Chlamydia pneumoniae arthritis in a patient with common variable immunodeficiency

Case report

Chlamydia pneumoniae arthritis in a patient with common variable immunodeficiency ¨ mu¨r Ardenı˙z, MD*; Okan Gu¨lbahar, MD*; Nı˙hal Mete, MD*; Candan C O ¸ ˙ıc¸ek, MD†; ¨ Ozen Kac¸maz Bas¸og˘lu, MD‡; Aytu¨l Sı˙n, MD*; and Alı˙ Kokuludag˘, MD*

Background: Arthritis is an important and sometimes life-threatening complication in patients with common variable immunodeficiency (CVID). Objective: To describe a patient with CVID and arthritis due to Chlamydia pneumoniae, which is usually regarded as a respiratory tract pathogen and has not previously been detected in the synovial fluid by cell culture technique. Methods: Routine bacteriologic, virologic, mycologic, and tuberculosis cultures were performed. The patient’s synovial fluid was examined for fastidious organisms that might be causative pathogens of arthritis, such as chlamydiae, and special cell culture methods were used. Serologic tests were performed to determine viral and bacteriologic etiology. Results: The patient had a history of recurrent respiratory tract infections, and the latest exacerbation was followed by arthritis. Cytologic examination of the fluid yielded abundant lymphocytes. Chlamydia pneumoniae was detected in synovial fluid specimens by cell culture technique. Her nasopharyngeal swab and sputum culture specimens were also positive for this pathogen. She was diagnosed as having arthritis caused by C pneumoniae and was given antibiotherapy. Conclusion: Chlamydia pneumoniae should be kept in mind as a causative pathogen in patients with CVID and arthritis, especially when effusion fluid is full of lymphocytes rather than polymorphonuclear cells and no organism is grown on routine cultures. Ann Allergy Asthma Immunol. 2005;94:504–508.

INTRODUCTION Common variable immunodeficiency (CVID) is the most prevalent significant antibody deficiency in adults and is characterized by low immunoglobulin levels (IgG, ⬍5 g/L; IgA, ⬍0.1 g/L; and variable IgM), age at onset older than 2 years, recurrent sinopulmonary infections, and poor response to vaccines. Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae are the most common pathogens in the respiratory tract.1 Mycoplasma infection is the most common cause of arthritis in these patients.2,3 We describe a patient with CVID and arthritis due to Chlamydia pneumoniae, which is usually regarded as a respiratory tract pathogen and has not previously been defined as a cause of arthritis in patients with CVID. CASE REPORT A 43-year-old woman was diagnosed as having CVID in 1993 based on low immunoglobulin levels (IgG, 212 mg/dL; IgA, ⬍20 mg/dL; and IgM, ⬍16.8 mg/dL), recurrent pneu* Division of Allergy and Clinical Immunology, Department of Internal Medicine, Ege University Medical Faculty, ˙Izmir, Turkey. † Department of Microbiology and Clinical Microbiology, Ege University Medical Faculty, ˙Izmir, Turkey. ‡ Department of Chest Disease, Ege University Medical Faculty, I˙zmir, Turkey. Received for publication June 25, 2004. Accepted for publication in revised form October 31, 2004.

