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Pneumocystosis in a patient with Crohn's disease treated with combination therapy with adalimumab
Journal of Crohn's and Colitis (2012) 6, 483–487
Available online at www.sciencedirect.com
SHORT REPORT
Pneumocystosis in a patient with Crohn's disease treated with combination therapy with adalimumab Ana L. Desales a , Jorge Mendez-Navarro a,⁎, Luis J. Méndez-Tovar b , Nayeli X. Ortiz-Olvera a , Garret Cullen c , Joaquín Ocampo d , Willian Lemus a , Amina E. Tun a , Arturo Mayoral-Zavala a , Margarita Dehesa-Violante a Gastroenterology Department, National Medical Center, Hospital de Especialidades, CMN “Siglo XXI,” IMSS, Mexico City, Mexico b Medical Research Laboratory in Dermatology and Mycology, National Medical Center, Hospital de Especialidades, CMN “Siglo XXI,” IMSS, Mexico City, Mexico c Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center, Boston, MA, USA d Internal Medicine Department, National Medical Center, Hospital de Especialidades, CMN “Siglo XXI,” IMSS, Mexico City, Mexico a
Received 8 September 2011; received in revised form 25 October 2011; accepted 26 October 2011
KEYWORDS PCP; Adalimumab; Crohn's disease; Pneumonia; Opportunistic infections; Anti-TNF
Abstract Pneumocystis jirovecii pneumonia (PCP) is a potential complication of immunosuppression. Crohn's disease (CD) is an immune granulomatous disorder characterized by transmural inflammation that can affect any part of the gastrointestinal tract. Its treatment is based on steroids and immunosuppressants but in non-responders, biologic compounds such as anti-tumor necrosis factor alpha (TNF) antibodies have been used. Neutralization of TNF causes a decrease in the inflammatory response but increases susceptibility to opportunistic infections such as fungal infections. We report a young male with chronic diarrhea, fever and weight loss who was diagnosed with CD and began conventional treatment with immunosuppressants, but due to lack of response after several weeks, biologic therapy with adalimumab was initiated. Seven weeks later he developed persistent fever and upper respiratory symptoms. After chest CT, bronchoscopy and bronchial lavage, P. jirovecii was identified by silver staining and confirmed by immunofluorescence. To our knowledge this is the second case of pneumocystosis associated with the use of adalimumab
Abbreviations: PCP, Pneumocystis jirovecii pneumonia; CD, Crohn's disease; TNF, tumor necrosis factor alpha; ESR, erythrocyte sedimentation rate. ⁎ Corresponding author at: Departamento de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, Av. Cuauhtémoc 330, Col. Doctores, 06725 México, DF, México. Tel.: + 52 55 56 27 69 00x21565. E-mail address: [email protected] (J. Mendez-Navarro). 1873-9946/$ - see front matter © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.crohns.2011.10.012
484
A.L. Desales et al. in CD and the first reported Mexican case confirmed by microbiological and immunological studies in this setting. © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
1. Introduction Pneumocystosis is an opportunistic infection caused by Pneumocystis jirovecii (PCP), formerly called Pneumocystis carinii. This infection was rare between 1950 and 1979, when it was mainly diagnosed in patients with severe malnutrition, cancer, post-transplant, chemotherapy, high dose steroids and immunosuppressants. 1,2 With the onset of the AIDS pandemic in the 1980s, the frequency of PCP infection increased to 80%, especially when CD4 counts were b 100 cells/mL. 3 With the advent of highly effective antiretroviral therapy and sulfa prophylaxis, the number of cases decreased significantly. 3 Crohn's disease (CD) is an immune granulomatous disorder characterized by focal, asymmetric transmural inflammation that can affect any part of the gastrointestinal tract. 4,5 Conventional medical therapy includes corticosteroids and immunosuppressants; in non-responders biologic compounds such as the tumor necrosis factor alpha (TNF) inhibitors, are indicated. 6,7 Since 1983, there have been reports of opportunistic infections including pneumocystis in patients with CD treated with immunosuppressants 8 and more recently with the use of anti-TNF. 9,10 In Mexico there is little information on pneumocystosis associated with biologics and CD. We report a case of PCP in a patient with CD treated with combination therapy using adalimumab, azathioprine and prednisone confirmed by microbiological and immunological tests.
