Recognizing infection-related arthritis

May 1, 2000

Arthritis can be caused by a range of viruses or other infectious agents, or develop in the wake of an enteric, genitourinary, or respiratory tract infection. Knowing the possible causes and typical signs and symptoms of infection-related arthritides helps make the diagnosis.

Recognizing infection-related arthritis

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By Lucia H. Lee, MD, and Caroline B. Hall, MD

Arthritis can be caused by a range of viruses or other infectious agents, or develop in the wake of an enteric, genitourinary, or respiratory tract infection. Knowing the possible causes and typical signs and symptoms of infection-related arthritides helps make the diagnosis.

Although pediatricians can readily identify septic joints, recognizing acute childhood arthritides associated with viruses and other infectious agents is more challenging. Diagnosing viral arthritis definitively is particularly difficult since methods for isolating viral organisms are limited. Another complicating factor is that although joint symptoms may accompany repeated minor trauma, an upper respiratory tract infection, or some other event, the relationship between the symptoms and the event may be coincidental. Confirming a temporal relationship between immunization and vaccine-induced arthritis, or between prior infection and Lyme arthritis or reactive arthritis, is also difficult. For these reasons, pediatricians are often uncertain when assessing possible acute childhood arthritides that do not present as classic septic joints. Knowing the causes of infection-associated arthritides and clues to their recognition can ease the diagnostic task and lead to appropriate counseling for the patient and family.

Viral arthritides

Viruses that cause arthritis include parvovirus B19, rubella, hepatitis B, and herpesvirus.

Parvovirus B19. Arthritis develops in about 60% of young women and 2.5% of young men with documented parvovirus B19 infection. This form of arthritis is marked by symmetric pain, swelling, and morning stiffness in multiple joints. In 75% of those with parvovirus B19 infection, the metacarpophalangeal and proximal interphalangeal (PIP) joints of the fingers are affected. Other common sites of arthritis are the knee (65%), wrist (55%) and ankle (40%).1

In a study of 22 children with parvovirus infection, the knee was the most common site of inflammation (82%), followed by the ankle (45%) and wrist (45%). Joints of the hands or feet were sites in 30% of the subjects, but the study did not note how often the PIP joints were affected. About half of the children experienced general nonspecific symptoms such as fever, anorexia, and malaise; seven children recently had erythema infectiosum. Joint symptoms in 11 children resolved within six weeks. The remaining eight children had persistent arthritis for two to 13 months. 2

Serologic tests can be used to detect infection in healthy children or adolescents with new-onset arthritis in whom parvovirus B19 is suspected. Immunoglobulin M (IgM) antibodies are present within three days after symptoms begin. IgM peaks at one month and becomes undetectable by two to three months. The presence of immunoglobulin G antibodies when symptoms first appear usually indicates past infection. Polymerase chain reaction also can be used to detect parvovirus B19 DNA in serum samples; this test is useful but not routinely recommended because it is expensive and reliability of results varies with the laboratory.3

Rubella arthritis caused by natural infection, before MMR vaccination was routine, affected mostly young adult women (50% of those infected) and men (6%), and was uncommon (0.5%) in children. In rubella arthritis, many large and small joints—knee, hip, fingers, wrists, elbows, and toes—are acutely affected in an asymmetric pattern. Arthralgia, tenosynovitis (inflammation of a tendon sheath) and carpal tunnel syndrome sometimes accompany joint symptoms. In natural infection, rheumatoid symptoms begin within one week after the rash appears. The joint symptoms of vaccine-induced arthritis are the same as those associated with natural infection and appear 10 to 28 days after immunization. Arthritis develops in 10% of young women who receive the MMR vaccine; vaccine-induced arthritis in children is rare.4 Both natural and vaccine-induced arthritides resolve within four weeks. Recurrent arthralgia and arthritis are rare and can last about two years.4

Hepatitis B virus. Arthralgia, along with transient, symmetric, painful arthritis in the small joints, may develop during the prodromal stage of acute infection. These rheumatologic features appear in about 30% of adults with acute hepatitis B infection.5 In children, joint symptoms may arise concurrently with papular acrodermatitis (Gianotti-Crosti syndrome), hepatomegaly, or generalized lymphadenopathy. Of children with Gianotti-Crosti syndrome, 85% are younger than 3 years.

