A seventy-eight-year-old Japanese woman with seropositive RA, diagnosed in 1998 based on the ACR 1987 criteria, underwent sulphasalazine (SASP) therapy before she visited our institute. In 2008 she was started on methotrexate (MTX) and low-dose prednisolone (PSL) therapies.
Despite administration of low-dose therapies of MTX (6 mg/week), SASP (500 mg/day), and PSL (2.5 mg/day), because of her age and history of drug intolerance, her RA disease activity remained high [tender joint count, 4/28, and swollen joint count, 11/28; patient global assessment score, 72 mm/100 mm; C-reactive protein (CRP), 2.55 mg/dL; erythrocyte sedimentation rate (ESR), 52 mm/hour; matrix metalloproteinase- 3, 71.7 ng/mL; and disease activity score 28-ESR, 5.82].
The patient was elderly and had a long-term smoking habit. Furthermore, she had pulmonary emphysema and slight fibrosis in her bilateral lower lungs, and her sister had previously suffered from tuberculosis. However, the patient had no other lung diseases, including tuberculosis (negative result on the tuberculin test quanti-FERON), no medical history of any viral infection, was not a hepatitis B virus carrier, and showed normal serum KL-6 and beta-D-glucan levels (410 U/mL and <2.84 pg/mL, respectively). She had also not undergone any surgery. Therefore, we decided to include anti-TNF therapy along with her current therapy after giving isoniazid (INH) 300 mg/day for three months.
ADA at a dose of 40 mg was introduced in addition to MTX (6 mg/week), SASP (500 mg/day), PSL (2.5 mg/day), and folic acid (5 mg/week) in June 2011. She experienced excellent pain relief in her joints after her first subcutaneous ADA injection, with no immediate adverse effects; her second injection was therefore safely administered two weeks after her first injection.
Eight days after her second ADA injection, she had fever (38.6  C), fatigue, and bloody sputum for two consecutive days; thereafter, she was admitted to our hospital. At that time, we first heard that she regularly visited a public bath and had continued to do so after ADA treatment.
On admission (day 0, 8 days after her second ADA injection), her body temperature was 38.6  C and she was slightly tachycardic (96 beats/minute) with a blood pressure of 142/68 mmHg. Her heart sounds were normal, and she had neither chest pain nor visible rash. However, coarse crackles were audible in her right lower lung, and oxygen monitoring showed hypoxemia (SpO2, 92%). Her joints were not swollen, painful, or warm, so we did not consider this state as a flare of RA. On the other hand, laboratory data showed marked acute inflammation (CRP, 27.05 mg/dL; white blood cell count, 20,600/mm3) and a positive urine L. pneumophila antigen test (Binax, Portland, OR, USA). However, her serum beta-D-glucan levels were normal (<3.30 pg/mL). In addition, her expectoration culture, collected two days later, was weakly positive for Haemophilus influenzae (BLNAR).
Chest X-ray showed a permeation shadow in her right lower lung, and chest computed tomography (CT) showed pleural thickening, light ground glass opacities (GGOs) right under the pleura, and consolidation with an air bronchogram in the right S6, S9, and S10 segments without fibrotic change from her baseline lung (Fig. 1). Two blood cultures taken at day 0 revealed no sepsis.
The patient was clinically diagnosed with pneumonia caused by L. pneumophila affecting her originally fibrotic RA lungs.
She was then admitted and given intravenous pazufloxacin (PZFX) 1000 mg/day (after an initial administration of 2 g twice daily at days 0 and 1) for 10 consecutive days. She showed remarkable recovery after being injected with PZFX and was discharged on day 10. Of course, she was forbidden to visit any public bath.
After discharge from our hospital, we confirmed her seroconversion of L. pneumophila and complete healing of pneumonia on chest CT. MTX (6 mg/week) and PSL (5 mg/day) therapies were then restarted without ADA because of an increase in her RA disease activity at day 20. However, pneumonia relapsed at day 55 along with loss of appetite, fatigue, and coughing. Laboratory data showed acute inflammation (CRP, 13.09 mg/dL; white blood cell count, 10,500/mm3), and her urine L. pneumophila antigen test (Binax) was again positive. In addition, both her serum KL-6 and beta-D-glucan levels were high (815 U/mL and 29.56 pg/mL, respectively) unlike before. Blood gas data showed severe hypoxemia (PO2, 47.5 mmHg; PCO2, 29.5 mmHg). Chest CT findings showed multifocal consolidation with GGO extending to the bilateral lower aggravated fibrotic lungs (Fig. 2A and B) unlike pneumocystis pneumonia (PCP), which mostly showed diffuse GGO of the bilateral lungs. Furthermore, neither DNA of Pneumocystis jiroveci from bronchoalveolar lavage fluid (BALF) nor serum Cryptococcus and Aspergillus antigens were positive. We could not detect any bacteria from her BALF culture. On the other hand, serum Candida antigen and culture of Candida albicans were positive. On the basis of these findings, we diagnosed a relapse of L. pneumophila pneumonia with deep mycosis (eg, Candida infection) and interstitial pneumonia (IP). The patient's lungs were previously affected by RA, but not PCP. Unfortunately, although we tried every possible treatment, the patient eventually died of aggravated IP on day 79 (KL-6, 5030 U/mL; beta-D-glucan, 8.05 pg/mL at day 72).
Day 55. (A) Computed tomography of the chest at the time of relapse. Same slice as shown in Figure 1. Consolidation appeared in the right S6 and S9 segments and GGO appeared in multiple affected segments. Lower slice of (A). Multifocal consolidation with GGO extending to both of the lower fibrotic lungs.