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Prevention of infections in patients with rheumatic diseases
Indian Journal of Rheumatology 2008 June Volume 3, Number 2; pp. 58–63
Review Article
Prevention of infections in patients with rheumatic diseases VR Joshi, P Kharbanda, A Tembe
ABSTRACT Patients with rheumatic diseases, such as systemic lupus erythematosus, are inherently susceptible to infections. This is further compounded by treatment with corticosteroids and immunosuppressives used to treat these disorders. The spectrum of infections is wide and diagnosis often difficult. Infections account for a fair proportion of deaths in these patients. Prevention is, therefore, important. This article reviews the reasons for increased susceptibility to infections, the deleterious effects of therapy on defenses against infections, and the preventive strategies to be adopted. Keywords: Rheumatic diseases, arthritis, infections, prophylaxis.
INTRODUCTION
Disease-related susceptibility
Infections often complicate the course of rheumatic diseases.1–3 About 30–50% of systemic lupus erythematosus (SLE) patients suffer a severe episode of infection during the course of their illness. With improved therapeutics that can adequately control disease activity and disease complications, infections are becoming an important cause of morbidity and mortality. It is one of the main causes of hospital admissions. Many unsuspected infections are diagnosed for the first time at autopsy.4 Prevention and treatment of infections, therefore, assume great importance. Most episodes of infection are due to common day-to-day microorganisms,5 but deaths due to infection are often by opportunistic infections.4,6 Infection is an important cause of death in SLE and rheumatoid arthritis (RA).7,8
Although in patients with immune mediated rheumatic diseases, certain aspects of the immune system are hyperactive; protective immunity may in fact be suboptimal. The abnormalities noted include: • Neutropenia and impaired function of neutrophils9 • Suppressed cellular immunity (lymphopenia, decreased cytokine production)10 • Dysfunctional humoral immunity [decreased immunoglobulin production, low complement levels, lower levels of mannose binding lectin (MBL)]2,11 • Decreased ability of reticuloendothelial system (RES) to eliminate microorganisms12 • Asplenia/hyposplenia • Disease activity is also a risk factor. Defects in phagocytic function are common in SLE patients with high disease activity.13–15 Inflamed joints of RA are susceptible to secondary infection. Frailty, malnutrition, organ failure (e.g. aspiration in scleroderma and dermatomyositis, interstitial lung disease, renal failure) and break in integrity of natural barriers, (mucosal ulceration, skin ulceration, gangrene,
RISK FACTORS The increased susceptibility to infection is both disease and therapy related.
PD Hinduja National Hospital & MRC, Veer Savarkar Marg, Mahim, Mumbai, Maharashtra, India. Correspondence: Dr. VR Joshi, email: [email protected]
Prevention of infections in patients with rheumatic diseases
etc.) due to disease, drugs, and procedures add to susceptibility to infections.
Therapy-related susceptibility The immunosuppressive therapy is an important risk factor. The risk is related to the degree, as well as duration of immunosuppression. Drugs affect different components of the immune system and hence cause variable susceptibility to infective organisms. Corticosteroids (CS): CS has a profound effect on the immune function. There is decreased cytokine production, suppression of functions of neutrophils, monocytes, and T-lymphocytes.16 Steroids breach the defense provided by skin and mucous membranes.17 Higher daily dose (> 20 mg/d), longer duration of therapy (> 21 days), and high total dose (> 700 mg) are associated with increased susceptibility to infection.17,18 Immunosuppressive (IS) agents: Cyclophosphamide (CPM) increases the risk of severe infection especially when combined with CS.19 Azathioprine, mycophenolate, methotrexate, and leflunomide also carry risk of infections.20 Table 1 summarizes effects of immunosuppressive agents on immune system and susceptibility to specific infections. Biologicals: These agents have a direct effect on the immune system. TNF-α antagonists depress granuloma formation and increase susceptibility to infections.21 Anti-CD 20
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59
monoclonal antibody increases susceptibility to usual but not to opportunistic infections.22 Procedures: Plasmapheresis, when combined with immunosuppressive therapy, because of effects on both cellular and humoral immune mechanisms is associated with increased risk of infections.23 Peritoneal dialysis carries a higher risk of infections. Joint surgery and joint aspiration can be complicated by infection.
ORGANISMS AND THE COMMON SITES OF INFECTION Skin, lower respiratory tract, urinary tract, central nervous system, bones, and joints are the common sites of infection.10 The spectrum of infections encompasses a wide range of organisms3,17 that include, viruses (HZV, CMV, EBV, parvovirus B19, influenza, HSV, RSV), bacteria (salmonella, streptococcus pneumoniae, nocardia, staphylococcus aureus, legionella, listeria, mycobacterium tuberculosis, non-tuberculous mycobacteria), fungi (candida, aspergillus, zygomycoses), and parasites (pneumocystis, toxoplasma, strongyloides).21,24–26 While there is no increase in the risk of HBV, HCV, and HIV infection, steroids definitely increase the risk of herpes virus infection.