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monia, sinusitis and bronchitis since the age of 16 years, and exclusion of the other known diseases associated with hypogammaglobulinemia. She has been given 600 mg/kg of intravenous immunoglobulin every 3 weeks since January 2003 owing to deterioration of respiratory functions, recurrent respiratory tract infections possibly caused by diffuse bronchiectasia, and leukopenia (white blood cell count, 3,100/mm3) related to granulomatous hepatic disease, portal hypertension, and hypersplenism. Because of the patient’s insufficient response to therapy and deterioration of respiratory function test results (forced expiratory volume in 1 second, 31.8% of predicted), 32 mg/kg of oral corticosteroids was also given in December 2003, and tapering of the dose by 8 mg per week was planned by the suggestion of a chest physician (O.K.B.). Ten days after beginning corticosteroid and amoxicillin-clavulanate therapy, she was hospitalized because of the complaints of sore throat, purulent sputum, dyspnea on exertion, and fever. Her white blood cell count increased from 3,100/ mm3 to 8,700/mm3, with polymorphonuclear lymphocyte dominance. Because chest radiographs showed pneumonic infiltration in the lower zone of the left lung, corticosteroid therapy was discontinued and levofloxacin was administered. After this treatment, the patient’s clinical symptoms improved, her chest radiographs showed complete resolution, and forced expiratory volume in 1 second increased to 44% of predicted. No organism was grown on routine sputum culture. Approximately 10 days after the cessation of antibiotherapy,

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Table 1. Laboratory and Blood Chemistry Values at Hospital Admission Mean Erythrocyte sedimentation rate, mm/h 21 CRP, mg/dL 5 White blood cell count, mm3 2,300 Hemoglobin, % 10.5 Hematocrit, % 34.5 Platelet count, mm3 125,000 AST, U/L 24 ALT, U/L 15 Alkaline phosphatase, U/L 334 GGT, U/L 55

Reference range ⬍20 ⬍0.5 4–10 ⫻ 103 12–18 36–52 150–450 ⫻ 103 5–35 5–40 98–290 11–50

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; GGT, ␥-glutamyl transpeptidase.

she experienced pain, warmness, and swelling of the right knee and was hospitalized again. On admission, her white blood cell count showed the progression of leukopenia (Table 1). On physical examination, her blood pressure was 100/60 mm Hg, pulse rate was 90/min, and temperature was 37°C. Her pharynx was erythematous, lung auscultation showed expiratory rhonchi, and her liver and spleen were palpable 6 and 10 cm, respectively, which was an existing finding for 10 years. There was no peripheral lymphadenopathy. Knee examination showed effusion, and a synovial fluid sample was aspirated for further evaluation. The appearance of the aspirated material was serous and dark yellow. Because of her known immunodeficiency, effusion fluid was evaluated for microorganisms that might be responsible for arthritis. The patient had similar complaints twice before (in 2001 and 2002) in the same joint. In these attacks, respiratory tract infection symptoms preceded arthritis, but symptoms improved with the short-term use of nonsteroidal anti-inflammatory drugs without any sequela. METHODS While working on effusion fluid, the He-La cell line was used to detect C pneumoniae. The McCoy cell line was used to detect Chlamydia trachomatis, and the Vero, He-La, and rhabdomyosarcoma cell lines were used to detect enteroviruses. These cell lines were supplied by the Department of Human and Animal Cell Cultures, Braunschweigh, Germany. The shell vial cell culture method was applied to detect C pneumoniae. Pathogen-specific monoclonal antibodies were used. An immunofluorescence assay kit (Chlamydia Cel Pn; Cellabs Pty Ltd, Brookvale, Australia) was used for C pneumoniae, and a C trachomatis culture confirmation test (MicroTrak; Syva, Palo Alto, CA) was used for C trachomatis. A light diagnostic test (Pan-Enterovirus Blend; Chemicon International Inc, Temecula, CA) was used to detect enteroviruses, which were analyzed using a fluorescent microscope (magnification ⫻100 and ⫻400). The presence of 1 inclusion body was regarded as positive for C pneu-