2. Case report A 36-year-old male presented with 20 kg weight loss, diarrhea, fever up to 39 °C (102.2 °F), nausea with occasional vomiting, myalgia, arthralgia and oral aphthous lesions. His past medical history was remarkable only for a family member with colon cancer and a positive smoking history (15 cigarettes per day for the last 15 years). Colonoscopy, performed 3 weeks later, showed nodular erythematous mucosa with confluent excavated aphthous ulcers alternating with healthy areas. Biopsies confirmed Crohn's disease with moderate activity; Ziehl–Neelsen and PAS were negative. Four weeks after onset of symptoms he was treated with mesalazine 3 g/day, azathioprine 150 mg/day and prednisone 50 mg/day. Despite this, symptoms persisted, with fever of 38.5 °C (101.3 °F), abdominal pain, diarrhea and episcleritis. Adalimumab (Humira, Abbott, Mexico City) 160 mg subcutaneous at week 0, 80 mg at week 2, and 40 mg at weeks 4, 6 and 8 was commenced, 7 weeks after the initial onset of symptoms. Prednisone was tapered to 10 mg/day. The patient responded clinically to adalimumab after the third dose. Between the seventh and eight week after the first dose of adalimumab, the patient developed intermittent fever between 38.5 °C and 40 °C (101.3 to 104 °F), accompanied by
chills, sweating, and occasional cough, runny nose, sore throat and weight loss (3 kg in 2 weeks). The patient remembers having spent several hours working under an air conditioner, a day before he developed fever. The fever persisted despite outpatient treatment with ciprofloxacin and he was hospitalized. His physical exam revealed heart rate of 98 beats/minute, respiratory rate of 20 breaths/minute and temperature of 39 °C (102.2 °F). The oropharynx, chest and abdomen were normal. The relevant test results were leucopenia of 1400 10 3/μL, total neutrophils 520 10 3/μL, lymphopenia of 0.31 10 3/μL, hemoglobin 8.8 g/dL, albumin 2.7 g/L, C-reactive protein 25 mg/dL and erythrocyte sedimentation rate (ESR) 115 mm. Tests for toxoplasmosis, cytomegalovirus, herpes simplex and Epstein–Barr virus were negative. Arterial blood gas was pH 7.43, PaO2 92 mmHg, PaCO2 35 mmHg, HCO3 23 mmol/L, oxygen saturation 98%. The pharyngeal exudate, acid-fast bacillus in sputum and blood/urine cultures were negative. The laboratory tests are shown in Table 1 . The initial chest X-ray was normal (Figure 1A); computed tomography chest scan identified lung parenchyma with axial interstitial thickening, increased central bronchovascular areas and ground-glass opacity with interlobular septa predominating in both bases (Figure 1B and C). Azathioprine, adalimumab and prednisone were stopped, filgrastim (granulocyte colony-stimulating factor) was initiated, and he also received imipenem plus clarithromycin. Despite improvement in leucopenia and neutropenia the patient persisted with fever N38.5 °C (101.3 °F). A bronchoscopy was performed which showed no bronchoalveolar abnormalities; culture and cytology were negative. Silver staining on bronchial lavage was performed observing structures compatible with P. jirovecii (Figure 2A); direct immunofluorescence for Pneumocystis was positive (Figure 2B). Trimethoprim–sulfamethoxazole 15 mg/kg/day was started with satisfactory response. After 7 days a repeat chest CT showed marked improvement (Figure 1D and E). Treatment was continued for 21 days and the patient was discharged with his immunosuppression on hold.
3. Discussion Studies about the pathogenesis of CD have demonstrated dysfunction of the intestinal immune system associated with an imbalance in the regulation of T helper cells (Th), leukocytes, cytokines, tissue repair molecules and overproduction of TNF by monocytes and macrophages in the deep layers of the lamina propria and submucosa. 11 Currently it is known that TNF plays an important role in the formation of granulomas, apoptosis, cytokine production (IL-1, IL-6 and IL-8), γ-interferon, adhesion molecules and monocyte chemo-attractant proteins. 12 The antagonism of TNF causes a decrease in the inflammatory response that increases susceptibility to opportunistic infections, including fungal infections. 13
Pneumocystosis in Crohn Table 1
485
Evolution of laboratory test.