Table 1 Effect on immune function and susceptibility to infections with immunosuppressive and biologic agents Immune abnormality
Agents
Infections
• Defective phagocytic function Neutropenia
Corticosteroids Cyclophosphamide Azathioprine
• S. aureus, Strep. spp, Nocadia • E. coli, Kleb. pneumoniae, Enterobacteriaceae • Candida, Aspergillus spp.
• Defective cell mediated immunity
Corticosteroids, Cyclophosphamide, Azathioprine, Cyclosporine A, Methotrexate
• Mycobact. spp, Listeria, Salmonella spp • Histoplasma capsulatum, Coccidiodes immitis, Cryptococcus neoformans • P. carinii, Toxoplasma gondii, Strongyloides stercoralis
• Defective humoral immunity
Cyclophosphamide, Corticosteroids (high dose), Azathioprine,
• S. pneumoniae, H. influenzae
• Cytokine antagonism
TNF-α blockers IL-1 receptor antagonist
• Common bacterial infections • No increased risk of opportunistic infections
• B cell depletion
Anti-CD 20 monoclononal antibody
• T-cell activation
Soluble CTLA-4 protein
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Indian Journal of Rheumatology 2008 June; Vol. 3, No. 2
PREVENTABLE INFECTIONS Streptococcus pneumoniae can cause fulminant sepsis in SLE patients. Soft tissue infections are also known. Tuberculosis: There is increased risk of tuberculosis on prolonged steroid therapy and biologicals. Often it is extrapulmonary or miliary.21,23,24 Nocardia: Lung, brain, and skin are the common sites of nocardial infection. Mortality is high (35%), more so with the CNS involvement. Pneumocystis carinii pneumonia (PCP) runs a rapidly progressive course in SLE patients. Usually these patients are on high-dose corticosteroid therapy. Infection occurs early in the disease course. It is rare in SLE patients and not on steroids. Strogyloidosis can occur as early as 10 days after initiation of high-dose steroid therapy. Varicella-zoster infection is common in SLE patients. It may involve multiple dermatomes or can be wide spread. Fungaemia is seen with the use of broad-spectrum antibiotics, indwelling central lines, and high doses of corticosteroids or immunosuppressives. Malaria is a serious infection in splenectomized patients.
PREVENTIVE MEASURES Prevention of infection necessitates a multi-pronged approach and moreover a clear control of disease activity is important.14,15 Another important measure is rational and judicious use of drugs to treat rheumatic diseases. Corticosteroids: Prescribing only when indicated, limiting the daily dose, duration, and frequency of administration are essential.17,27 Cyclophosphamide: It is not necessary to achieve profound neutropenia or lymphopenia for therapeutic efficacy.
Joshi et al.
A white count of less than 3000/mm3 increases the risk of infection.19 In patients who develop agranulocytosis with CPM, changing to mycophenolate or azathioprine is desirable. If the fear of infection is high because of pretreatment leucopenia, IV immunoglobulin is an available alternative. Fungaemia can be prevented by minimizing the use of broad-spectrum antibiotics and indwelling central lines.25 Joint aspiration as well as joint surgery (joint replacement) carries risk of infection. Aseptic precautions are mandatory. Active immunization: Active immunization is the best measure to prevent infection. However, in immunocompromised patients several points need to be considered.28 • The incidence and severity of infection under consideration (should be high). • Efficacy and toxicity of vaccine. • Risk of causing clinical infection (with live as well as attenuated vaccine). • Oral polio vaccination of close family contacts should be avoided for fear of transmission to the patient. • Oral polio vaccination of close family contacts should be avoided for fear of transmission to the patient. • BCG vaccination is prohibited. Therefore, the cost benefit ratio depends upon the likelihood of acquiring infection, its morbidity and mortality, and the efficacy, toxicity and safety of the vaccine. Guidelines for vaccinations in HIV infected individuals exist.29 Whether these guidelines can be applied to patients receiving immunosuppressive therapy is not clear. The vaccinations recommended for patients receiving immunosuppressive therapy are shown in Table 2.28 Cholera, diphtheria, pertussis, typhoid (inj), rabies, and tetanus vaccinations are permitted. Oral polio, oral typhoid, BCG, MMR and HZV vaccination is contraindicated in patients currently on or treated with immunosuppressive therapy in immediate past (< 3 months). In patients treated with bone-marrow ablative therapy followed by stem cell transplantation, there is loss of
Table 2 Recommended vaccinations for adult patients with rheumatic diseases and immunosuppressive therapy Vaccine
Indication
Schedule
Revaccination
• Pneumococcal (polysaccharide)
All patients
One dose
Once after 5 years
• Influenza
All patients
One dose
Annually
• H. influenzae (type b)
Post splenectomy, asplenia
One dose
–
• Meningococcal (polysaccharide)
