Clin Rheumatol (2014) 33:415–418 DOI 10.1007/s10067-013-2475-0
BRIEF REPORT
Pneumocystis jirovecii pneumonia in two patients with systemic lupus erythematosus after rituximab therapy F Bonilla-Abadía & J F Betancurt & J C Pineda & J D Vélez & G J Tobón & C A Cañas
Received: 21 January 2013 / Revised: 30 June 2013 / Accepted: 22 December 2013 / Published online: 9 January 2014 # Clinical Rheumatology 2013
Abstract New cases of Pneumocystis jirovecii pneumonia (PJP) have recently been reported in patients with systemic lupus erythematosus (SLE) after rituximab therapy. Several factors may contribute to susceptibility to P. jirovecii infection in this type of patients, including the immunological characteristics of the disease, the mechanisms of rituximab action, environmental factors, and the biological characteristics of the fungus. We report two patients with SLE who developed PJP after rituximab therapy. Keywords Pneumonia . Pneumocystis . Pneumocystis jirovecii . Rituximab . Systemic . Systemic lupus erythematosus
Introduction Systemic lupus erythematosus (SLE) is characterized by loss of self-tolerance associated with activation of autoreactive T and B cells, leading to the production of pathogenic autoantibodies F. Bonilla-Abadía : G. J. Tobón : C. A. Cañas (*) Rheumatology Unit, Cra. 98N. 18-49, Fundación Valle del Lili-ICESI University, Cali, Colombia e-mail: [email protected]
and tissue injury [1]. Rituximab is a chimeric human/murine monoclonal antibody against the B cell-specific antigen CD20. It has been used extensively in the treatment of hematological malignancies and autoimmune diseases, including rheumatoid arthritis (RA), anti-neutrophil cytoplasmic antibody-associated vasculitis, and hepatitis C-associated vasculitis [2–4] and is currently recognized as an adjuvant therapeutic agent in difficult cases of SLE [5]. Rituximab causes rapid depletion of preB and mature B cells, which remain at low or undetectable levels for 2–12 months before returning to pretreatment levels. Evidence suggests that in addition to its effect on B cells, rituximab also influences T cell immunity and predisposes patients to opportunistic infections [6]. Pneumocystis jirovecii pneumonia (PJP) is a serious condition associated with high morbidity and mortality. It frequently develops in patients with human immunodeficiency virus infection with CD4 T cell depletion. However, patients with other types of immunodeficiency and depletion of CD4 T cells are also susceptible to PJP, including those receiving immunosuppressive drugs. PJP has been reported in patients treated with rituximab for lymphoma or some autoimmune diseases, such as RA [7], Wegener's granulomatosis [8], and more recently for SLE [9, 10]. We report two patients with severe SLE who developed PJP after use of rituximab.
C. A. Cañas e-mail: [email protected] J. F. Betancurt Internal Medicine Unit, Fundación Valle del Lili-CES University, Cali, Colombia J. C. Pineda Internal Medicine Unit, Fundación Valle del Lili-ICESI University, Cali, Colombia J. D. Vélez Infectious Diseases Unit, Fundación Valle del Lili, Cali, Colombia
Case reports Case 1 A 20-year-old female patient was diagnosed with SLE 6 years previously, with the following manifestations: class IV glomerulonephritis, lupus pneumonitis, peripheral neuropathy, discoid lupus, hemolytic anemia, and positive antinuclear
416
and anti-Ro antibodies. She had received rituximab pulse therapy consisting of 2 g rituximab (1 g initial dose followed by 1 g 2 weeks later) every 9 months for the last 4 years for refractory disease. She also received prednisone 5 mg/day and azathioprine 50 mg bid. The patient was admitted 1 month after her last rituximab dose because of constitutional symptoms including fatigue, weakness, hyporexia, weight loss, and right upper quadrant abdominal pain with hepatosplenomegaly, pallor, and productive cough. On admission, the physical exam showed the patient to be in an acceptable condition, without dyspnea. Her blood pressure was 120/70 mmHg, her heart rate