Parameter
16/Jul/ 2010
09/Aug/ 2010
Event
Start AZA, PDN 9400 12 690 7.5 1.29 0.51 0.04 4.5 91
After 1st dose ADA 10,100 11.6 607 6.8 2.61 0.72 0
5800 11.3 642 3.82 1.63 0.31 0
94
96
WBC Hemoglobin Platelets Neutrophils Lymphocytes Monocytes Eosinophils CRP MCV (fL)
06/Sept/ 2010
05/Oct/ 2010
11/Oct/ 2010
Resp. S
In-patient
3100 11.1 299 1.36 1.72 0.04 0.01
1700 8.8 167 0.52 1.2 0.14 0.03
13/Oct/ 2010
15/Oct/ 2010
18/Oct/ 2010
12/Nov/ 2010
20/Jan/ 2011
10,100 10.0 420 3.7 4.0 1.3 0.02
10,000 14.3 331 6.2 3.65 0.72 0.06 2.0 91
D/C 1400 8.4 160 0.76 0.31 0.13 0.01 25 96
1920 9.8 178 0.57 0.14 0.07 0.02 94
4600 9.4 207 1.77 1.21 0.14 0.0 10.3 94
104
3
WBC, neutrophils, lymphocytes, monocytes, eosinophils and platelets are reported as x10 /μL; hemoglobin as g/dL and CPR as mg/dL. WBC, white blood cells; MCV, mean cell volume; CRP, C-reactive protein; AZA, azathioprine; PDN, prednisone; ADA, adalimumab; Resp. S, respiratory symptoms; D/C, discharge.
Adalimumab, a recombinant human monoclonal antibody (IgG1) against TNF, has been approved as second-line treatment for CD with moderate to severe activity, treatment failure or intolerance to infliximab. 14–16 Despite the benefits of biological treatment such as anti-TNFs, they increase the risk of infection by intracellular pathogens, granulomatous infections, protozoa, mycobacteria, cytomegalovirus, listeriosis, aspergillosis, histoplasmosis, hepatitis B reactivation, among others. 16–18 Moreover, the concomitant use of corticosteroids as a third immunosuppressive agent can increase the relative risk of serious and opportunistic infections. 7,12 A review by Tsiodras et al. 12 identified 282 cases of invasive fungal infection associated with TNF inhibitors, and
found 226 cases with infliximab (80%) and 11 cases (4%) with adalimumab (4 cases of Histoplasma, 2 Aspergillus, 2 Candida, 1 Cryptococcus, 1 tinea and 1 Pityriasis versicolor). In 98% of the cases, patients were receiving at least another immunomodulatory medication (corticosteroids, methotrexate or thiopurines) during the course of infection. The incidence of serious infections in patients with inflammatory bowel disease is 2–5.8%. 7,19 Inflammatory autoimmune diseases account for almost 20% of PCP infection in HIV-negative patients, with a mortality that can exceed 50%. 11,20,21 Colombel et al. 19 evaluated the safety profile of adalimumab in six international clinical trials with more than 3160 patients and did not identify any cases of PCP.
Figure 1 Imaging studies before diagnosis and after treatment. A) Chest radiograph on admission. B and C) High-resolution computed tomography (CT) prior to diagnosis with the typical image of ground-glass opacities and interlobular septa. D and E) CT after 1 week of treatment with radiographic improvement.
486
A.L. Desales et al.
Figure 2 Pictures of microbiology and immunology. A) Bronchoalveolar lavage smears with silver stain (Groccott) with round brown 6 to 8 micrometers structures corresponding to Pneumocystis jirovecii asci or sexual spore-bearing cells. B) Direct immunofluorescence test of bronchoalveolar lavage positive to P. jirovecii with the typical clear-cut round shaped apple-green fluorescence structures of 4 to 5 micrometers in chains.