As for healthy individuals
One dose
After 5 years in high risk patients
• Hepatitis B
As for healthy individuals
Three doses (0, 1–2, 4–6 months)
–
• Hepatitis A
As for healthy individuals
Two doses (0, 6–12 months)
–
Prevention of infections in patients with rheumatic diseases
response to new immunizations and also loss of preexisting immunity.30 Reimmunization is necessary. Response to immunization may be impaired with methotrexate, SSZ, CPM, AZA and TNF-α antagonists.31 Rituximab does not reduce pretreatment antibodies but post-treatment response to vaccination may be severely impaired and hence vaccination should be carried out prior to treatment. The same strategy may be followed whenever possible in patients planned to receive immunosuppressive therapy. SLE patients may show impaired response to pneumococcal and influenza vaccines. Despite all the above limitations, the response to vaccines may still be adequate to reduce both morbidity and mortality of infections especially if the risk of serious infections is high.28
ANTIBIOTIC PROPHYLAXIS Nonspecific antibiotic prophylaxis is not indicated except possibly for patients with absolute neutrophil count of less than 500/mm3. GCSF is preferred to GMCSF to treat agranulocytosis as the latter can, by activating macrophages, exacerbate underlying rheumatic condition.28 In our context, the most important infections needing chemoprophylaxis are tuberculosis, Pneumocystis carinii, nocardia, and strongyloides. Perioperative antibiotic prophylaxis is necessary for prosthetic joint replacement surgery. Tuberculosis: Before starting immunosuppressive therapy active tuberculosis should be excluded with careful history, physical examination, and an x-ray chest. Mantoux test has been used to diagnose ‘latent’ tuberculosis in developed countries and forms an indication to treat it before initiating treatment with TNF-α antagonists.32 Its relevance, sensitivity, and specificity are debatable in Indian context. Recently, ELISA Quantiferon, ELISPOT, T-SPOT tests have been approved by FDA. Studies have shown that these tests are not affected by cross-reactivity with BCG or environmental mycobacteria and correlate better with exposure to M. tuberculosis. These may replace the traditional tuberculin test to diagnose latent tuberculosis and initiate INH prophylaxis. Until then, INH prophylaxis is indicated in all patients without active tuberculosis and is to receive more than 15–20 mg prednisolone for more than 3–4 weeks.33,34 Nine months of INH prophylaxis is effective in reducing reactivation of latent tuberculosis. Same strategy may be applied to TNF-α antagonist therapy. The fear of INH resistance is unfounded as the load of TB bacilli in latent tuberculosis is so low that chances of having an INH resistant bacillus are extremely low and only a mutation can induce it.35 Malaria: Patients with splenectomy, asplenia, or hyposplenia residing in endemic areas or while traveling to an
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61
endemic area should receive malaria prophylaxis and penicillin prophylaxis for protection against infection with capsulated organisms. P. carinii: Indications for prophylaxis against P. carinii are not as well defined in patients with rheumatic diseases as are in HIV infected individuals. Some advocate cotrimoxazole prophylaxis for all patients receiving more than 40 mg prednisolone per day for more than a month, but opinions differ. The risk of PCP is maximum in the first few months after diagnosis of rheumatic disease and initiation of treatment. Patients receiving corticosteroid+cyclophosphomide combination and pretreatment low lymphocyte or CD4 count are at an increased risk. Whether lymphocyte count (absolute/CD4) can be used to guide decision on primary PCP prophylaxis is not clear. As against this, secondary prophylaxis is indicated to all patients recovering from PCP and is to be continued on steroids.36,37 Daily or 3 doses per week schedules of cotrimoxazole are equally effective, the latter has the advantage of lesser side-effects. In SLE, cotrimoxazole can cause aseptic meningitis. Alternatives include dapsone, atovaquone, or monthly aerosolized pentamidine. Strongyloides: It has been suggested to screen patients from endemic areas for strongyloidosis and treat the infection before initiating immunosuppressive therapy.17 Nocardia: Prophylaxis with cotrimoxazole should be provided to all patients on > 20 mg/d of prednisolone for more than 1 month.38
POST-EXPOSURE PROPHYLAXIS Herpes: Prevention of recurrent genital herpes simplex with acyclovir or famicolovir though effective carries the risk of development of resistance. Varicella zoster: After exposure, varicella zoster immunoglobulin should be administered as soon as possible (< 96 hour post exposure) (125 mg/10 kg maximum 625 U IM). Measles: Susceptible patients exposed to measles patient should be passively immunized as soon as possible (immunoglobulin 0.5 ml/kg maximum 15 ml IM).