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moniae.4 Serologic evaluation for C pneumoniae IgG-IgAIgM antibodies was performed using a microenzyme immunoassay. RESULTS Cytologic examination of the fluid yielded abundant lymphocytes, and some of them had atypical and active patterns. Therefore, we searched for underlying hematologic disease. Bone marrow aspiration and biopsy were performed. Pathologic examination showed hypercellular marrow (85%), which was thought to be due to hypersplenism related to granulomatous liver disease. There was an increase in mature granulocytes, with no tumoral infiltration. Chest radiographs showed no infiltration, and abdominal ultrasonography results were normal except for hepatosplenomegaly. Computed tomography of the abdomen did not show abnormalities that suggest an underlying lymphoma. The effusion fluid was examined by performing bacteriologic and mycologic cultures, Gram staining, a transmediated amplification test for tuberculosis, and cell cultures for enteroviruses and chlamydia. On Gram staining, there was no bacteriologic morphology. Bacteriologic, mycologic, and virologic cell cultures for enteroviruses and C trachomatis and Neisseria gonorrhea (CT/NG hybridization) tests all had negative results. The transmediated amplification test result was negative, and there were no acid-fast bacteria on direct examination. A polymerase chain reaction (PCR) for mycoplasma-ureaplasma was not performed because it was not available at that time. Serologic tests for mycoplasma were performed, and anti–M pneumonia IgG and IgM antibodies were negative. The patient’s biochemical variables were within the reference ranges, except for high C-reactive protein, alkaline phosphatase, and ␥-glutamyl transpeptidase levels (Table 1). Her immunologic markers and autoantibody levels were all negative (Table 2).

Table 2. Immunologic Markers at Hospital Admission

Antinuclear antibodies ASMA Antimitochondrial antibodies GPCA ANCA Rheumatoid factor LKM IgG, mg/dL IgM, mg/dL IgA, mg/dL IgE, IU/mL Complement 3, mg/dL Complement 4, mg/dL

Mean

Reference range

Negative Negative Negative Negative Negative ⬍10 Negative 913 ⬍16.8 ⬍25.4 2 86 20

Negative Negative Negative Negative Negative 0–20 Negative 700–1,600 40–230 70–400 ⬍100 90–180 10–40

Abbreviations: ANCA, antineutrophil cytoplasmic antibodies; ASMA, anti–smooth muscle antibodies; GPCA, gastric parietal cell antibodies; LKM, liver kidney microsomal antibodies.

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Moxifloxacin was given orally once a day during the incubation time because the patient had a fever. She was given intravenous immunoglobulin, 600 mg/kg, although her through immunoglobulin level was 913 mg/dL. The routine sputum culture performed at hospital admission showed growth of H influenzae. On physical examination of the knees, no swelling or erythema was found 5 days after beginning therapy, but she complained of pain in both knees. At this time, ultrasonographic evaluation of the knees showed no effusion or synovial hypertrophy. Her sputum became lighter. Fever was not recorded during moxifloxacin treatment. She was discharged from the hospital and was advised to continue antibiotherapy for 2 weeks. When the patient was taking moxifloxacin as an outpatient, the microbiology department informed us about positive C pneumonia cell culture results in the synovial fluid. Cell culture tests were then performed on her nasopharyngeal swab and sputum specimens twice after cessation of antibiotherapy for a week. Her nasopharyngeal swab specimen and sputum cell culture also showed positive results for C pneumoniae; the sputum study showed stronger positivity. Her serologic evaluation revealed negative results for anti–C pneumoniae IgG-IgM-IgA antibodies. Treatment with doxycycline hyclate, 200 mg/d, was started. One week after beginning therapy, the patient experienced pain in her left knee, but there was no sign of septic arthritis. Treatment with doxycycline was scheduled to continue for 6 weeks. Two weeks after beginning treatment, magnetic resonance imaging (MRI) of both knees was performed. Bilateral minimal effusion and cellulitis in fat tissue were detected, and effusion in the left knee was greater (Fig 1A and C). On MRI, the bone marrow was found to be hyperactive, and this was thought to be due to hypersplenism. Clarithromycin, 500 mg twice daily, was given in conjunction with doxycycline for 1 month. One month after beginning this treatment, the patient’s pain improved, and on physical ex-

Figure 1. Magnetic resonance images of the knees.