was 74 beats per minute, her respiratory rate was 18 breaths per minute, and her temperature was 36.8 °C. She had rhythmic heart sounds without murmurs and clear breath sounds to auscultation. She verbalized no pain in her abdomen, had mild hepatomegaly, and had no signs of acute abdomen. No signs of articular or cutaneous lupus activity were evident on physical examination. A complete blood count showed 2,190 cells/mm3, lymphocytes 920 cells/mm3, hemoglobin 10.7 mg/dl, platelets 413,000, creatinine 0.78 mg/dl, albumin 2.5 g/l, C-reactive protein 0.35 mg/dl, and an erythrocyte sedimentation rate of 2 mm/h (normal range, 2–20 mm/h). Clotting studies, aspartate aminotransferase, and alanine aminotransferase levels were all normal. Urinalysis revealed protein 150 mg/dl with normal sediment. Three negative acid-fast bacilli direct smears were reported. High-resolution chest computed tomography (CT) showed ground glass opacities in both lungs (Fig. 1). Bronchoscopy showed mild endobronchitis without active bleeding. Bronchoalveolar lavage was performed, and methenamine silver staining confirmed the presence of P. jirovecii. Polymerase chain reaction was not performed. Staining for bacteria and mycobacteria was negative. Immediate management with clindamycin 600 mg tid and primaquine 15 mg bid was initiated because of an existing sulfa allergy. A bone marrow aspirate and biopsy were performed and showed reduced cellularity and reduced granulocytic series. No bone marrow infiltration was detected. The patient showed a quick resolution of infection symptoms with normalization of liver and spleen functions. She was discharged with ambulatory treatment consisting of 21 days of primaquine and clindamycin.
Clin Rheumatol (2014) 33:415–418
Fig. 1 Thoracic high-resolution computed tomography scan revealing diffuse ground-glass opacities in bilateral lungs in case 1
beats per minute, respiratory rate of 18 breaths per minute, blood pressure of 131/85 mmHg, temperature 37.2 °C, and oxygen saturation of 88 %. Cardiopulmonary auscultation demonstrated tachycardia without murmurs and decreased breath sounds without rales. Her abdomen was non-tender, with no masses or organ enlargement. Articular and cutaneous manifestations were absent. Laboratory tests on admission revealed leukocytes 13,110 cells/mm3, lymphocytes 550 cells/mm3, hemoglobin 9.6 mg/dl, platelets 261,000, urea
Case 2 A 19-year-old female patient had been diagnosed with SLE 2 years previously, with cutaneous and articular involvement and severe renal compromise with chronic renal failure requiring peritoneal dialysis therapy. Polyarthritis and cutaneous vasculitis persisted despite prednisone 25 mg/day, and rituximab infusion was indicated (1 g initial and 1 g 2 weeks after). The patient was admitted 6 weeks later because of a 1-month history of non-productive cough associated with moderate dyspnea, intermittent fever, and malaise. Physical exam on admission revealed Cushing facies. Her vital signs were a heart rate of 138
Fig. 2 Thoracic high-resolution computed tomography scan revealing centrilobular nodules with ground-glass lesions in case 2
Clin Rheumatol (2014) 33:415–418
nitrogen 90 mg/dl, creatinine 16.3 mg/dl, and C-reactive protein 1.61 mg/dl. Blood cultures were negative. Highresolution thoracic CT scan revealed centrilobular nodules and ground-glass type opacities in the lower lobes (Fig. 2). Bronchoscopy and bronchoalveolar lavage were performed and were negative for Gram staining, potassium hydroxide stain, and acid-fast bacilli, but methenamine silver stain revealed the presence of P. jirovecii. Polymerase chain reaction was not performed. Sulfamethoxazole-trimethoprim (800 mg/160 mg) was initiated. However, the patient deteriorated 12 h later, presenting with increasing dyspnea and cyanosis. Pulse oximetry showed an oxygen saturation of 87 %, and arterial blood gas analysis showed a partial pressure of O 2 of 124 mmHg (normal range, 80– 105 mmHg), PCO2 of 31 mmHg (normal range, 35– 45 mmHg), and a methemoglobin concentration of 25.1 % (normal level
