Campylobacter fetus Bacteremia with Purulent Pleurisy in a Young Adult with Primary Hypogammaglobulinemia

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1 CASE REPORT Campylobacter fetus Bacteremia with Purulent Pleurisy in a Young Adult with Primary Hypogammaglobulinemia Keiko Yamagami 1, Tomoko Miyashita 1, Tomoyuki Nakamura 1, Michinori Shirano 2, Tadahiro Nakamura 2, Kazuaki Kameda 2, Masayoshi Nishijima 3, Masahiro Imanishi 1,XiYang 4 and Hirokazu Kanegane 4 Abstract A 24-year-old man presented with fever and pleural predominantly containing lymphocytes. Cultures of the pleural and blood revealed Campylobacter fetus, and laboratory studies showed a low serum level of immunoglobulin. The patient was diagnosed with C. fetus pleuritis, bacteremia and primary hypogammaglobulinemia, and subsequent treatment with meropenem and immunoglobulin improved his condition. Although the underlying cause of the primary hypogammaglobulinemia remains unclear, the patient s status improved under immunoglobulin replacement therapy. C. fetus pleuritis is a rare infectious disease usually observed in immunocompromised hosts. We herein describe the first report of C. fetus pleuritis in a young adult with primary hypogammaglobulinemia. Key words: Campylobacter fetus bacteremia, purulent pleurisy, hypogammaglobulinemia () () Introduction Campylobacter are Gram-negative bacilli, including approximately 18 species and subspecies. Of the Campylobacter species associated with human disease, C. jejuni is the prototype for enteric infection, and C. fetus is the prototype for extraintestinal infection. C. fetus sometimes causes severe systemic infections, such as bacteremia, meningitis and endocarditis, in immunocompromised individuals with acquired immune deficiency syndrome, liver dysfunction, renal failure or diabetes (1). Primary agammaglobulinemia can be caused by various diseases, including X-linked agammaglobulinemia (XLA) (2), common variable immunodeficiency (CVID) (3) and others. The condition involves impaired B-cell development and differentiation, which clinically appears as a marked reduction in the serum immunoglobulin (Ig) levels (IgG, <300 mg/dl; IgA, <5 mg/dl). Patients with primary hypogammaglobulinemia display a high incidence of infectious diseases and are treated with immunoglobulin replacement therapy and antibiotics. We herein describe a case of C. fetus pleuritis associated with primary hypogammaglobulinemia. Case Report A 24-year-old man visited our hospital in May 2010 with a three-day history of a high fever, fatigue and general malaise. The patient had been admitted to another hospital for pneumonia three months earlier. He had subsequently experienced a recurrent fever of unknown origin. Chest radiography showed left pleural (Fig. 1A). On admission, a physical examination revealed a body temperature of 36.6 on antipyretic drugs, an oxygen saturation of 95% and a generally good condition. Laboratory testing showed the following results: hemoglobin, 13.3 g/dl; platelets, /L; white blood cells (WBC), 7, /L Department of Internal Medicine, Osaka City General Hospital, Japan, Department of Infectious Disease, Osaka City General Hospital, Japan, Department of Pulmonary Disease, Osaka City General Hospital, Japan and Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan Received for publication August 22, 2013; Accepted for publication January 5, 2014 Correspondence to Dr. Keiko Yamagami, yamasanz@qb3.so-net.ne.jp 1221

