'B19 arthropathy and seronegative rheumatoid arthritis. We then began to consider the diagnosis of tlPV BI9 infection in children referred to our pediatric rheumatology clinic for evaluation of joint complaints. We report here the clinical characteristics of 22 children with joint complaints and evidence of recent HPV Bi9 infection.
Submitted for publication Aug. 14, 1992; accepted Sept. 29, 1992. Reprint requests: James J. Nocton, b,ID, Box 286, New England Medical Center, 750 Washington St., Boston, MA 0211 I. Copyright 9 1993 by Mosby-Year Book, Inc. 0022-3476/93/$1.00 + .10 9/20/43055 186
METHODS One hundred four children initially seen in the pediatric rheumatology clinic of the Floating Hospital for Infants and Children, Boston, Mass., between February 1991 and April 1992 were screened for antibodies to IIPV BI9 because the acute onset of joint symptoms, associated constitutional symptoms, or exposure to viral illness raised the suspicion ANA ELISA HPV BI9 JRA
Antinuelear antibody Enzyme-linked immunosorbent assay tluman parvovirus BI9 Juvenile rheumatoid arthritis
of recent viral infection. Twenty of these children had detectable lgM anti-llPV BI9 antibodies and are included in this report. An additional two patients are included who did not have IgM anti-HPV BI9 antibodies but who had clinical findings consistent with erythema infectiosum at the time of onset of their symptoms. These patients were seen in November 1990 and August 1991, respectively. Serum from one of these patients was tested, and IgM anti-HPV BI9 antibodies were not detected. Serum from the other patient was not tested. The presence or absence of IgM and IgG anti-HPV B19 antibodies was determined by enzyme-linked immunosorbent assay (16 patients) or Western blot (four patients)
The Journal of Pediatrics Volume 122, Number 2
(Microbiology Reference Laboratory, Cypress, Calif.). The ELISA results were reported as an index, calculated as the ratio of the optical density of the test serum to the optical density of a serum with confirmed positivity. An index of >__0.8 was established by the reference laboratory to indicate a borderline antibody level, and an index of >__1.2 was established to indicate an unequivocally elevated antibody level. The patients included in this report had either (1) an lgM index of 1.2 or greater, (2) the combination of an IgM index of 0.8 to 1.2 initially, an IgG index greater than 1.2, and a fall in the IgM index on a second serum sample, or (3) a positive lgM Western blot. Each of these results was considered indicative of recent infection with HPV BI9 on the basis of the previous demonstration that lgM and lgG antibodies both appear early after infection, and that IgM antibodies then decrease, generally within a few months. It Data collected included age, gender, history of joint pain, warmth, erythema or swelling, evidence of arthritis on physical examination, number of joints affected, history of fever, rash, anorexia, malaise or fatigue, and history of parvovirus exposure. In addition to results of anti-HPV BI9 antibody screening (21 patients), laboratory data collected included complete blood cell count and erythrocyte sedimentation rate (all patients), antinuclear antibody titer (21 patients), ELI.SA for antibody to Borrelia burgdorferi (19 patients), rheumatoid factor (10 patients), total hemolytic complement (CHs0) (6 patients), and joint radiograph or ultrasonogram (10 patients). Patients were followed until resolution of their symptoms. Those with persistent symptoms continue to be followed. All patient s were examined by one of us. Except for anti-HPV BI9 antibody testing, 21 patients had laboratory testing performed at the clinical laboratory of New England Medical Center, Boston, Mass., and one at Beverly Hospital Laboratory, Beverly, Mass. All radiographs were obtained in the department of radiology of New England Medical Center, and interpreted by a staff radiologist. RESULTS
Serologic testing for HPV B19. The IgM anti-HPV B19 antibody titer was significantly elevated in 20 children; 16 had IgM antibody by ELISA, and four patients had IgM antibody by Western blot. Of the 16 patients in whom antibody was detected by ELISA, 14 patients had an IgM index > !.2 (range 1.52 to > 10). Of these 16 patients, two had equivocal lgM indexes initially (0.90, 1.19); when convalescent serum was tested 2 weeks to 3 months later, these two patients had decreased lgM indexes, and lgG indexes > I0. The two patients who did not fulfill serologic criteria for recent HPV BI9 infection had an illness consistent with erythema infectiosum at the time of onset of joint complaints, and one of them first had serum tested for anti-HPV antibodies 4 months after the onset of symptoms, when IgM
Nocton et al.