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amination of both knees, no significant effusion was found. Her C-reactive protein level declined to the reference range (0.47 mg/L). Fifteen days after the cessation of antibiotherapy, she had purulent sputum, fever, sore throat, and pain in the left knee and left leg. Plain radiologic examination of the chest did not show pneumonic infiltration. Control MRI of both knees was performed again. There was significant regression in soft tissue edema and effusion in the left knee, and minimal soft tissue swelling was found to be the same in the right knee on MRI, but there were no destructive changes in either joint (Fig 1B and D) Sputum cell cultures and nasopharyngeal swab cultures for C pneumoniae were performed again, and all had positive results. The routine sputum culture was positive for H influenzae. Although we detected regression of the joint findings, therapy with levofloxacin, 500 mg/d, was started because of the positive culture results and clinical symptoms. This treatment was scheduled to be continued for 6 months. The serologic tests for C pneumoniae were repeated 2 months later, and anti–C pneumoniae IgG antibody was found to be positive at a titer of 1/64. DISCUSSION In this article, we describe a patient with CVID and respiratory infection followed by arthritis that was found to be due to C pneumoniae by performing specific cell culture methods on the effusion fluid. To our knowledge, this is the first case report of chlamydia as a causative pathogen of arthritis in a patient with CVID. Arthritis is an important and sometimes life-threatening complication in patients with CVID, and it may cause destructive changes and osteomyelitis. In patients with CVID, an aseptic form of arthritis may develop. Circulating immune complexes that deposit in the synovium may be responsible for this kind of arthritis,5 or microbial products such as superantigens may persist at the synovial membrane and could trigger aseptic arthritis.6,7 It is usually symmetrical polyarthritis localized to large joints and responsive to treatment with intravenous immunoglobulin. Since this patient has been treated with intravenous immunoglobulin for a long time and her arthritis is oligoarthritis, we did not accept it as an aseptic form of arthritis. Besides, her complement levels were within the reference ranges (Table 2). Septic arthritis in CVID generally involves large joints such as the knee, wrist, and ankle as a monoarthritis, and sometimes it is present as asymmetrical oligoarthritis. Streptococcus pneumoniae and H influenzae may be responsible for arthritis. Mycoplasma species and Ureaplasma urealyticum are the best known pathogens related to septic arthritis in these patients.2,3,8,9 Large joints are affected, although finger joints can be involved, and the appearance of the aspirated effusion is usually purulent. Left untreated, this arthritis may cause polyarthropathy and abscess formation. Mycoplasma hominis– and Mycoplasma orale–related forms of septic arthritis have been reported in patients with CVID, and M orale

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can cause disseminated infection with chronic osteomyelitis and destructive synovitis.10 The effusion material was not evaluated for mycoplasmal or ureaplasmal infection by PCR because it was not available at that time, although we did not think about mycoplasma as a cause of arthritis owing to the patient’s clinical and synovial cytologic findings (the appearance of the effusion was not purulent, arthrocentesis did not yield white blood cell infiltration with polymorphonuclear cell dominance, and the patient was stable). We applied serologic tests for mycoplasma, and the findings were negative for anti–M pneumonia IgG and IgM. The other reasons for acute monoarthritis, such as gout, spondyloarthropathies, psoriatic arthritis, inflammatory bowel disease, rheumatoid arthritis, leukemia, and sarcoid arthritis, were searched, and no abnormalities were found. There have been case reports11–16 related to C pneumoniae and reactive arthritis. Because the patient did not have a history of diarrhea or urethritis, reactive arthritis secondary to gastroenteritis or a urogenital infection was not likely. Lymphocyte accumulation with atypical forms prompted us to search for underlying hematologic malignancy. Her bone marrow aspiration biopsy and computed tomography evaluation did not show any abnormalities that suggest lymphoma or malignancy. Chlamydia pneumonia has been identified in the synovial fluid of patients diagnosed as having rheumatoid arthritis or undiagnosed arthritis using PCR primers that target sequences in C pneumoniae.17 However, to our knowledge, chlamydia has not yet been isolated in the joint effusion fluid of patients with CVID and arthritis by cell culture method. Schumacher et al18 searched for C pneumoniae DNA in the synovial tissue of patients with arthritis and found that 12.7% of all samples were positive for C pneumoniae DNA. Because they did not find C pneumoniae DNA in control subjects, they concluded that this organism might have a role in the pathogenesis of some types of arthritis. Gerard et al19 demonstrated that C pneumoniae in the synovium of patients with arthritis is viable and metabolically active by using reverse transcription–PCR, and these data would explain chronic joint inflammation in these patients. Although immunocompetent patients infected with C pneumoniae may be asymptomatic, this pathogen may cause severe disease, especially in patients with chronic illnesses. It has been associated with pneumonia and acute sinusitis.20 It usually begins with upper respiratory tract symptoms such as pharyngitis and hoarseness. These are followed by persistent cough, sputum, and malaise, and this patient showed all these symptoms. Her chronic sinusitis might also be associated with C pneumoniae persistence in the upper airways, and this pathogen would be related to refractory sinusitis in patients with CVID. In a recent study, it was shown that C pneumoniae infection could trigger cutaneous T-cell lymphoma by leading to the expansion of C pneumoniae–specific T cells.21 Chlamydia infection was also found to be associated with immunoblastic lymphoma.22 The presence of abundant lymphocytes with atypical appearance would be related to chlamydia-specific