PROSTHETIC JOINT REPLACEMENT Before joint replacement surgery patient should be examined carefully to exclude dental, urinary tract, and skin infections. If present these should be treated appropriately before surgery. Perioperative antibiotic therapy should follow standard guidelines.39
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Indian Journal of Rheumatology 2008 June; Vol. 3, No. 2
Joshi et al.
GENERAL MEASURES
7.
Maintaining good health and nutrition, avoidance of crowded places, contact with patients with infection, and uncooked food are important nonspecific measures.
8. 9. 10.
CONCLUSION 11.
Patients suffering from rheumatic diseases are at an increased risk of infection. Both disease activity and immunosuppressive therapy contribute to the increased susceptibility. Infections are associated with increased morbidity, hospitalization, and increased mortality. Most infections are due to common organisms. Preventive strategies include effective disease control, judicious use of immunosuppressives, general health measures, proper screening of patients for infections, immunization, and antibiotic prophylaxis.
12.
13. 14.
15.
ACKNOWLEDGEMENTS Source of funding: None. Disclosure statement: Authors have declared no conflict of interest.
16.
17. 18.
REFERENCES 1.
2.
3. 4.
5.
6.
Gladman DD, Hussain F, Ibanez D, et al. The nature and outcome of infection in systemic lupus erythematosus. Lupus 2002; 11: 234–9. Alarcon G. Infections in systemic connective tissue diseases: systemic lupus erythematosus, scleroderma, and polymyositis/ dermatomyositis. Infect Dis Clin N Am 2006; 20: 849–975. Abruzzo J. Rheumatoid arthritis and mortality. Arthritis Rheum 1982; 25: 1020. Iriya SM, Capelozzi VL, Calich I, et al. Causes of death in patients with systemic lupus erythematosus in Sao Paulo Brazil: a study of 113 autopsies. Arch Intern Med 2001; 161: 1557–61. Zonana-Nacach A, Camargo-Coronel A, Yanez P, et al. Infections in outpatients with systemic lupus erythematosis: a prospective study. Lupus 2001; 10: 505–10. Ginzler E, Diamond H, Kaplan D, et al. Computer analysis of factors influencing frequency of infection in systemic lupus erythematous. Arthritis Rheum 1978; 21: 37–44.
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Bernatsky S, Bovin JF, Joseph L, et al. Mortality in systemic lupus erythematosus. Arthritis Rheum 2006; 54: 2550–7. Kelley C, Hamilton J. What kills patients with rheumatoid arthritis. Rheumatology 2007; 46: 183–4. Keeling D, Isenberg D. Hematological manifestations of systemic lupus erythematosus. Blood Rev 1993; 7: 199. Bermas B, Petri M, Goldman D. T-helper cell dysfunction in systemic lupus erythematosus (SLE) relation to disease activity. J Clin Immunol 1994; 14: 169. Garred P, Madsen HO, Halberg P, et al. Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus. Arthritis Rheum 1999; 42: 2145–52. Cunha BA. Infections in non leucopenic compromised hosts (diabetes mellitus, SLE, steroids and asplenia) in critical care. Crit Care Clin North Am 1998; 14: 263–82. Petri M. Infection in systemic lupus erythematosus. Rheum Dis Clin North Am 1998; 24: 423–56. Petri M, Genovese M. Incidence and risk factors for hospitalizations in systemic lupus erythematosus. J Rheumatol 1992; 19: 1559–65. Duffy KN, Duffy CM, Gladman DD. Infection and disease activity in systemic lupus erythematosus: a review of hospitalized patients. J Rheumatol 1991; 18: 1180–4. Boumpas DT, Chrousos GP, Wilder RL, et al. Glucocorticoid therapy for immune-mediated disease: basic and clinical correlates. Ann Intern Med 1993; 119: 1198–208. Klein NC, Chi-Hiong-U GO, Cunha BA. Infections associated with steroid use. Infect Dis Clin North Am 2001; 15: 423–32. Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in patients taking glucocorticoids. Rev Infect Dis 1989; 11: 954–63. Pryor BD, Bologna SG, Kahl LE. Risk factors for serious infection during treatment with cyclophosphamide and high dose corticosteroids for systemic lupus erythematosus. Arthritis Rheum 1996; 39: 1475–82. Contreras G, Pardo V, Leelereg B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004; 350: 971–80. Mohan AK, Cote TR, Siegel JN, Braun MM. Infectious complications of biologic treatments of rheumatoid arthritis. Curr Opin Rheumatol 2003; 15: 179–84. Smolen JS, Keystone EC, Emery P, et al. Consensus statement on use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66: 143–50. Aringer M, Smolen JS, Graninger WB. Severe infections in plasmapheresis treated systemic lupus erythematosus. Arthritis Rheum 1998; 41: 414–20. Skogberg K, Rutto P, Tukiainen P. Effect of immunosuppressives on clinical presentation of and outcome of tuberculosis. Clin Infect Dis 1993; 56: 1549.