One case was reported with adalimumab and CD 22 but our case is the second (first in Mexico) and is a complete case with confirmatory diagnostic testing. This patient was started on steroids and azathioprine for moderate activity of CD, but after 2 months and persistence of moderate to severe intestinal symptoms, biologic was started. This combination improved his CD, but increased susceptibility to opportunistic diseases. Another factor that may have contributed to the PCP was the severe neutropenia probably associated with the use of azathioprine. Risk factors for PCP in patients with inflammatory diseases treated with anti-TNFs include concomitant use of corticosteroids (especially N 8 weeks), advanced age (N 65 years), lung disease or fibrosis, leucopenia b500/μL, hypoalbuminemia and lymphopenia. 20,23 The patient described in this report had corticosteroid use, leucopenia, lymphopenia and hypoalbuminemia as risk factors. AntiTNF can decrease CD4 lymphocytes and agranulocytosis has been also reported. 10,23 The interval identified between the first infusion and the start of the PCP has been reported between 9 and 14 weeks. 10,20 In our case, we observed a time interval of 8 weeks. In our case, the definitive diagnosis of P. jirovecii was made by Grocott–Gomori staining and immunofluorescence in a respiratory sample. The patient presented with fever and neutropenia without any low respiratory symptoms to suspect PCP, but due to the use of combination immunosuppression, with consequent severe neutropenia, an opportunistic disease was suspected as the cause of persistent fever. There are no established criteria for PCP prophylaxis in HIVnegative patients; prophylaxis is prescribed inconsistently in only 25% of patients using immunosuppressants. The first-line agent is trimethoprim–sulfamethoxazole; the dosage ranges from 80–400 mg to 800–160 mg/day or 3 times a week; 21,24 pentamidine and dapsone 100 mg/day can be used as a second option, although clindamycin/primaquine appears to be superior. 25 Biologic agents such as adalimumab are a promising alternative in the management of a number of inflammatory diseases including IBD. However, this case reminds us that serious opportunistic infections can occur, particularly in the context of combination immunosuppression. The American Gastroenterology Association (AGA) 16 and the Mexican guidelines 15 on the use of biologics and IBD do
not specifically recommend antifungal prophylaxis in immunosuppressed patients. The only recommendation before starting anti-TNF therapy is to perform a tuberculin skin test (PPD) and chest radiograph as was done in our patient. The European Crohn's and Colitis Organization (ECCO) in their most recent guidelines on infections and IBD does recommend prophylaxis in those on triple immunosuppression therapy, although they highlight the fact that cases of PCP have been reported in anti-TNF monotherapy, thiopurine monotherapy and/or steroid monotherapy and so this infection is not exclusive to those on combination immunosuppression. 26 It is important to remain alert to the possibility of such infections in any immunosuppressed patient.
Conflict of interest statement None has been declared.
Acknowledgements and disclosures Ana L. Desales, Jorge Mendez-Navarro, Luis J. Méndez-Tovar, Nayeli X. Ortiz-Olvera, Garret Cullen, Joaquín Ocampo, Willian Lemus, Amina E. Tun, Arturo Mayoral-Zavala, and Margarita Dehesa-Violante have nothing to disclose.
References 1. Russian DA, Levine SJ. Pneumocystis carinii pneumonia in patients without HIV infection. Am J Med Sci 2001;321:56–65. 2. Thomas Jr CF, Limper AH. Pneumocystis pneumonia. N Engl J Med 2004;350:2487–98. 3. Cheng CY, Chen MY, Hsieh SM, Sheng WH, Sun HY, Lo YC, et al. Risk of pneumocystosis after early discontinuation of prophylaxis among HIV-infected patients receiving highly active antiretroviral therapy. BMC Infect Dis 2010;10:126–33. 4. Sands BE. Inflammatory bowel disease: past, present, and future. J Gastroenterol 2007;42:16–25. 5. Lichtenstein GR, Hanauer SB, Sandborn WJ. Management of Crohn's disease in adults. Am J Gastroenterol 2009;104:465–83. 6. Rutgeerts P, Assche G, Vermeire S. Optimizing anti-TNF treatment in inflammatory bowel disease. Gastroenterology 2004;126: 1593–610.
Pneumocystosis in Crohn 7. Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, et al. Infliximab, azathioprine or combination therapy for Crohn's disease. N Engl J Med 2010;362: 1383–95. 8. Peters JW, Sattler FR. Atypical Pneumocystis carinii pneumonia: the potential hazards of empiric treatment. South Med J 1983;76:800–3. 9. Seddik M, Meliez H, Seguy D, Viget N, Cortot A, Colombel JF. Pneumocystis carini pneumonia following initiation of infliximab and azathioprine therapy with Crohn's disease. Inflamm Bowel Dis 2004;49:1438–60. 10. Kaur N, Mahl TC. Pneumocystis jiroveci (carinii) pneumonia after infliximab therapy: a review of 84 cases. Dig Dis Sci 2007;52:1481–4. 11. Lee TW, Fedorak RN. Tumor necrosis factor α monoclonal antibodies in the treatment of inflammatory bowel disease: clinical practice pharmacology. Gastroenterol Clin North Am 2010:543–57. 12. Tsiodras S, Samonis G, Boumpas DT, Kontoyiannis DP. Fungal infections complicating tumor necrosis factor α blockade therapy. Mayo Clin Proc 2008;83:181–94. 13. Reenaers C, Louis E, Belaiche J. Current directions of biologic therapies in inflammatory bowel diseases. Ther Adv Gastroenterol 2010;3:99–106. 14. Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease : the CHARM trial. Gastroenterology 2007;132:52–65. 15. Yamamoto-Furusho JK, Bosques-Padilla F. Consenso mexicano sobre el uso de agentes anti-TNF-α en el tratamiento de la enfermedad inflamatoria intestinal. Rev Gastroenterol Mex 2009;74:265–78. 16. Clark M, Colombel JF, Feagan BC, Fedorak RN, Hanauer SB, Kamm MA, et al. American gastroenterological association consensus development conference on the use of biologics in the treatment of inflammatory bowel disease, June 21–23, 2006. Gastroenterology 2007;133:312–39. 17. Méndez-Navarro J, Corey KE, Zheng H, Barlow LL, Jang JY, Lin W, et al. Hepatitis B Screening, prophylaxis and reactivation in the era of rituximab-based chemotherapy. Liver Int 2011;31:330–9.