187
antibody may no longer be present. This patient had an IgG index of 7.54, indicating past infection. Timing of serologic testing for HPV BI9. Of the 22 patients, 18 were examined within I0 weeks of the onset of joint symptoms, when IgM antibody titers would be expected to be highest 3. II and therefore readily detectable. The remaining four patients were examined and tested 4 to 12 months after the onset of joint symptoms (patients 6, 8, 9, and 16). The patient tested at 7 months had increased IgM anti-HPV BI9 antibody. This patient had an increase in the severity of his joint complaints 2 months before serologic testing. The patient tested 12 months after the onset of symptoms had a slowly evolving symmetric polyarthrifts, and also had increased IgM anti-HPV B 19 antibody. One patient initially did not have detectable IgM antibody by Western blot 1 week after the onset of his symptoms; additional testing 4 months later revealed IgM and IgG. Seven patients had paired serum samples tested by ELISA. All seven had a decrease in IgM index on the second sample. The change in IgG index from the first to second serum was variable. Clinical manifestations. Sixteen patients are female and six male. Age range is 2 to 19 years and median age is 7.5 years. Only three patients had known HPV BI9 exposure shortly before the onset of symptoms. Eleven of the patients had constitutional symptoms, defined as fever, anorexia, malaise, or fatigue. Only seven had a history of rash (four patients) or had rash at the time of examination (three p~tients). Four patients had erythematous patches on the cheeks and extremities. One patient had a history of a peteehial rash on his lower extremities that lasted only 24 hours. One patient had erythematous papules on the face and one leg, and one patient had a remote history of urticaria. Joint symptoms. Arthritis occurred in 20 patients; two patients had arthralgias only. Two patterns of arthritis or arthralgia were evident. In 10 patients, arthritis or arthralgia was polyarticular, affecting >__5joints; in 12 patients the pattern was pauciarticular, affecting four or fewer joints. Two patients had monoarticular arthritis. Ofthe 12 patients with a pauciarticular pattern, two had a migratory component to their complaints and one had hip arthralgias only. Large joints were affected more often than small joints (Figure). The knee was the most common joint affected (82%). The duration of joint symptoms was generally brief, with complete resolution within 6 weeks in l l children and within 4 months in three additional children. Eight children continue to have persistent joint symptoms (six arthritis, two arthralgia) 2 to 13 months after onset of their complaints. Those with symptoms 2 months (two patients), 2'/2 months, 5 months, I 1 months, and 13 months in duration have arthritis and fulfill criteria for the diagnosis of juvenile rheumatoid arthritis (Table I). 12
18 8
Nocton et al.
The Journal of Pediatrics February 1993
knee allkle
wrist em
elbow neck
hand/foot
~1
hip shoulde~ s-clav 0
5
10
15
20
# of patients Figure. Distribution of affected joints in children with ttPV B19-associated joint complaints. Handffoot, Small joints of the hands and feet; S-clay, sternoclavicular joint. Laboratory results (Table II). Hematocrit values were ~_0.35 (35%) in 12 patients, but no patient had a hematocrit <0.31 (31%). Leukocyte counts were normal (4.5 to 10.0 • 109/L [4500 to 10,000/mm3]) in 16 patients; no patient had a leukocyte count >15.0 • 109/L (15,000/ mm3). Likewise, the erythrocyte sedimentation rate was usually normal. Antinuclear antibodies were detected in 7 of 21 patients. Three sera had ANA titers of 1:40 in a speckled pattern, one had an ANA titer of 1:320 speckled, and one had an ANA titer of 1:640 in a mixed speckled and diffuse pattern. In the other two sera, diffuse pattern ANA in titers of 1:40 and 1:160 were detected. One patient had a mild elevation of serum aminotransferase values (<3 times normal); values returned to normal as his symptoms (fever, malaise, rashr arthralgias) resolved. Rheumatoid factor was absent in all 10 patients tested. Total hemolytic complement (CHs0) was found to be decreased in three of six patients tested. Radiography or ultrasonography was performed in 10 patients, and results were abnormal in eight. Joint effusions were seen in five patients, and synovial thickening was detected by ultrasonography in one patient. An additional two patients' radiographs revealed soft tissue swelling with osteopenia. Each of these patients with abnormal radiographs had arthritis by examination. DISCUSSION In a 1962 epidemic, 9 nearly 80% of adults with erythema infectiosum had joint symptoms, but fewer than 8% of those
less than 20 years of age had joint symptoms. With the availability of serologic testing for HPV BI9, it became possible to diagnose acute infection in the absence of typical symptoms associated with erythema infectiosum. In 1985, two reports emphasized the association of HPV BI9 with an arthropathy that in some patients can appear similar to rheumatoid arthritis. 