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T-cell expansion in this case, and this finding would be regarded as a sign to search for chlamydia in patients with arthritis. Chlamydia pneumoniae infection has been implicated in the development of asthma and chronic obstructive pulmonary disease,23 and the progressive deterioration of pulmonary functions in this patient might be associated with chronic C pneumoniae infection. A diagnosis of chlamydia infection can be established by serologic testing, isolation in cell culture, or PCR techniques. Cell culture is the most sensitive and specific method for detecting chlamydia24 that was applied in this case. Chlamydia pneumonia has been detected in pharyngeal swab specimens obtained from persons who are persistently seronegative. In patients with antibody deficiency such as CVID, serologic tests may not be useful for diagnosis because these patients may not generate normal antibody responses to infectious pathogens. This patient’s first serologic examination did not show any positivity, but, 2 months later, we found her to be anti–C pneumoniae IgG antibody positive, although at a low titer. After detecting C pneumoniae in the effusion fluid, nasopharyngeal swab and sputum cultures were performed to search for a primary site of infection, and they were also found to be positive for this pathogen. Diffuse bronchiectasis might be responsible for the colonization of C pneumoniae in this patient. Studies25 have indicated that C trachomatis reaches the joint via circulating monocytes from the urogenital system, and this mechanism would also be possible for the dissemination of C pneumoniae from the primary site of infection to the synovium. It is suggested that colonized patients be treated with high-dose intravenous immunoglobulin, and this patient was given intravenous immunoglobulin at a dose of 600 mg/kg every 3 weeks to keep her through levels at 900 to 1,000 mg/dL, but her colonization and infection frequency could not be controlled despite satisfactory immunoglobulin levels. For mycoplasma-related septic arthritis eradication, longterm uninterrupted treatment has been advocated. There is not enough experience on the treatment of arthritis associated with C pneumoniae, and, as with other intracellular pathogens, eradication would necessitate months of antibiotherapy. A TH1-type cellular immune response is required for eradication of chlamydia infection, and interferon-␥ inhibits the growth of C pneumoniae.26 Chlamydiae may escape the immune system by down-regulating the T-cell response. In a study27 based on analyzing the antigen-specific T-cell response in reactive arthritis by flow cytometry, antigen-specific interleukin 10 secretion has been detected in patients with Chlamydia-induced reactive arthritis, and this finding might be related to defective clearance. We decided to continue antibiotherapy with levofloxacin because of its effectiveness on atypical pathogens such as chlamydiae and mycoplasma.28 The other properties that made us choose this drug are good tissue concentration and effective minimum inhibitory concentration,29 high uptake of the drug by phagocytes related to its effective concentration