BRIEF REPORT
Pneumocystis jirovecii pneumonia in two patients with systemic lupus erythematosus after rituximab therapy F Bonilla-Abadía & J F Betancurt & J C Pineda & J D Vélez & G J Tobón & C A Cañas
Received: 21 January 2013 / Revised: 30 June 2013 / Accepted: 22 December 2013 / Published online: 9 January 2014 # Clinical Rheumatology 2013
Abstract New cases of Pneumocystis jirovecii pneumonia (PJP) have recently been reported in patients with systemic lupus erythematosus (SLE) after rituximab therapy. Several factors may contribute to susceptibility to P. jirovecii infection in this type of patients, including the immunological characteristics of the disease, the mechanisms of rituximab action, environmental factors, and the biological characteristics of the fungus. We report two patients with SLE who developed PJP after rituximab therapy. Keywords Pneumonia . Pneumocystis . Pneumocystis jirovecii . Rituximab . Systemic . Systemic lupus erythematosus
Introduction Systemic lupus erythematosus (SLE) is characterized by loss of self-tolerance associated with activation of autoreactive T and B cells, leading to the production of pathogenic autoantibodies F. Bonilla-Abadía : G. J. Tobón : C. A. Cañas (*) Rheumatology Unit, Cra. 98N. 18-49, Fundación Valle del Lili-ICESI University, Cali, Colombia e-mail: [email protected]
and tissue injury [1]. Rituximab is a chimeric human/murine monoclonal antibody against the B cell-specific antigen CD20. It has been used extensively in the treatment of hematological malignancies and autoimmune diseases, including rheumatoid arthritis (RA), anti-neutrophil cytoplasmic antibody-associated vasculitis, and hepatitis C-associated vasculitis [2–4] and is currently recognized as an adjuvant therapeutic agent in difficult cases of SLE [5]. Rituximab causes rapid depletion of preB and mature B cells, which remain at low or undetectable levels for 2–12 months before returning to pretreatment levels. Evidence suggests that in addition to its effect on B cells, rituximab also influences T cell immunity and predisposes patients to opportunistic infections [6]. Pneumocystis jirovecii pneumonia (PJP) is a serious condition associated with high morbidity and mortality. It frequently develops in patients with human immunodeficiency virus infection with CD4 T cell depletion. However, patients with other types of immunodeficiency and depletion of CD4 T cells are also susceptible to PJP, including those receiving immunosuppressive drugs. PJP has been reported in patients treated with rituximab for lymphoma or some autoimmune diseases, such as RA [7], Wegener's granulomatosis [8], and more recently for SLE [9, 10]. We report two patients with severe SLE who developed PJP after use of rituximab.
C. A. Cañas e-mail: [email protected] J. F. Betancurt Internal Medicine Unit, Fundación Valle del Lili-CES University, Cali, Colombia J. C. Pineda Internal Medicine Unit, Fundación Valle del Lili-ICESI University, Cali, Colombia J. D. Vélez Infectious Diseases Unit, Fundación Valle del Lili, Cali, Colombia
Case reports Case 1 A 20-year-old female patient was diagnosed with SLE 6 years previously, with the following manifestations: class IV glomerulonephritis, lupus pneumonitis, peripheral neuropathy, discoid lupus, hemolytic anemia, and positive antinuclear
416
and anti-Ro antibodies. She had received rituximab pulse therapy consisting of 2 g rituximab (1 g initial dose followed by 1 g 2 weeks later) every 9 months for the last 4 years for refractory disease. She also received prednisone 5 mg/day and azathioprine 50 mg bid. The patient was admitted 1 month after her last rituximab dose because of constitutional symptoms including fatigue, weakness, hyporexia, weight loss, and right upper quadrant abdominal pain with hepatosplenomegaly, pallor, and productive cough. On admission, the physical exam showed the patient to be in an acceptable condition, without dyspnea. Her blood pressure was 120/70 mmHg, her heart rate was 74 beats per minute, her