Postmarketing observational studies reporting incidence or risk of opportunistic infections as a combined outcome measure
| Author/year Country/Data source/Study dates | Disease cohort/Biologics under study | Bacterial OIs included in definition | Mycobacterial OIs included in definition | Fungal OIs included in definition | Viral OIs included in definition | Parasitic OIs included in definition | Incidence (patient-year) biologic treated Incidence (patient-year) comparator group | Risk ratio (biologic treated) (95% CI) |
|---|---|---|---|---|---|---|---|---|
| Naganuma 201310 Japan/multicentre/2009–2010 | IBD/anti-TNF | C difficile E coli S pneumoniae | M avium TB | Candidiasis Histoplasmosis | CMV EBV Herpes simplex HPV VZV | NR | NR NR | OR 1.08 (0.37 to 3.22) Infliximab |
| Beukelman 201311 USA/Medicaid database/2000–2005 | JIA/anti-TNF | Legionellosis Listeriosis Salmonellosis | Nocardiosis NTM disease TB | Aspergillosis Blastomycosis Coccidioidomycosis Cryptococcosis Histoplasmosis PJP | Herpes zoster PML | Toxoplasmosis | 300/100 000 JIA cohort* 125/100 000 Cohort without JIA | NR |
| Baddley 201312 USA/Administrative databases/1998–2007 | RA, AS, PsO, PsA, IBD/Anti-TNF | Legionellosis Listeriosis Salmonellosis | Actinomycosis Nocardiosis NTM disease TB | Aspergillosis Blastomycosis Coccidioidomycosis Cryptococcosis ‘endemic fungal infection’† Histoplasmosis PJP | None‡ | Toxoplasmosis | 270/100 000 New users anti-TNF 170/100 000 Non-biologic DMARDs | aHR 1.6 (1.0 to 2.6) New users of anti-TNF vs Non-biologic DMARDs |
| Nguyen-Khoa 201213 § USA/insurance claims database/2001–2007 | RA/anti-TNF | Diphtheria Meningococcal disease Pertussis Syphilis and other venereal diseases¶ Tetanus | Leprosy NTM disease TB | Mycoses¶ | Poliomyelitis/other non-arthropod viral diseases of central nervous system¶ Viral hepatitis** | NR | 820/100 000 Anti-TNF in last 90 days NR | NR |
| Salmon-Ceron 201114 †† France/RATIO/2004–2007 | RA, IBD, AS, PsO, PsA, JIA‡‡/anti-TNF | Listeriosis Non-typhoid bacteraemic salmonellosis | Nocardiosis NTM disease TB§§ | ‘Invasive’ aspergillosis¶ Cryptococcosis PJP | ‘Disseminated’ CMV¶ ‘Extensive’ herpes simplex¶ ‘Severe’ herpes zoster¶ Varicella with visceral involvement | Leishmaniasis | 151.6/100 000 Anti-TNF NR | OR 17.6 (4.3 to 72.9) Infliximab vs etanercept 10.28 (2.35 to 44.94) Adalimumab vs etanercept |
| Greenberg 201015 ¶¶ USA/CORRONA/2001–2006 | RA/Anti-TNF | Listeriosis | TB | Cryptococcosis Histoplasmosis PJP | Varicella zoster | NR | 3000/100 000 Anti-TNF 1600/100 000 Methotrexate | aIRR 1.67 (0.95 to 2.94) Anti-TNF vs other DMARDs |
| Garcia-Vidal 200916 ***,††† Spain/single centre/1999–2005 | RA, AS, PsA, JIA, Crohn's/infliximab | Legionellosis Listeriosis Salmonellosis S pneumoniae‡‡‡ | TB | Coccidioidomycosis Cryptococcosis Histoplasmosis | CMV HBV reactivation HCV** Zoster | Leishmaniasis Toxoplasmosis | NR NR | OR 8.0 (2 to 50) first year of infliximab |
| Marehbian 200917 §§§ USA/administrative claims database/2002–2005 | Crohn's/anti-TNF | NR | NR | NR | NR | NR | 3767/100 000 Anti-TNF 1946/100 000 Crohn's cohort not on therapy | HR 2.03 (1.10 to 3.77) Anti-TNF vs no therapy |
| Toruner 200818 USA/single centre/1998–2003 | IBD/infliximab | E coli Streptococcal infection | NTM disease TB | Blastomycosis Candidiasis Cryptococcosis Histoplasmosis | CMV EBV Herpes simplex Herpes zoster VZV | NR | NR NR | OR 4.4 (1.1 to 17) Infliximab vs no infliximab |