13, t4 Most patients bad joint symptoms in the absence of rash or prodromal illness. Only three children were described in detail. All had rash and an asymmetric arthritis involving small and large joints. One of these children had persistent arthritis lasting longer than 7 months, ta More recently, Naides et al. t~ reported 21 adult patients with serologic evidence of recent HPV BI9 infection, 20 of whom had polyarthralgia or polyarthritis and three of whom had joint symptoms for longer than 2 years. In two of these three patients with chronic symptoms, HPV B19 DNA has been detected in synovial tissue by polymerase chain reaction, ts Our experience suggests that recent HPV BI9 infection is associated with the onset of arthritis in children more frequently than has been previously recognized. Although we did not test all children with recent-onset arthritis, 19% (20/104) of the children with recent joint complaints who were tested for lgM anti-HPV B19 were found to have antibody in amounts consistent with recently acquired infection. In adult patients with HPV Bl9-associated arthritis, the arthritis is typically polyarticular and symmetric and has
The Journal o f Pediatrics Volume 122, Number 2
Nocton et al.
1g 9
Table I. Patients with chronic joint symptoms Patient No.
Sex
Age (yr)
ANA
Duration (me)
Joint signs and symptoms
6
M
7
Neg
11
7
F
12
1:320
289
8
F
12
Neg
13
9
F
3
1:40
7
I0
F
2
Neg
2
13
F
2
1:160
2
16
M
9
Neg
5
20
F
16
Neg
3
Initially, right wrist pain, swelling;then bilateral wrist and finger PIP joint swelling, loss of range of motion Monoarticular knee arthritis with mild swelling and pain Symmetric, mild swelling, and gradual loss of range of motion of shoulders, elbows, wrists, hips, knees, and ankles Bilateral knee arthritis that resolved within 2 me; recurrent arthralgia of one knee for an additional 5 me Monoarticular knee arthritis with swelling, mild stiffness Swelling of one knee, one finger PIP joint, one toe PIP joint, with knee and finger stiffness Initially, bilateral index finger PIP joint and right knee swelling with bilateral MCP pain; all resolved except right index finger PIP swelling Intermittent, symmetric arthralgias of knees, wrists after initial polyarthralgia
Neg, Negative;PIP, proximalinterphalangeal;MCP, metacarpalphalangeal.
been described as evolving to a form that is often indistinguishable from rheumatoid arthritis) e, 13, 14, 16 Some of our patients had polyartieular and symmetric symptoms, but 12 had symptoms in fewer than five joints. These patients had an illness similar to early pauciarticular JRA. Constitutional symptoms Were not consistently present, and therefore fever, rash, malaise, or other viral symptoms cannot be viewed as reliable clues to distinguish HPV BI9 infection from the onset of pauciarticular JRA. As in reports of adult patients, l~ ~3, 14most ofour patients had a brief period of illness with complete resolution of their symptoms. Eight of our patients, however, have had ongoing complaints for 2 months or longer. Six of these eight patients have arthritis and ffould meet diagnostic criteria for JRA. There were no clinical or laboratory findings that distinguished the patients with chronic symptoms; they ineluded several young girls with signs and symptoms consistent with pauciarticular JRA, as well as some older children with varying joint signs and symptoms. Six of the eight patients with chronic symptoms are female, a ratio similar to that seen in adults with chronic joint symptoms associated with HPV BI9 infection,l~ All but two of these patients have been examined by an ophthalmologist, and none has iritis. With each of these patients, we cannot exclude the possibility that ttPV BI9 infection was coincidental and that the presence of IgM anti-llPV BI9 antibodies reflects re-
T a b l e II. Laboratory characteristics Hematocrit 0.31-0.35 0.36-0.40 Leukocyte count 4.5-10.0 • 109/L 10.1-14.4 X 109/L ESR _<25 >25 ANA >_1:40 RF negative Low CHs0 Lyme serologic findings negative X-ray or ultrasound studies abnormal (effusion, synovial thickening, or soft tissue swelling)
12/22 10/22 16/22 6/22 17/22 5/22 7/21 10/10 3/6 19/19 8/10
ESR, Erythrocytesedimentationrate; RF, rheumatoidfactor; Cit5o, total
hemolyticcomplement.