487 18. Verhelst X, Orlent H, Colle I, Geerts A, De Vos M, Van Vlierberghe H. Subfulminant hepatitis B during treatment with adalimumab in a patient with rheumatorid arthritis and chronic hepatitis B. Eur J Gastroenterol Hepatol 2010;22:494–9. 19. Colombel JF, Sandborn WJ, Panaccione R, Robinson AM, Lau W, Li J, et al. Adalimumab safety in global clinical trials of patients with Crohn's disease. Inflamm Bowel Dis 2009;15:1308–19. 20. Komano Y, Harigai M, Koike R, Sugiyama H, Ogawa J, Saito K, et al. Pneumocystis jiroveci pneumonia in patients with Rheumatoid Arthritis treated with infliximab: a retrospective review and case–control study of 21 patients. Arthritis Rheum 2009;61:305–12. 21. Itaba S, Iwasa T, Sadamoto Y, Nasu T, Misawa T, Inoue K, et al. Pneumocystis pneumonia during combined therapy of infliximab, corticosteroid and azathioprine in a patient with Crohn's disease. Dig Dis Sci 2007;52:1438–41. 22. Lawrance IC, Radford-Smith GL, Bampton PA, Andrews JM, Tan PK, Croft A, et al. Serious infections in patients with inflammatory bowel disease receiving anti-tumor-necrosis-factor-alpha therapy: an Australian and New Zealand experience. J Gastroenterol Hepatol 2010;25:1732–8. 23. Cottone M, Kohn A, Daperno M, Armuzzi A, Guidi L, D´Inca R, et al. Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease. Clin Gastroenterol Hepatol 2011;9:30–5. 24. Roblot F. Management of Pneumocystis pneumonia in patients with inflammatory disorders. Expert Rev Anti Infect Ther 2005;3:1098–107. 25. Helweg-Larsen J, Benfield T, Atzori C, Miller RF. Clinical efficacy of first-and second-line treatments for HIV-associated Pneumocystis jirovecii pneumonia: a tri-centre cohort study. JAC 2009;64:1282–90. 26. Rahier JF, Ben-Horin S, Chowers Y, Conlon C, De Munter P, D´Haens G, et al. European evidence-based Consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis 2009;3:47–91.
Available online at www.sciencedirect.com
SHORT REPORT
Pneumocystosis in a patient with Crohn's disease treated with combination therapy with adalimumab Ana L. Desales a , Jorge Mendez-Navarro a,⁎, Luis J. Méndez-Tovar b , Nayeli X. Ortiz-Olvera a , Garret Cullen c , Joaquín Ocampo d , Willian Lemus a , Amina E. Tun a , Arturo Mayoral-Zavala a , Margarita Dehesa-Violante a Gastroenterology Department, National Medical Center, Hospital de Especialidades, CMN “Siglo XXI,” IMSS, Mexico City, Mexico b Medical Research Laboratory in Dermatology and Mycology, National Medical Center, Hospital de Especialidades, CMN “Siglo XXI,” IMSS, Mexico City, Mexico c Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center, Boston, MA, USA d Internal Medicine Department, National Medical Center, Hospital de Especialidades, CMN “Siglo XXI,” IMSS, Mexico City, Mexico a
Received 8 September 2011; received in revised form 25 October 2011; accepted 26 October 2011
KEYWORDS PCP; Adalimumab; Crohn's disease; Pneumonia; Opportunistic infections; Anti-TNF
Abstract Pneumocystis jirovecii pneumonia (PCP) is a potential complication of immunosuppression. Crohn's disease (CD) is an immune granulomatous disorder characterized by transmural inflammation that can affect any part of the gastrointestinal tract. Its treatment is based on steroids and immunosuppressants but in non-responders, biologic compounds such as anti-tumor necrosis factor alpha (TNF) antibodies have been used. Neutralization of TNF causes a decrease in the inflammatory response but increases susceptibility to opportunistic infections such as fungal infections. We report a young male with chronic diarrhea, fever and weight loss who was diagnosed with CD and began conventional treatment with immunosuppressants, but due to lack of response after several weeks, biologic therapy with adalimumab was initiated. Seven weeks later he developed persistent fever and upper respiratory symptoms. After chest CT, bronchoscopy and bronchial lavage, P. jirovecii was identified by silver staining and confirmed by immunofluorescence. To our knowledge this is the second case of pneumocystosis associated with the use of adalimumab