2 A Figure 1. Chest radiography on admission (A) and on hospital day 4 (B) A Figure 2. B B Chest radiography (A) and chest computed tomography (B) on day 19 (58% neutrophils; 23.5% lymphocytes); serum creatinine, 0.56 mg/dl; and C-reactive protein, mg/dl. However, a procalcitonin test yielded negative results. The patient had no past medical or family history of note. He was not considered to have a bacterial infection and was followed without antibiotics. On hospital day 4, he experienced difficulty breathing, and the left pleural increased (Fig. 1B). Laboratory findings of the pleural fluid showed exudate containing a WBC count of 2, /L (12% neutrophils; 82% lymphocytes), a specific gravity of and tuberculous pleuritis with an extremely high level of adenosine deaminase (ADA) (115.2 IU/L). No mycobacterium was found on an acid-fast staining, and tuberculosis polymerase chain reaction (PCR) of the pleural yielded negative results. A tuberculin skin test reaction was strongly positive (17 23 mm with induration), although the patient had received the BCG vaccination in childhood. He was tentatively diagnosed with tuberculous pleuritis and immediately treated with antituberculosis medications, including isoniazid (300 mg/day), rifampicin (450 mg/day), ethambutol (750 mg/day) and pyrazinamide (1,800 mg/day) start- ing on day 4. The high fever persisted; however, this finding was attributed to an adverse reaction to the antituberculosis drugs. On day 13, Gram-negative rods were isolated from the aerobic blood culture drawn on the day of admission, and tuberculosis blood tests, including QuantiFERON, yielded negative results; therefore, the antituberculosis drugs were discontinued and the administration of ceftriaxone was started. Samples of the blood culture drawn on the day of admission and pleural on day 4 were then subcultured onto blood agar and chocolate agar, and the organism appeared to be C. fetus based on the appearance of the colonies, Gram stain findings, negative hippurate hydrolysis test results and the inability to grow at 42. Confirmation of C. fetus was obtained based on the 16S rdna gene sequence on day 19. At that time, the patient s high fever continued and the pleural increased (Fig. 2A, B). Treatment with meropenem (3 g/day) and fluid drainage of the left pleural space were started after performing a left pleural needle biopsy. At that time, the laboratory investigation disclosed low levels of IgG (498 mg/dl) and IgM (13 mg/dl), although the level of IgA (191 mg/dl) was normal. The sus- 1222

3 Table 1. Antibiotic Susceptibility Profiles Antibiotics MIC Susceptibility ABPC 1 S PCG 2 N/A CCL 2 S CEZ >4 N/A CDTR >4 N/A CTM >4 N/A CTX 4 N/A FMOX 1 S MEPM 0.06 S IPM-CS 0.06 S MINO 0.5 S CLDM 0.12 N/A EM 0.5 N/A ST 4 I LVFX 8 N/A MIC: Minimum Inhibitory Concentration, S: susceptible, R: rejistant, I: intermediate, N/A: not applicable, ABPC: ampicillin, PCG: penicilling, CCL: cefaclor, CEZ: cefazolin, CDTR: cefditoren, CTM: cefotiam, CTX: ceftriaxone, FMOX: cephalosporin, MEPM: meropenem, IPM-CS: imipenem-cilastatin, MINO: minomycin, CLDM: clindamycin, EM: erythromycin, ST: sulfamethoxazole and trimethoprim, LVFX: levofloxacin ceptibility of C. fetus to meropenem and imipenem-cilastatin appeared good. Ceftriaxone was not markedly effective in improving the patient s condition and showed no applicability to the isolation of C. fetus in this case (Table 1). The administration of meropenem was therefore continued. Immunoglobulin replacement therapy (2.5 g/day for six days) was started, resulting in a serum IgG level of 704 mg/dl. Transthoracic echocardiography revealed no signs of vegetation on the valves, ruling out a diagnosis of infectious endocarditis. The patient s fever subsided within 48 hours, with no reaccumulation of pleural after starting intravenous meropenem treatment. The pleural tissues showed only chronic inflammation with no signs of tuberculosis on tuberculosis PCR or cultivation of the pleural. A flow cytometric analysis demonstrated a severely decreased number of B cells (0.1%) with a predominance of T cells (89.9%). A B-cell defect and hypogammaglobulinemia suggested the presence of XLA, although the patient was an adult. A flow cytometric analysis of intracellular BTK proteins (4) yielded a normal expression with no BTK mutations, ruling out a diagnosis of XLA. The definitive diagnosis underlying the primary hypogammaglobulinemia remains unclear; however, the patient was treated with regular immunoglobulin replacement therapy. The patient s immunocompromised condition may have led to C. fetes pleuritis and bacteremia. The pleuritis healed, and the patient was