Prevention of infections in patients with rheumatic diseases
25. Balarishnan C, Mangat G, Mittal G, Joshi VR. Tuberculosis in patients with systemic lupus erythematosus. J Assoc Physicians India 1998; 46: 751–2. 26. Sule A, Gaitonde S, Pathan E, et al. Strongyloides in a case of SLE. J Indian Rheumatol Assoc 2001; 9: 45–6. 27. Dale DC, Fauci AS, Wolff SM. Alternate-day prednisolone leukocyte kinetics and susceptibility to infections. N Engl J Med 1974; 291: 1154. 28. Mounzer KC, Dinubile MJ. Prophylactic use of antibiotics and vaccine in patients with rheumatologic disorders. Rheum Dis Clin North Am 1997; 23: 259–75. 29. British National Formulary 2006; 51: 611–2. 30. Van Burik JAH, Weisdorf DJ. Infections in recipients of blood and marrow transplantation. Haemat Oncol Clinics North Am 1999; 13: 1065–89. 31. Kapetanovic MC, Saxne T, Sjoholm TL, Jonsson G, Geborek P. Influence of methotrexate, TNF-blockers, and prednisolone on antibody responses to pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis. Rheumatology (Oxf) 2006; 45: 106–11. 32. Seyal BH, Sneller MC, Infectious complications of immunosuppressive therapy in patients with rheumatic diseases. Rheum Dis Clin North Am 1997; 23: 219–37.
Review Article
33. Matulis G, June P, Villiger PM, Gadola SD. Detection of latent tuberculosis in immunosuppessed patients with autoimmune diseases: performance of a Mycobacterium tuberculosis antigen-specific interferon Y assay. Ann Rheum Dis 2008; 67: 84–90. 34. Gaitonde S, Pathan E, Sule A, Mittal G, Joshi VR. Efficacy of isoniazid prophylaxis Segal in patients with systemic lupus erythematosus receiving long term steroid therapy. Rheumatol 2002; 41: 346–7. 35. Parsons LM, Driscoll JR, Taber HW, Salfinger M. Drug resistance in tuberculosis. Infect Dis Clin North Am 1997; 11: 905–28. 36. Sepkowitz KA, Brown AE, Telzak EF, et al. Pneumocystis carinii pneumonia without acquired immunodeficiency syndrome: who should receive prophylaxis (Editorial). Mayo Clin Proc 1996; 71: 102–3. 37. Godeau B, Coutant-Perronne V, et al. Pneumocystis carinii pneumonia in the course of connective tissue diseases: report of 34 cases. J Rheumatol 1994; 21: 246–51. 38. Mok CC, Yuen KY, Lau CS. Nocardiosis in systemic lupus erythematosus. Sem Arthritis Rheum 1997; 26: 675–83. 39. Norden C. A critical review of antibiotic prophylaxis in orthopaedic surgery. Rev Infect Dis 1983; 5: 928–32.
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63
Rheumatologists, Orthopedic Surgeons, & Physicians
Review Article
Prevention of infections in patients with rheumatic diseases VR Joshi, P Kharbanda, A Tembe
ABSTRACT Patients with rheumatic diseases, such as systemic lupus erythematosus, are inherently susceptible to infections. This is further compounded by treatment with corticosteroids and immunosuppressives used to treat these disorders. The spectrum of infections is wide and diagnosis often difficult. Infections account for a fair proportion of deaths in these patients. Prevention is, therefore, important. This article reviews the reasons for increased susceptibility to infections, the deleterious effects of therapy on defenses against infections, and the preventive strategies to be adopted. Keywords: Rheumatic diseases, arthritis, infections, prophylaxis.