Abbreviations: PCP, Pneumocystis jirovecii pneumonia; CD, Crohn's disease; TNF, tumor necrosis factor alpha; ESR, erythrocyte sedimentation rate. ⁎ Corresponding author at: Departamento de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, Av. Cuauhtémoc 330, Col. Doctores, 06725 México, DF, México. Tel.: + 52 55 56 27 69 00x21565. E-mail address: [email protected] (J. Mendez-Navarro). 1873-9946/$ - see front matter © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.crohns.2011.10.012
484
A.L. Desales et al. in CD and the first reported Mexican case confirmed by microbiological and immunological studies in this setting. © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
1. Introduction Pneumocystosis is an opportunistic infection caused by Pneumocystis jirovecii (PCP), formerly called Pneumocystis carinii. This infection was rare between 1950 and 1979, when it was mainly diagnosed in patients with severe malnutrition, cancer, post-transplant, chemotherapy, high dose steroids and immunosuppressants. 1,2 With the onset of the AIDS pandemic in the 1980s, the frequency of PCP infection increased to 80%, especially when CD4 counts were b 100 cells/mL. 3 With the advent of highly effective antiretroviral therapy and sulfa prophylaxis, the number of cases decreased significantly. 3 Crohn's disease (CD) is an immune granulomatous disorder characterized by focal, asymmetric transmural inflammation that can affect any part of the gastrointestinal tract. 4,5 Conventional medical therapy includes corticosteroids and immunosuppressants; in non-responders biologic compounds such as the tumor necrosis factor alpha (TNF) inhibitors, are indicated. 6,7 Since 1983, there have been reports of opportunistic infections including pneumocystis in patients with CD treated with immunosuppressants 8 and more recently with the use of anti-TNF. 9,10 In Mexico there is little information on pneumocystosis associated with biologics and CD. We report a case of PCP in a patient with CD treated with combination therapy using adalimumab, azathioprine and prednisone confirmed by microbiological and immunological tests.
2. Case report A 36-year-old male presented with 20 kg weight loss, diarrhea, fever up to 39 °C (102.2 °F), nausea with occasional vomiting, myalgia, arthralgia and oral aphthous lesions. His past medical history was remarkable only for a family member with colon cancer and a positive smoking history (15 cigarettes per day for the last 15 years). Colonoscopy, performed 3 weeks later, showed nodular erythematous mucosa with confluent excavated aphthous ulcers alternating with healthy areas. Biopsies confirmed Crohn's disease with moderate activity; Ziehl–Neelsen and PAS were negative. Four weeks after onset of symptoms he was treated with mesalazine 3 g/day, azathioprine 150 mg/day and prednisone 50 mg/day. Despite this, symptoms persisted, with fever of 38.5 °C (101.3 °F), abdominal pain, diarrhea and episcleritis. Adalimumab (Humira, Abbott, Mexico City) 160 mg subcutaneous at week 0, 80 mg at week 2, and 40 mg at weeks 4, 6 and 8 was commenced, 7 weeks after the initial onset of symptoms. Prednisone was tapered to 10 mg/day. The patient responded clinically to adalimumab after the third dose. Between the seventh and eight week after the first dose of adalimumab, the patient developed intermittent fever between 38.5 °C and 40 °C (101.3 to 104 °F), accompanied by
chills, sweating, and occasional cough, runny nose, sore throat and weight loss (3 kg in 2 weeks). The patient remembers having spent several hours working under an air conditioner, a day before he developed fever. The fever persisted despite outpatient treatment with ciprofloxacin and he was hospitalized. His physical exam revealed heart rate of 98 beats/minute, respiratory rate of 20 breaths/minute and temperature of 39 °C (102.2 °F). The oropharynx, chest and abdomen were normal. The relevant test results were leucopenia of 1400 10 3/μL, total neutrophils 520 10 3/μL, lymphopenia of 0.31 10 3/μL, hemoglobin 8.8 g/dL, albumin 2.7 g/L, C-reactive protein 25 mg/dL and erythrocyte sedimentation rate (ESR) 115 mm. Tests for toxoplasmosis, cytomegalovirus, herpes simplex and Epstein–Barr virus were negative. Arterial blood gas was pH 7.43, PaO2 92 mmHg, PaCO2 35 mmHg, HCO3 23 mmol/L, oxygen saturation 98%. The pharyngeal exudate, acid-fast bacillus in sputum and blood/urine cultures were negative. The laboratory tests are shown in Table 1 . The initial chest X-ray was normal (Figure 1A); computed tomography chest