discharged after three weeks of meropenem treatment. The administration of immunoglobulin was continued every month in order to maintain a serum IgG level of >500 mg/dl. The patient continues to do well with no severe infections. Discussion This is the first report of C. fetus pleuritis and bacteremia associated with primary hypogammaglobulinemia. Campylobacter bacteremia is primarily caused by C. fetus (53%), and the 30-day mortality rate for C. fetus bacteremia is as high as 15%. C. fetus infection represents an independent risk factor for death in patients with Campylobacter bacteremia (1). The presence of C. fetus pleuritis or massive pleural with positive pleural fluid cultures, as observed in this case, is a very unusual manifestation. Some reports have described C. fetus pleuritis in immunosuppressed individuals, such as intravenous drug abusers and patients receiving immunosuppressive treatment (5), with pleuritis mostly occurring in association with emphysema or lung abscesses, whereas the patient in this case showed no concomitant pulmonary disease. As the present patient exhibited lymphocyte-dominant pleural, a high level of ADA and a positive tuberculin skin test reaction, a diagnosis of tuberculosis pleuritis was initially suspected. Mononuclear cell-dominant pleural is characteristic of C. fetus pleuritis, although this finding alone has only been described in two other cases (6, 7) (Table 2). In addition, C. fetus meningitis sometimes presents with cerebrospinal fluid primarily containing monocytes, leading to potential misdiagnosis as tuberculosis meningitis (8). The present patient was initially diagnosed with tuberculosis based on the lymphocyte-dominant contents of the pleural. This is because C. fetus is resistant to phagocytosis by neutrophils, with the surface layer of the bacterial body resisting opsonization and activation. As a result, C. fetus pleuritis may appear with lymphocyte-dominant contents of pleural (9). C. fetus bacteremia appears to recur readily, and the administration of antibiotic treatment over three weeks is therefore recommended. Quinolones are not recommended for the empirical treatment of Campylobacter bacteremia due to the increasing frequency of resistance (1). In addition C. fetus isolates are resistant to third- generation cephalosporins in 20% of cases (10). In contrast, all strains of C. fetus remain susceptible to imipenem (minimum inhibitory concentration (MIC) 0.06 μg/ml) (11); therefore, thirdgeneration cephalosporins and quinolones are avoided (1) in cases of Campylobacter bacteremia, and the use of antibiotic treatment with imipenem (namely, carbapenems) has been suggested. One patient with hypogammaglobulinemia reportedly experienced recurrent bacteremia seven years after the initial infection (12). C. fetus bacteremia often recurs because the proteins of the surface layer readily exhibit antigenic variation (9). Our patient will therefore be carefully followed for the long term. Patients with XLA are usually diagnosed in early childhood due to their susceptibility to infection or repeated episodes of severe infectious disease. XLA is caused by muta- 1223

4 Table 2. Campylobacter fetus Pleuritis Age Sex Past history X-ray findings Blood culture Pleural fluid Medication Reference 79 male 80 male coronary stenosis, cardiac thrombosis hypertension, cerebral infarction, hypothyroidism left pleural pleural sterile positive no data Monocytes 90%, neutrophils 10% amoxicillin-clavulanate 1g three times/day, gentamicin 5 mg/kg once a day (serum creatinine level increased) ofloxacin 200 mg/12 h piperacillin 2 g two times/day 7 64 male tuberculosis pleural positive no data clindamycin male liver cirrhosis 24 female drug abuse right pleural infiltration in right lobe and pleural positive 27 male nothing pleural positive lymphocytes 59%, neutrophils 34% imipenem 1g/6 h, ciprofloxacin 400 mg/12 h sterile no data 19 lymphocytes 82%, neutrophils 12% meropenem 1g, three times/day 5 6 Present case tions in BTK and defective B-cell development. A small number of XLA patients