cent asymptomatic infection unrelated to the joint complaints. In particular, we cannot exclude the finding that the two patients tested 7 and 12 months after the onset of their symptoms had acute HPV BI9 infection superimposed on a preexisting chronic arthritis. However, we speculate that these patients may have had a prolonged lgM response to an acute infection at the time of onset of their joint symptoms, similar to the prolonged lgM antibody response seen in some patients with Lyme arthritis. 17 It is also possible
19 0
Nocton et aL
that antibodies detected in the serum are part of a nonspecific anamnestic response from a stimulated immune system and are not related to an acute infection. The presence of IgM antibodies, however, indicates specific anti-HPV BI9 antibody production as a result of recent infection with H P V . B I 9 . II Three of the six patients tested had low levels of total hemolyiic complement (CHso), a finding described in adult patients with HPV BI9 infection. 13 The association of a recent H P V BI9 infection with a low complement level suggests that immune complexes may play a role in the pathogenesis of joint complaints in these patients. Previous studies in which complement and immune complexes have been measured 13 have found evidence of complement consumption and an increase in circulating immune complexes in H P V BI9 infection, providing support for this mechanism of pathogenesis. A t present, the relationship of HPV B19 infection to the development of chronic arthritis remains unclear. Further advances in the ability to diagnose acute HPV BI9 infection accurately, such as the development of culture and D N A amplification techniques, and further study of synovial tissue and fluid in these patients will help clarify this relationship. REFERENCES I. Smith CA, Woolf AD, Lenci M. Parvoviruses: infections and arthropatbies. Rheum Dis Clin North Am 1987;13:249-63. 2. Anderson LJ. Role of parvovirus BI9 in human disease. Pediatr Infect Dis J 1987;6:711-8. 3. Anderson LJ. Human parvoviruses. J Infect Dis 1990; 161:603-8.
The Journal of Pediatrics February 1993
4. Ware RW. Human parvovirus infection. J PEDIATR 1989; 114:343-7.
5. Nunoue T, Okochi K, Mortimer PP, Cohen BJ. tluman parvovirus (BI9) and erythema infectiosum. J PEmA'rg 1985; 107:138-40.
6..Serjeant GR, Topley JM, Mason K, et al. Outbreak of aplastic crises in sickle cell anaemia associated with parvovirus-like agent. Lancet 1981;2:595-7. 7. Kelleher JF, Luban NLC, Cohen BJ, Mortimer PP. ttuman serum parvovirus as the cause of aplastic crisis in sickle cell disease. Am J Dis Child 1984;138:401-3. 8. Anand A, Gray E, Brown T, Clewley JP, Cohen BJ. Human parvovirus infection in pregnancy and hydrops fetalis. N Engl J Med 1987;316:183-6. 9. Ager EA, Chin TDY, Poland JD. Epidemic erythema infectiosum. N Engl J Med 1966;275:1326-31. 10. Naides S J, Scharosch LL, Foto F, Howard EJ. Rheumatologic manifestations of human parvovirus BI9 infection in adults. Arthritis Rheum 1990;33:1297-309. I I. Anderson L J, Tsou C, Parker RA, et al. Detection of antibodies and antigens of human parvovirus BI9 by enzyme-linked immunosorbent assay. J Clin Microbiol 1986;24:522-6. 12. Brewer E J, Bass J, Baum J, et al. Current proposed revision of JRA criteria. Arthritis Rheum 1977;20(suppl 2):195-9. 13. White DG, Mortimer PP, Blake DR, Woolf AD, Cohen BJ, Bacon PA. Human parvovirus arthropathy. Lancet 1985;I :41921. 14. Reid DM, Brown T, Reid TMS, Rennie JAN, Eastmond CJ. Human parvovirus-associated arthritis: a clinical and laboratory description. Lancet 1985;1:422-5. 15. Foto F, Marsh JL, Scharosch LL, Howard EJ, Naides SJ. Synovialiissue analysis in patients with chronic parvovirus BI 9 arthropathy [Abstract]. Arthritis Rheum 1991 ;34(suppl):103. 16. Naides S J, Field EM. Transient rheumatoid factor positivity in acute human parvovirus BI9 infection. Arch Intern Med 1988;148:2587-9. 17. Steere AC. Lyme disease. N Engl J Med 1989;321:586-96.