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in the site of infection,30 and availability for use in patients with hepatic disfunction. In conclusion, this case shows that C pneumoniae is an important pathogen in patients with CVID and that it may cause arthritis and respiratory tract symptoms. Cell culture methods are helpful in making a diagnosis, and this kind of arthritis has unique properties on cytologic examination. REFERENCES 1. Sneller M, Strober W, Eisenstein E, Jaffe J, CunninghamRundles C. New insights into common variable immunodeficiency. Ann Intern Med. 1993;118:720 –730. 2. Franz A, Webster ADB, Furr PM, Taylor-Robinson D. Mycoplasmal arthritis in patients with primary immunoglobulin deficiency: clinical features and outcome in 18 patients. Br J Rheumatol. 1997;36:661– 668. 3. Hermaszewski RA, Webster ADB. Primary hypogammaglobulinemia: a survey of clinical manifestations and complications. Q J Med. 1993;86:31– 42. 4. Wiedbrauk DL, Johnston SL, eds. Chlamydia. In: Manual of Clinical Virology. New York, NY: Raven Press; 1993:64 –75. 5. Lee AH, Levinson AI, Schumacher HR Jr. Hypogammaglobulinemia and rheumatic disease. Semin Arthritis Rheum. 1993; 22:252–264. 6. Itescu S. Adult immunodeficiency and rheumatic disease. Rheum Dis Clin North Am. 1996;22:53–73. 7. Iyer M, Gorevic PD. Reactive arthropathy and autoimmunity in non-HIV-associated immunodeficiency. Curr Opin Rheumatol. 1993;5:475– 482. 8. Puechal X, Hilliquin P, Renoux M. Ureaplasma urealyticum destructive septic polyarthritis revealing a common variable immunodeficiency. Arthritis Rheum. 1995;38;1524 –1527. 9. Forgacs P, Kundsin RB, Margies SW, Silverman ML, Perkins RE. A case of Ureaplasma urealyticum septic arthritis in a patient with hypogammaglobulinemia. Clin Infect Dis. 1993;16: 293–294. 10. Paessler M, Levinson A, Patel JB, Schuster M, Minda M, Nachamkin I. Disseminated Mycoplasma orale infection in a patient with common variable immunodeficiency syndrome. Diagn Microbiol Infect Dis. 2002;44:201–204. 11. Gran JT, Hjetland R, Andreassen AH. Pneumonia myocarditis and reactive arthritis due to Chlamydia pneumoniae. Scand J Rheumatol. 1993,22:43– 44. 12. Braun J, Laitko S, Treharne J, et al. Chlamydia pneumoniae: a new causative agent of reactive arthritis and undifferentiated oligoarthritis. Ann Rheum Dis. 1994;53:100 –105. 13. Saario R, Toivanen A. Chlamydia pneumoniae as a cause of reactive arthritis. Br J Rheumatol. 1994;33:1112–1119. 14. Moling O, Pegoretti S, Rielli M, et al. Chlamydia pneumoniae–reactive arthritis and persistent infection. Br J Rheumatol. 1996;35:1189 –1190. 15. Hannu T, Puolakkainen M, Leirisalorepo M. Chlamydia pneumoniae as a triggering infection in reactive arthritis. Rheumatology. 1999;38:411– 414. 16. Cascina A, Marone Bianco A, Mangiarotti P, Montecucco CM, Meloni F. Cutaneous vasculitis and reactive arthritis following

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Requests for reprints should be addressed to: ¨ mu¨r Ardenı˙z, MD O ¨ niversitesi Tıp Faku¨ltesi I˙c¸ Hastalıkları AD Ege U Klinik ˙Immu¨noloji ve Alerji BD 35 100 Bornova I˙zmir, Turkey E-mail: [email protected]

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