Hepatitis B arthritis may be difficult to distinguish from systemic lupus erythematosus (SLE) since similar joint features, antinuclear antibodies (ANA), leukopenia and decreased serum complement can develop in both these diseases. Hepatitis B infection, unlike SLE, is marked by elevated aminotransferase and hepatitis B surface antigen at the onset of joint symptoms, however. Since hepatitis B arthritis occurs early in the course of infection, an individual is considered contagious until an antibody response develops.6 Thus, when hepatitis B infection is suspected, antibody tests should be performed.

Herpesvirus—varicella, herpes zoster, Epstein-Barr virus (EBV), herpes simplex virus (HSV), cytomegalovirus (CMV). Varicella arthritis has been reported in only a few children, in whom transient arthritis of the knee or hip appeared about 10 days after the onset of acute infection.7 Since the child with varicella is at risk of developing group A streptococcal (GAS) infection, consider an evaluation for septic arthritis caused by GAS as soon as joint symptoms begin. Herpes zoster arthritis, which develops as a monoarticular arthritis shortly before the onset of vesicular rash, is also rare.8

Arthritis caused by EBV develops early in primary infection. Laboratory findings in adolescents and children with EBV arthritis can be similar to those associated with SLE: leukopenia, thrombocytopenia, and the presence of ANA. The two diseases have similar rheumatologic patterns of painful, symmetric arthritis of the knee and PIP joints, with prominent arthralgias. The appearance of rheumatologic symptoms along with classic symptoms of infectious mononucleosis helps to distinguish EBV arthritis from rubella, bacterial, and other viral causes of arthritis.9

HSV I and CMV are rare causes of infectious arthritis. Polyarthritis caused by HSV I may appear with erythema multiforme.10

Other viruses. Mumps arthritis (paramyxovirus) accompanies orchitis and pancreatitis, but develops after the onset of parotitis. Influenza arthritis develops less frequently than myositis. The number of HIV­infected individuals with Reiter's syndrome, psoriatic arthritis, and human leukocyte antigen-B27 associated arthritides has been increasing. The direct role of HIV in the pathogenesis of these diseases is not fully characterized, however. Nonspecific patterns of severe arthralgia, intermittent large joint involvement, or persistent, symmetric polyarthritis have been described in HIV­infected individuals.11 Joint symptoms were more severe, lasted longer, and were less responsive to treatment than in individuals who were not infected with HIV.12

Table 1 summarizes frequency and features of virus-related arthritides.

 

Table 1
Sorting out virus-related arthritides

VirusWho is affectedType of joint affectedPossible extra-articular manifestations
Parvovirus B19*Adolescent/adult women (60% of those infected)Large, smallErythema infectiosum
Rubella (natural infection)*Adolescent/adult women (50% of those infected), adolescent/adult men (6% of those infected)Large, smallArthralgia, tenosynovitis carpal tunnel syndrome
Rubella (vaccine-related infection)*Adolescent/adult women (10% of those infected)Large, smallArthralgia, tenosynovitis carpal tunnel syndrome
Paramyxovirus (mumps)Adolescents and adultsLargeOrchitis, pancreatitis, arthralgia
HIVAdolescents and adultsLargeArthralgia
Cytomegalovirus*Adolescents and adultsLargeArthralgia
Epstein-Barr*Adolescents and adultsLarge, smallArthralgia, mononucleosis symptoms
Hepatitis B (natural andAdolescents and adultsSmallArthralgia, vasculitis
vaccine-related infection)ChildrenSmallGianotti-Crosti syndrome
Herpes zoster*Adolescents and adultsLargeShingles
Varicella*ChildrenLargeArthralgia