| Smitten 200819 USA/medical and pharmacy claims database/1999–2006 | RA/anti-TNF and anakinra | NR | Mycobacterial¶ Nocardiosis | Blastomycosis Coccidioidomycosis Histoplasmosis PJP ‘Other opportunistic mycoses’††† Systemic candidiasis | NR | NR | 65.9/100 000* RA patients 23.0/100 000 Patients without RA | NR |
| Schneeweiss 200720 USA Medicare and/Pharmacy database/1995–2003 | RA/anti-TNF | Listeriosis | NTM disease ‘Pulmonary’ TB | Aspergillosis Cryptococcosis¶¶¶ Histoplasmosis PJP | NR | Leishmaniasis | 200/100 000* Patients with RA NR | NR |
| Dixon 200621 †††,**** UK/BSRBR/2001–2005 | RA/anti-TNF | Legionellosis Listeriosis Salmonellosis | TB NTM disease | NR | NR | NR | 200/100 000 ‡‡‡‡ NR | NR |
All studies used the term OI or a similar term. For all studies it was difficult to discern if the stated definitions and/or lists or organisms/diseases were complete or if the organisms listed were just a subset of those considered opportunistic.
*OI incidence in the entire cohort, not just biologic treated.
†Defined using ICD-9 484.7 (pneumonia in systemic mycoses).
‡Considered only non-viral OIs.
§Specified a list of clinically important infections, did not specifically list OIs.
¶Not defined in primary paper.
**Primary infection or reactivation not specified.
††This table includes only the OIs reported in the primary paper. Additional infections considered to be OIs as well as some definitions were available in supplementary materials.
‡‡Also included polyarteritis nodosa, sarcoidosis, mesenteric fibrosis, pyoderma gangrenosum.
§§Not studied in this article but included in the OI definition.
¶¶Also included ‘other OIs’ in the OI definition.
***Defined OI as infectious disease related to dysfunction of the immune system due to the administration of infliximab.
†††Not clear which other organisms were considered in their definition but these were specified by authors as occurring or were screened for prior to therapy initiation.
‡‡‡Muscular abscess, unclear if any infection with S. pneumoniae was considered opportunistic.
§§§Calculation included OIs or candidiasis or TB but didn't further define OIs.
¶¶¶Aspergillosis, cryptococcosis.
****Used term bacterial intracellular infection.
‡‡‡‡Calculated by authors.
aHR, adjusted hazard ratio; aIRR, adjusted incident rate ratio; AS, ankylosing spondylitis; BSRBR, British Society for Rheumatology Biologics Register; CI, confidence interval; C difficile, Clostridium difficile; CMV, cytomegalovirus; CORRONA, Consortium of Rheumatology Researchers of North America; DMARDs, disease modifying antirheumatic drugs; E coli, Escherichia coli; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HPV, human papilloma virus; IBD, inflammatory bowel disease; ICD, International Classification of Diseases; JIA, juvenile idiopathic arthritis; M avium, Mycobacterium avium; NR, not reported; NTM, non-tuberculous mycobacteria; OIs, opportunistic infections; OR, odds ratio; PJP, Pneumocystis jirovecii pneumonia; PML, progressive multifocal leucoencephalopathy; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis; RATIO, Research Axed on Tolerance of Biotherapies; S pneumoniae, Streptococcus pneumoniae; TB, tuberculosis; TNF, tumour necrosis factor; UK, United Kingdom; USA, United States of America; VZV, varicella zoster virus.