scan identified lung parenchyma with axial interstitial thickening, increased central bronchovascular areas and ground-glass opacity with interlobular septa predominating in both bases (Figure 1B and C). Azathioprine, adalimumab and prednisone were stopped, filgrastim (granulocyte colony-stimulating factor) was initiated, and he also received imipenem plus clarithromycin. Despite improvement in leucopenia and neutropenia the patient persisted with fever N38.5 °C (101.3 °F). A bronchoscopy was performed which showed no bronchoalveolar abnormalities; culture and cytology were negative. Silver staining on bronchial lavage was performed observing structures compatible with P. jirovecii (Figure 2A); direct immunofluorescence for Pneumocystis was positive (Figure 2B). Trimethoprim–sulfamethoxazole 15 mg/kg/day was started with satisfactory response. After 7 days a repeat chest CT showed marked improvement (Figure 1D and E). Treatment was continued for 21 days and the patient was discharged with his immunosuppression on hold.
3. Discussion Studies about the pathogenesis of CD have demonstrated dysfunction of the intestinal immune system associated with an imbalance in the regulation of T helper cells (Th), leukocytes, cytokines, tissue repair molecules and overproduction of TNF by monocytes and macrophages in the deep layers of the lamina propria and submucosa. 11 Currently it is known that TNF plays an important role in the formation of granulomas, apoptosis, cytokine production (IL-1, IL-6 and IL-8), γ-interferon, adhesion molecules and monocyte chemo-attractant proteins. 12 The antagonism of TNF causes a decrease in the inflammatory response that increases susceptibility to opportunistic infections, including fungal infections. 13
Pneumocystosis in Crohn Table 1
485
Evolution of laboratory test.
Parameter
16/Jul/ 2010
09/Aug/ 2010
Event
Start AZA, PDN 9400 12 690 7.5 1.29 0.51 0.04 4.5 91
After 1st dose ADA 10,100 11.6 607 6.8 2.61 0.72 0
5800 11.3 642 3.82 1.63 0.31 0
94
96
WBC Hemoglobin Platelets Neutrophils Lymphocytes Monocytes Eosinophils CRP MCV (fL)
06/Sept/ 2010
05/Oct/ 2010
11/Oct/ 2010
Resp. S
In-patient
3100 11.1 299 1.36 1.72 0.04 0.01
1700 8.8 167 0.52 1.2 0.14 0.03
13/Oct/ 2010
15/Oct/ 2010
18/Oct/ 2010
12/Nov/ 2010
20/Jan/ 2011
10,100 10.0 420 3.7 4.0 1.3 0.02
10,000 14.3 331 6.2 3.65 0.72 0.06 2.0 91
D/C 1400 8.4 160 0.76 0.31 0.13 0.01 25 96
1920 9.8 178 0.57 0.14 0.07 0.02 94
4600 9.4 207 1.77 1.21 0.14 0.0 10.3 94
104
3
WBC, neutrophils, lymphocytes, monocytes, eosinophils and platelets are reported as x10 /μL; hemoglobin as g/dL and CPR as mg/dL. WBC, white blood cells; MCV, mean cell volume; CRP, C-reactive protein; AZA, azathioprine; PDN, prednisone; ADA, adalimumab; Resp. S, respiratory symptoms; D/C, discharge.
Adalimumab, a recombinant human monoclonal antibody (IgG1) against TNF, has been approved as second-line treatment for CD with moderate to severe activity, treatment failure or intolerance to infliximab. 14–16 Despite the benefits of biological treatment such as anti-TNFs, they increase the risk of infection by intracellular pathogens, granulomatous infections, protozoa, mycobacteria, cytomegalovirus, listeriosis, aspergillosis, histoplasmosis, hepatitis B reactivation, among others. 16–18 Moreover, the concomitant use of corticosteroids as a third immunosuppressive agent can increase the relative risk of serious and opportunistic infections. 7,12 A review by Tsiodras et al. 12 identified 282 cases of invasive fungal infection associated with TNF inhibitors, and
found 226 cases with infliximab (80%) and 11 cases (4%) with adalimumab (4 cases of Histoplasma, 2 Aspergillus, 2 Candida, 1 Cryptococcus, 1 tinea and 1 Pityriasis versicolor). In 98% of the cases, patients were receiving at least another immunomodulatory medication (corticosteroids, methotrexate or thiopurines) during the course of infection. The incidence of serious infections in patients with inflammatory bowel disease is 2–5.8%. 7,19 Inflammatory autoimmune diseases account for almost 20% of PCP infection in HIV-negative patients, with a mortality that can exceed 50%. 11,20,21 Colombel et al. 19 evaluated the safety profile of adalimumab in six international clinical trials with more than 3160 patients and did not identify any cases of PCP.