 

Other infectious agents

Mycoplasma can cause arthritis of the ankle or knee and polyarthralgia in healthy children. In a study of 33 hospitalized children with acute arthropathies, four had arthritis associated with Mycoplasma pneumoniae or Mycoplasma hominis (three with septic arthritis and one with reactive arthritis).13 These children also had constitutional symptoms of acute mycoplasma infection, such as fever and weight loss. Serology confirmed prior M pneumoniae infection in the child with reactive arthritis; mycoplasma was isolated in cultures from the other children. Mycoplasma and ureaplasma septic arthritis occurs most frequently in hypogammaglobulinemic children and adolescents.14

Lyme arthritis in children with Lyme disease who have not been treated develops a few months after the initial infection. Five patterns may be observed:

  • Episodic swelling of one to four joints for up to one week

  • Continuous swelling of one to four joints for up to four weeks

  • Persistent swelling of one to four joints for more than four weeks

  • Migratory pattern of swelling in three or more joints, with symptoms predominating in one joint at any given time and

  • Swelling of five or more joints for any length of time.15

More recognizable features of Lyme disease, such as erythema migrans, are not usually present at the same time as the arthritis.15 Lyme arthritis is less common than it used to be because early disease now is treated successfully with antibiotics. In a study of 44 children who did develop Lyme arthritis, joint symptoms in 39 (88%) resolved after four weeks of treatment with either amoxicillin or doxycycline. After the initial treatment course, five children continued to have arthritis, three children responded to an additional four-week course of intravenous daily ceftriaxone, and two children needed an additional eight-week course.15 Doxycycline is preferable to amoxicillin in children older than 9 years because doxycycline is dosed less frequently and has better bioavailability and cerebral spinal fluid penetration.

Reactive arthritis

Reactive arthritis is a sterile arthritis that develops after an enteric, genitourinary (GU), or respiratory tract infection (Table 2). Microbial components are detected in the joint fluid or tissue by polymerase chain reaction or by histologic examination, but no viable organism is isolated.16 Tables 3 and 4 summarize the general characteristics of reactive arthritis compared with other arthritides and the corresponding synovial fluid features.

 

Table 2
Bacteria commonly associated with reactive arthritis

 

Table 3
Comparing arthritides

Type of arthritisKnown infection?Organism isolated from joint fluid or tissue?Microbial component present in joint fluid or tissue?Examples
Infectious viral arthritidesYesYesYesSeptic arthritis, infective
ReactiveYesNoYesArthritis associated with Chlamydia, Salmonella, Shigella, Yersinia, or Neisseria meningitidis
InflammatoryNoNoNoRheumatoid arthritis ankylosing spondylitis

 

Table 4
Synovial fluid features of arthritides

ConditionWhite blood count/?LPolymorphonuclear neutrophil leukocytesMiscellaneous findings
Normal
  Septic50,000–300,000>75%Low glucose, bacteria, turbid appearance
  ViralVariable (200–>50,000)10%–40%
  Reiter’s syndrome20,00080%Reiter’s cells
  Systemic lupus erythematosus5,00010%Lupus erythematosus cells
  Juvenile rheumatoid arthritis15,000–20,00075%

 

Migratory joint swelling in acute rheumatic fever is a well-recognized form of reactive arthritis. The triad of arthritis, urethritis, and conjunctivitis seen in Reiter's syndrome reflects a spectrum of multiorgan inflammation.