demonstrate adult onset (13). However, the diagnosis of XLA was not confirmed. CVID patients with a sufficient number of peripheral B cells usually exhibit adult onset of the disease, although some patients display a reduced B-cell count. A tentative diagnosis in this case may be CVID. Whole-exome sequencing of a larger cohort may help to clarify the genetic basis of this syndrome, which has not yet been explored (3, 14). Although many cases of C. fetus bacteremia have been reported, few cases of primary agammaglobulinemia associated with Campylobacter bacteremia have been described. Cases of C. jejuni with hypogammaglobulinemia (15), C. coli bacteremia with the absence of opsonizing antibodies (12), C. coli bacteremia with XLA (16) and Helicobacter-like organism with hypogammaglobulinemia (17) have been documented. In summary, we herein reported a case of C. fetus bacteremia with purulent pleurisy presenting with lymphocytedominant pleural. An unusual severe infection of C. fetus led to primary hypogammaglobulinemia in this patient. Primary hypogammaglobulinemia should therefore be included in the differential diagnosis, even in adult patients presenting with severe infection. The administration of adequate intravenous immunoglobulin replacement therapy is warranted in order to minimize the risk of subsequent infection. The authors state that they have no Conflict of Interest (COI). Acknowledgement We are grateful to Mr. Hitoshi Moriuchi and Mrs. Chikako Sakai for their technical assistance and Dr. Katsunobu Yoshioka for the useful comments. References 1. Pacanowski J, Lalande V, Lacombe K, et al. Campylobacter bacteremia: clinical features and factors associated with fatal outcome. Clin Infect Dis 47: , Conley ME, Broides A, Hernandez-Trujillo V, et al. Genetic analysis of patients with defects in early B-cell development. Immunol Rev 203: , Park JH, Resnick ES, Cunningham-Rundles C. Perspectives on common variable immune deficiency. Ann NY Acad Sci 1246: 41-49, Kanegane H, Futatani T, Wang Y, et al. Clinical and mutational characteristics of X-linked agammaglobulinemia and its carrier identified by flow cytometric assessment combined with genetic analysis. J Allergy Clin Immunol 108: , Decousser JW, Prouzet-Mauléon V, Bartizel C, et al. Fatal relapse of a purulent pleurisy caused by Campylobacter fetus subsp. fetus. J Clin Microbiol 45: , Nadir A, Wright HI, Nadir F, Van Thiel DH. Campylobacter fetus presenting as a septic pleural : a case report. J Okla State Med Assoc 87: , Tsuchiya M, Ito T, Yamada T, Yoshida M, Nosaka H, Hiraishi T. Campylobacter fetus ni yoru kyoumakuenn no ichisyourei. Nihon Noson Igakukai Zasshi (Japanese Association of Rural Medicine) 56: 299, 2007 (in Japanese). 8. Inoue Y, Ohtsubo T, Mori N, et al. A case of Campylobacter fetus subspecies fetus meningitis. Kansenshogaku Zasshi 67: 66-70, 1993 (in Japanese, Abstact in English). 9. Tu ZC, Gaudreau C, Blaser MJ. Mechanisms underlying Campylobacter fetus pathogenesis in humans: surface-layer protein variation in relapsing infections. J Infect Dis 191: , Fernández-Cruz A, Muñoz P, Mohedano R, et al. Campylobacter bacteremia: clinical characteristics, incidence, and outcome over 23 years. Medicine (Baltimore) 89: , Tremblay C, Gaudreau C, Lorange M. Epidemiology and antimicrobial susceptibilities of 111 Campylobacter fetus subsp. fetus strains isolated in Québec, Canada, from 1983 to J Clin Microbiol 41: , Neuzil KM, Wang E, Haas DW, Blaser MJ. Persistence of Campylobacter fetus bacteremia associated with absence of opsonizing antibodies. J Clin Microbiol 32: , Fujioka T, Kawashima H, Nishimata S, et al. Atypical case of X- linked agammaglobulinemia diagnosed at 45 years of age. Pediatr Int 53: , Salzer U, Unger S, Warnatz K. Common variable immunodeficiency (CVID): exploring the multiple dimensions of a heterogeneous disease. Ann NY Acad Sci 1250: 41-49, van der Meer JW, Mouton RP, Daha MR, Schuurman RK. Campylobacter jejuni bacteraemia as a cause of recurrent fever in a pa- 1224

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