Figure 1 Imaging studies before diagnosis and after treatment. A) Chest radiograph on admission. B and C) High-resolution computed tomography (CT) prior to diagnosis with the typical image of ground-glass opacities and interlobular septa. D and E) CT after 1 week of treatment with radiographic improvement.
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Figure 2 Pictures of microbiology and immunology. A) Bronchoalveolar lavage smears with silver stain (Groccott) with round brown 6 to 8 micrometers structures corresponding to Pneumocystis jirovecii asci or sexual spore-bearing cells. B) Direct immunofluorescence test of bronchoalveolar lavage positive to P. jirovecii with the typical clear-cut round shaped apple-green fluorescence structures of 4 to 5 micrometers in chains.
One case was reported with adalimumab and CD 22 but our case is the second (first in Mexico) and is a complete case with confirmatory diagnostic testing. This patient was started on steroids and azathioprine for moderate activity of CD, but after 2 months and persistence of moderate to severe intestinal symptoms, biologic was started. This combination improved his CD, but increased susceptibility to opportunistic diseases. Another factor that may have contributed to the PCP was the severe neutropenia probably associated with the use of azathioprine. Risk factors for PCP in patients with inflammatory diseases treated with anti-TNFs include concomitant use of corticosteroids (especially N 8 weeks), advanced age (N 65 years), lung disease or fibrosis, leucopenia b500/μL, hypoalbuminemia and lymphopenia. 20,23 The patient described in this report had corticosteroid use, leucopenia, lymphopenia and hypoalbuminemia as risk factors. AntiTNF can decrease CD4 lymphocytes and agranulocytosis has been also reported. 10,23 The interval identified between the first infusion and the start of the PCP has been reported between 9 and 14 weeks. 10,20 In our case, we observed a time interval of 8 weeks. In our case, the definitive diagnosis of P. jirovecii was made by Grocott–Gomori staining and immunofluorescence in a respiratory sample. The patient presented with fever and neutropenia without any low respiratory symptoms to suspect PCP, but due to the use of combination immunosuppression, with consequent severe neutropenia, an opportunistic disease was suspected as the cause of persistent fever. There are no established criteria for PCP prophylaxis in HIVnegative patients; prophylaxis is prescribed inconsistently in only 25% of patients using immunosuppressants. The first-line agent is trimethoprim–sulfamethoxazole; the dosage ranges from 80–400 mg to 800–160 mg/day or 3 times a week; 21,24 pentamidine and dapsone 100 mg/day can be used as a second option, although clindamycin/primaquine appears to be superior. 25 Biologic agents such as adalimumab are a promising alternative in the management of a number of inflammatory diseases including IBD. However, this case reminds us that serious opportunistic infections can occur, particularly in the context of combination immunosuppression. The American Gastroenterology Association (AGA) 16 and the Mexican guidelines 15 on the use of biologics and IBD do
not specifically recommend antifungal prophylaxis in immunosuppressed patients. The only recommendation before starting anti-TNF therapy is to perform a tuberculin skin test (PPD) and chest radiograph as was done in our patient. The European Crohn's and Colitis Organization (ECCO) in their most recent guidelines on infections and IBD does recommend prophylaxis in those on triple immunosuppression therapy, although they highlight the fact that cases of PCP have been reported in anti-TNF monotherapy, thiopurine monotherapy and/or steroid monotherapy and so this infection is not exclusive to those on combination immunosuppression. 26 It is important to remain alert to the possibility of such infections in any immunosuppressed patient.
Conflict of interest statement None has been declared.
Acknowledgements and disclosures Ana L. Desales, Jorge Mendez-Navarro, Luis J. Méndez-Tovar, Nayeli X. Ortiz-Olvera, Garret Cullen, Joaquín Ocampo, Willian Lemus, Amina E. Tun, Arturo Mayoral-Zavala, and Margarita Dehesa-Violante have nothing to disclose.
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