INTRODUCTION
Disease-related susceptibility
Infections often complicate the course of rheumatic diseases.1–3 About 30–50% of systemic lupus erythematosus (SLE) patients suffer a severe episode of infection during the course of their illness. With improved therapeutics that can adequately control disease activity and disease complications, infections are becoming an important cause of morbidity and mortality. It is one of the main causes of hospital admissions. Many unsuspected infections are diagnosed for the first time at autopsy.4 Prevention and treatment of infections, therefore, assume great importance. Most episodes of infection are due to common day-to-day microorganisms,5 but deaths due to infection are often by opportunistic infections.4,6 Infection is an important cause of death in SLE and rheumatoid arthritis (RA).7,8
Although in patients with immune mediated rheumatic diseases, certain aspects of the immune system are hyperactive; protective immunity may in fact be suboptimal. The abnormalities noted include: • Neutropenia and impaired function of neutrophils9 • Suppressed cellular immunity (lymphopenia, decreased cytokine production)10 • Dysfunctional humoral immunity [decreased immunoglobulin production, low complement levels, lower levels of mannose binding lectin (MBL)]2,11 • Decreased ability of reticuloendothelial system (RES) to eliminate microorganisms12 • Asplenia/hyposplenia • Disease activity is also a risk factor. Defects in phagocytic function are common in SLE patients with high disease activity.13–15 Inflamed joints of RA are susceptible to secondary infection. Frailty, malnutrition, organ failure (e.g. aspiration in scleroderma and dermatomyositis, interstitial lung disease, renal failure) and break in integrity of natural barriers, (mucosal ulceration, skin ulceration, gangrene,
RISK FACTORS The increased susceptibility to infection is both disease and therapy related.
PD Hinduja National Hospital & MRC, Veer Savarkar Marg, Mahim, Mumbai, Maharashtra, India. Correspondence: Dr. VR Joshi, email: [email protected]
Prevention of infections in patients with rheumatic diseases
etc.) due to disease, drugs, and procedures add to susceptibility to infections.
Therapy-related susceptibility The immunosuppressive therapy is an important risk factor. The risk is related to the degree, as well as duration of immunosuppression. Drugs affect different components of the immune system and hence cause variable susceptibility to infective organisms. Corticosteroids (CS): CS has a profound effect on the immune function. There is decreased cytokine production, suppression of functions of neutrophils, monocytes, and T-lymphocytes.16 Steroids breach the defense provided by skin and mucous membranes.17 Higher daily dose (> 20 mg/d), longer duration of therapy (> 21 days), and high total dose (> 700 mg) are associated with increased susceptibility to infection.17,18 Immunosuppressive (IS) agents: Cyclophosphamide (CPM) increases the risk of severe infection especially when combined with CS.19 Azathioprine, mycophenolate, methotrexate, and leflunomide also carry risk of infections.20 Table 1 summarizes effects of immunosuppressive agents on immune system and susceptibility to specific infections. Biologicals: These agents have a direct effect on the immune system. TNF-α antagonists depress granuloma formation and increase susceptibility to infections.21 Anti-CD 20
Review Article
59
monoclonal antibody increases susceptibility to usual but not to opportunistic infections.22 Procedures: Plasmapheresis, when combined with immunosuppressive therapy, because of effects on both cellular and humoral immune mechanisms is associated with increased risk of infections.23 Peritoneal dialysis carries a higher risk of infections. Joint surgery and joint aspiration can be complicated by infection.
ORGANISMS AND THE COMMON SITES OF INFECTION Skin, lower respiratory tract, urinary tract, central nervous system, bones, and joints are the common sites of infection.10 The spectrum of infections encompasses a wide range of organisms3,17 that include, viruses (HZV, CMV, EBV, parvovirus B19, influenza, HSV, RSV), bacteria (salmonella, streptococcus pneumoniae, nocardia, staphylococcus aureus, legionella, listeria, mycobacterium tuberculosis, non-tuberculous mycobacteria), fungi (candida, aspergillus, zygomycoses), and parasites (pneumocystis, toxoplasma, strongyloides).21,24–26 While there is no increase in the risk of HBV, HCV, and HIV infection, steroids definitely increase the risk of herpes virus infection.
Table 1 Effect on immune function and susceptibility to infections with immunosuppressive and biologic agents Immune abnormality
Agents
Infections
• Defective phagocytic function Neutropenia
Corticosteroids Cyclophosphamide Azathioprine
• S. aureus, Strep. spp, Nocadia • E. coli, Kleb. pneumoniae, Enterobacteriaceae • Candida, Aspergillus spp.