Reactive arthritis associated with Yersinia enterocolitica infection presents in adolescents with mesenteric adenitis or symptoms resembling inflammatory bowel disease, sometimes accompanied by uveitis, scleritis, or myocarditis. Dysentery is more common in children than in adolescents.17 Isolating Y enterocolitica by stool culture is a reasonable way to confirm prior infection, since this pathogen is excreted for approximately two weeks following primary infection. Arthritis appears one to two weeks after a gastrointestinal (GI) infection and lasts about three months. Severe, chronic, or recurrent arthritis is particularly likely among human leukocyte antigen-B27 carriers and may in part be caused by the persistent presence of the organism in the joint.18

The manifestations of GI infection, onset of joint symptoms, and pattern of acute and chronic arthritis that result from infection by Salmonella enteritidis, Salmonella typhimurium, and Campylobacter jejuni are similar to those of arthritis caused by Yersinia.18 Since prolonged excretion of Salmonella is common, obtaining a stool culture at the time joint symptoms appear is a feasible way to confirm infection. Reactive arthritis caused by Salmonella is less common than septic arthritis, which is a well-recognized complication of bacteremia.10 C jejuni septic arthritis arises mostly among immunocompromised individuals or those who have prior joint disease.18 Antibiotic treatment for reactive arthritis caused by enteric pathogens has not shown consistent benefit.

Chlamydia trachomatis infection is often associated with reactive arthritides in young adults that are caused by Reiter's syndrome and GU infection. Arthritis occurs in 1% to 3% of individuals with C trachomatis infection, and adolescent and adult men are particularly prone to it.19 The clinician may not suspect that the arthritis is associated with earlier infection because most chlamydial infections are asymptomatic. Conjunctivitis and uveitis more often accompany reactive arthritis that is preceded by GU infection than reactive arthritis preceded by GI infection; the onset of reactive arthritis and the pattern of joint symptoms is similar in the two situations. Reactive arthritides caused by C trachomatis are reported to respond to antibiotic treatment.20

Neisseria gonorrhoeae septic and reactive arthritides develop in a polyarticular pattern that affects the large joints and often are accompanied by tenosynovitis; these arthritides result from disseminated infection and should be treated with antibiotics.10 C pneumoniae, Chlamydia psittaci, M pneumoniae, and Neisseria meningitidis are rarely associated with reactive arthritides.

Table 5 summarizes clinical features of reactive arthritis.

 

Table 5
Clinical findings in reactive arthritis

 

Vaccine-associated arthritides

Despite the proven benefit of childhood immunization, the growing number of vaccines being added to the routine immunization schedule prompts questions and concerns about vaccine safety. Of the vaccines currently on the schedule, only the rubella component (RA 27/3 strain) of the MMR vaccine has a proven association with acute arthritis. Pediatricians can use Table 6 as a guide to the likelihood of an association between common vaccinations of childhood and development of arthritis.

 

Table 6
Association of arthritis and common immunizations

VaccineType of arthritisPossible association with development of arthritisEvidence in children and adults: Uncontrolled studies*Evidence in children and adults Controlled studies**
Diphtheria and tetanus toxoidsAcuteTheoretical (biologically possible)IndeterminateNo data
Hepatitis BAcuteSupportive (supported by animal and in vitro studies)IndeterminateNo data
RubellaAcuteSupportiveSupportiveSupportive
ChronicTheoreticalIndeterminateIndeterminate
LymeAcuteTheoreticalNo dataIndeterminate

 

The Vaccine Adverse Event Reporting System (VAERS), to which clinicians report vaccine-related reactions, is a resource for evaluating new, unusual, or extremely rare adverse events in the US. The usefulness of the VAERS database is limited by underreporting and incomplete and biased reporting, however. More information about VAERS is available from the Web site www.fda.gov/cber/vaers/vaers.htm.

The last word

Infectious and reactive arthritides are associated with common viruses, Mycoplasma, spirochetes, and bacteria. Careful epidemiologic evaluation and recognition of joint pattern and extra-articular features with supporting microbiologic and immunologic laboratory examination help to determine the cause of infection. Antibiotic treatment is effective only in certain circumstances. When the cause is viral, treatment is generally symptomatic. The relationship between vaccines and arthritis requires more clarification.