respiratory rate was 18 breaths per minute, and her temperature was 36.8 °C. She had rhythmic heart sounds without murmurs and clear breath sounds to auscultation. She verbalized no pain in her abdomen, had mild hepatomegaly, and had no signs of acute abdomen. No signs of articular or cutaneous lupus activity were evident on physical examination. A complete blood count showed 2,190 cells/mm3, lymphocytes 920 cells/mm3, hemoglobin 10.7 mg/dl, platelets 413,000, creatinine 0.78 mg/dl, albumin 2.5 g/l, C-reactive protein 0.35 mg/dl, and an erythrocyte sedimentation rate of 2 mm/h (normal range, 2–20 mm/h). Clotting studies, aspartate aminotransferase, and alanine aminotransferase levels were all normal. Urinalysis revealed protein 150 mg/dl with normal sediment. Three negative acid-fast bacilli direct smears were reported. High-resolution chest computed tomography (CT) showed ground glass opacities in both lungs (Fig. 1). Bronchoscopy showed mild endobronchitis without active bleeding. Bronchoalveolar lavage was performed, and methenamine silver staining confirmed the presence of P. jirovecii. Polymerase chain reaction was not performed. Staining for bacteria and mycobacteria was negative. Immediate management with clindamycin 600 mg tid and primaquine 15 mg bid was initiated because of an existing sulfa allergy. A bone marrow aspirate and biopsy were performed and showed reduced cellularity and reduced granulocytic series. No bone marrow infiltration was detected. The patient showed a quick resolution of infection symptoms with normalization of liver and spleen functions. She was discharged with ambulatory treatment consisting of 21 days of primaquine and clindamycin.
Clin Rheumatol (2014) 33:415–418
Fig. 1 Thoracic high-resolution computed tomography scan revealing diffuse ground-glass opacities in bilateral lungs in case 1
beats per minute, respiratory rate of 18 breaths per minute, blood pressure of 131/85 mmHg, temperature 37.2 °C, and oxygen saturation of 88 %. Cardiopulmonary auscultation demonstrated tachycardia without murmurs and decreased breath sounds without rales. Her abdomen was non-tender, with no masses or organ enlargement. Articular and cutaneous manifestations were absent. Laboratory tests on admission revealed leukocytes 13,110 cells/mm3, lymphocytes 550 cells/mm3, hemoglobin 9.6 mg/dl, platelets 261,000, urea
Case 2 A 19-year-old female patient had been diagnosed with SLE 2 years previously, with cutaneous and articular involvement and severe renal compromise with chronic renal failure requiring peritoneal dialysis therapy. Polyarthritis and cutaneous vasculitis persisted despite prednisone 25 mg/day, and rituximab infusion was indicated (1 g initial and 1 g 2 weeks after). The patient was admitted 6 weeks later because of a 1-month history of non-productive cough associated with moderate dyspnea, intermittent fever, and malaise. Physical exam on admission revealed Cushing facies. Her vital signs were a heart rate of 138
Fig. 2 Thoracic high-resolution computed tomography scan revealing centrilobular nodules with ground-glass lesions in case 2
Clin Rheumatol (2014) 33:415–418
nitrogen 90 mg/dl, creatinine 16.3 mg/dl, and C-reactive protein 1.61 mg/dl. Blood cultures were negative. Highresolution thoracic CT scan revealed centrilobular nodules and ground-glass type opacities in the lower lobes (Fig. 2). Bronchoscopy and bronchoalveolar lavage were performed and were negative for Gram staining, potassium hydroxide stain, and acid-fast bacilli, but methenamine silver stain revealed the presence of P. jirovecii. Polymerase chain reaction was not performed. Sulfamethoxazole-trimethoprim (800 mg/160 mg) was initiated. However, the patient deteriorated 12 h later, presenting with increasing dyspnea and cyanosis. Pulse oximetry showed an oxygen saturation of 87 %, and arterial blood gas analysis showed a partial pressure of O 2 of 124 mmHg (normal range, 80– 105 mmHg), PCO2 of 31 mmHg (normal range, 35– 45 mmHg), and a methemoglobin concentration of 25.1 % (normal level