• Defective cell mediated immunity
Corticosteroids, Cyclophosphamide, Azathioprine, Cyclosporine A, Methotrexate
• Mycobact. spp, Listeria, Salmonella spp • Histoplasma capsulatum, Coccidiodes immitis, Cryptococcus neoformans • P. carinii, Toxoplasma gondii, Strongyloides stercoralis
• Defective humoral immunity
Cyclophosphamide, Corticosteroids (high dose), Azathioprine,
• S. pneumoniae, H. influenzae
• Cytokine antagonism
TNF-α blockers IL-1 receptor antagonist
• Common bacterial infections • No increased risk of opportunistic infections
• B cell depletion
Anti-CD 20 monoclononal antibody
• T-cell activation
Soluble CTLA-4 protein
60
Indian Journal of Rheumatology 2008 June; Vol. 3, No. 2
PREVENTABLE INFECTIONS Streptococcus pneumoniae can cause fulminant sepsis in SLE patients. Soft tissue infections are also known. Tuberculosis: There is increased risk of tuberculosis on prolonged steroid therapy and biologicals. Often it is extrapulmonary or miliary.21,23,24 Nocardia: Lung, brain, and skin are the common sites of nocardial infection. Mortality is high (35%), more so with the CNS involvement. Pneumocystis carinii pneumonia (PCP) runs a rapidly progressive course in SLE patients. Usually these patients are on high-dose corticosteroid therapy. Infection occurs early in the disease course. It is rare in SLE patients and not on steroids. Strogyloidosis can occur as early as 10 days after initiation of high-dose steroid therapy. Varicella-zoster infection is common in SLE patients. It may involve multiple dermatomes or can be wide spread. Fungaemia is seen with the use of broad-spectrum antibiotics, indwelling central lines, and high doses of corticosteroids or immunosuppressives. Malaria is a serious infection in splenectomized patients.
PREVENTIVE MEASURES Prevention of infection necessitates a multi-pronged approach and moreover a clear control of disease activity is important.14,15 Another important measure is rational and judicious use of drugs to treat rheumatic diseases. Corticosteroids: Prescribing only when indicated, limiting the daily dose, duration, and frequency of administration are essential.17,27 Cyclophosphamide: It is not necessary to achieve profound neutropenia or lymphopenia for therapeutic efficacy.
Joshi et al.
A white count of less than 3000/mm3 increases the risk of infection.19 In patients who develop agranulocytosis with CPM, changing to mycophenolate or azathioprine is desirable. If the fear of infection is high because of pretreatment leucopenia, IV immunoglobulin is an available alternative. Fungaemia can be prevented by minimizing the use of broad-spectrum antibiotics and indwelling central lines.25 Joint aspiration as well as joint surgery (joint replacement) carries risk of infection. Aseptic precautions are mandatory. Active immunization: Active immunization is the best measure to prevent infection. However, in immunocompromised patients several points need to be considered.28 • The incidence and severity of infection under consideration (should be high). • Efficacy and toxicity of vaccine. • Risk of causing clinical infection (with live as well as attenuated vaccine). • Oral polio vaccination of close family contacts should be avoided for fear of transmission to the patient. • Oral polio vaccination of close family contacts should be avoided for fear of transmission to the patient. • BCG vaccination is prohibited. Therefore, the cost benefit ratio depends upon the likelihood of acquiring infection, its morbidity and mortality, and the efficacy, toxicity and safety of the vaccine. Guidelines for vaccinations in HIV infected individuals exist.29 Whether these guidelines can be applied to patients receiving immunosuppressive therapy is not clear. The vaccinations recommended for patients receiving immunosuppressive therapy are shown in Table 2.28 Cholera, diphtheria, pertussis, typhoid (inj), rabies, and tetanus vaccinations are permitted. Oral polio, oral typhoid, BCG, MMR and HZV vaccination is contraindicated in patients currently on or treated with immunosuppressive therapy in immediate past (< 3 months). In patients treated with bone-marrow ablative therapy followed by stem cell transplantation, there is loss of
Table 2 Recommended vaccinations for adult patients with rheumatic diseases and immunosuppressive therapy Vaccine
Indication
Schedule
Revaccination
• Pneumococcal (polysaccharide)
All patients
One dose
Once after 5 years
• Influenza
All patients
One dose
Annually
• H. influenzae (type b)
Post splenectomy, asplenia
One dose
–
• Meningococcal (polysaccharide)
As for healthy individuals
One dose
After 5 years in high risk patients
• Hepatitis B
As for healthy individuals
Three doses (0, 1–2, 4–6 months)
–
• Hepatitis A
As for healthy individuals
Two doses (0, 6–12 months)
–
Prevention of infections in patients with rheumatic diseases
response to new immunizations and also loss of preexisting immunity.30 Reimmunization is necessary. Response to immunization may be impaired with methotrexate, SSZ, CPM, AZA and TNF-α antagonists.31 Rituximab does not reduce pretreatment antibodies but post-treatment response to vaccination may be severely impaired and hence vaccination should be carried out prior to treatment. The same strategy may be followed whenever possible in patients planned to receive immunosuppressive therapy. SLE patients may show impaired response to pneumococcal and influenza vaccines. Despite all the above limitations, the response to vaccines may still be adequate to reduce both morbidity and mortality of infections especially if the risk of serious infections is high.28