This article represents the views of its authors and does not represent the official view of the US Food and Drug Administration.

References

1. Portmore AC: Parvoviruses, in Mandell GL, Bennett JE, Dolin R (eds): Principles and Practice of Infectious Diseases, ed 4. New York, NY, Churchill Livingstone, 1995

2. Nocton JJ, Miller LC, Tucker LB, et al: Human parvovirus B19­asssociated arthritis in children. J Pediatr 1993;122:186

3. Reid DK, Reid TMS, Brown T, et al: Human parvovirus associated arthritis: A clinical and laboratory description. Lancet 1985;1:422

4. Tingle AJ, Allen M, Petty RE, et al: Rubella-associated arthritis: I. Comparative study of joint manifestations associated with natural rubella infection and RA 27/3 rubella immunization. Ann Rheum Dis 1986;45:110

5. Kalden JR: Viral arthritis, in Klippel JH, Dieppe PA (eds): Rheumatology, ed 2. London, England, Mosby, 1998

6. Mangi RJ: Viral arthritis—the great masquerader. Bull Rheum Dis 1994;43:5

7. Priest JR, Urick A, Groth KE, et al: Varicella arthritis documented by isolation of virus from joint fluid. J Pediatr 1978;93(6):990

8. Aarons EJ, Beeching NJ: Aseptic arthritis associated with herpes zoster. J Infect 1993;26:87

9. Adebonojo FO: Monarticular arthritis: An unusual manifestation of infectious mononucleosis. Clin Pediatr 1972;11:549

10. Rose CD, Eppes SC: Infection-related arthritis. Rheum Dis Clin North Am 1997;23:677

11. Calabrese LH: Human immunodeficiency (HIV) infection and arthritis. Rheum Dis Clin North Am 1991; 19:477

12. Forester SK, Seifert MH, Keat AC, et al: Inflammatory joint disease and human deficiency virus infection. BMJ 1988;296:1625

13. Poggio TV, Orlando N, Galanternik L, et al: Microbiology of acute arthropathies among children in Argentina: Mycoplasma pneumoniae and hominis and Ureaplasma urealyticum. Pediatr Infect Dis J 1998;17:304

14. Furr PM, Taylor-Robinson D, Webster AD: Mycoplasmas and ureaplasmas in patients with hypogammaglobulinaemia and their role in arthritis: Microbiologic observations over twenty years. Ann Rheum Dis 1994;53:183

15. Rose CD, Fawcett PT, Eppes SC, et al: Pediatric Lyme arthritis: Clinical spectrum and outcome. J Ped Orthop 1994;14:238

16. Toivanen A: Reactive arthritis, in Klippel JIL, Dieppe PA (eds): Rheumatology, ed 2. London, England, Mosby, 1998

17. Taccetti G, Trapani S, Efimini S, et al: Reactive arthritis triggered by Yersinia enterocolitica: A review of 18 pediatric cases. Clin Exp Rheumatol 1994;12:681

18. Peterson MC: Rheumatic manifestations of Campylobacter jejuni and C fetus infections in adults. Scand J Rheum 1994;23:167

19. Rahman MU, Hudson AP, Schumacher HR: Chlamydia and Reiter's syndrome (reactive arthritis). Rheum Dis Clin North Am 1992;18:67

20. Barth WF, Segal K: Reactive arthritis. Amer Fam Physician 1999;60:499

DR. LEE is Medical Officer, FDA­Division of Vaccines and Related Product Applications, Rockville, MD.
DR. HALL is Professor of Pediatrics and Medicine, University of Rochester Medical Center, Rochester, NY, and a member of the Contemporary Pediatrics Editorial Board.

 

Caroline Hall,Lucia Lee. Recognizing infection-related arthritis. Contemporary Pediatrics 2000;5:119.