ANTIBIOTIC PROPHYLAXIS Nonspecific antibiotic prophylaxis is not indicated except possibly for patients with absolute neutrophil count of less than 500/mm3. GCSF is preferred to GMCSF to treat agranulocytosis as the latter can, by activating macrophages, exacerbate underlying rheumatic condition.28 In our context, the most important infections needing chemoprophylaxis are tuberculosis, Pneumocystis carinii, nocardia, and strongyloides. Perioperative antibiotic prophylaxis is necessary for prosthetic joint replacement surgery. Tuberculosis: Before starting immunosuppressive therapy active tuberculosis should be excluded with careful history, physical examination, and an x-ray chest. Mantoux test has been used to diagnose ‘latent’ tuberculosis in developed countries and forms an indication to treat it before initiating treatment with TNF-α antagonists.32 Its relevance, sensitivity, and specificity are debatable in Indian context. Recently, ELISA Quantiferon, ELISPOT, T-SPOT tests have been approved by FDA. Studies have shown that these tests are not affected by cross-reactivity with BCG or environmental mycobacteria and correlate better with exposure to M. tuberculosis. These may replace the traditional tuberculin test to diagnose latent tuberculosis and initiate INH prophylaxis. Until then, INH prophylaxis is indicated in all patients without active tuberculosis and is to receive more than 15–20 mg prednisolone for more than 3–4 weeks.33,34 Nine months of INH prophylaxis is effective in reducing reactivation of latent tuberculosis. Same strategy may be applied to TNF-α antagonist therapy. The fear of INH resistance is unfounded as the load of TB bacilli in latent tuberculosis is so low that chances of having an INH resistant bacillus are extremely low and only a mutation can induce it.35 Malaria: Patients with splenectomy, asplenia, or hyposplenia residing in endemic areas or while traveling to an
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endemic area should receive malaria prophylaxis and penicillin prophylaxis for protection against infection with capsulated organisms. P. carinii: Indications for prophylaxis against P. carinii are not as well defined in patients with rheumatic diseases as are in HIV infected individuals. Some advocate cotrimoxazole prophylaxis for all patients receiving more than 40 mg prednisolone per day for more than a month, but opinions differ. The risk of PCP is maximum in the first few months after diagnosis of rheumatic disease and initiation of treatment. Patients receiving corticosteroid+cyclophosphomide combination and pretreatment low lymphocyte or CD4 count are at an increased risk. Whether lymphocyte count (absolute/CD4) can be used to guide decision on primary PCP prophylaxis is not clear. As against this, secondary prophylaxis is indicated to all patients recovering from PCP and is to be continued on steroids.36,37 Daily or 3 doses per week schedules of cotrimoxazole are equally effective, the latter has the advantage of lesser side-effects. In SLE, cotrimoxazole can cause aseptic meningitis. Alternatives include dapsone, atovaquone, or monthly aerosolized pentamidine. Strongyloides: It has been suggested to screen patients from endemic areas for strongyloidosis and treat the infection before initiating immunosuppressive therapy.17 Nocardia: Prophylaxis with cotrimoxazole should be provided to all patients on > 20 mg/d of prednisolone for more than 1 month.38
POST-EXPOSURE PROPHYLAXIS Herpes: Prevention of recurrent genital herpes simplex with acyclovir or famicolovir though effective carries the risk of development of resistance. Varicella zoster: After exposure, varicella zoster immunoglobulin should be administered as soon as possible (< 96 hour post exposure) (125 mg/10 kg maximum 625 U IM). Measles: Susceptible patients exposed to measles patient should be passively immunized as soon as possible (immunoglobulin 0.5 ml/kg maximum 15 ml IM).
PROSTHETIC JOINT REPLACEMENT Before joint replacement surgery patient should be examined carefully to exclude dental, urinary tract, and skin infections. If present these should be treated appropriately before surgery. Perioperative antibiotic therapy should follow standard guidelines.39
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Joshi et al.
GENERAL MEASURES
7.
Maintaining good health and nutrition, avoidance of crowded places, contact with patients with infection, and uncooked food are important nonspecific measures.
8. 9. 10.
CONCLUSION 11.
Patients suffering from rheumatic diseases are at an increased risk of infection. Both disease activity and immunosuppressive therapy contribute to the increased susceptibility. Infections are associated with increased morbidity, hospitalization, and increased mortality. Most infections are due to common organisms. Preventive strategies include effective disease control, judicious use of immunosuppressives, general health measures, proper screening of patients for infections, immunization, and antibiotic prophylaxis.
12.
13. 14.
15.
ACKNOWLEDGEMENTS Source of funding: None. Disclosure statement: Authors have declared no conflict of interest.
16.
17. 18.
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Review Article
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Rheumatologists, Orthopedic Surgeons, & Physicians