Table 1

Postmarketing observational studies reporting incidence or risk of opportunistic infections as a combined outcome measure

Country/Data source/Study dates
Disease cohort/Biologics under studyBacterial OIs included in definitionMycobacterial OIs included in definitionFungal OIs included in definitionViral OIs included in definitionParasitic OIs included in definitionIncidence (patient-year) biologic treated
Incidence (patient-year) comparator group
Risk ratio (biologic treated) (95% CI)
Naganuma 201310
IBD/anti-TNFC difficile E coli
S pneumoniae
M avium
Candidiasis HistoplasmosisCMV
Herpes simplex HPV
OR 1.08 (0.37 to 3.22) Infliximab
Beukelman 201311
USA/Medicaid database/2000–2005
JIA/anti-TNFLegionellosis Listeriosis SalmonellosisNocardiosis NTM disease TBAspergillosis Blastomycosis Coccidioidomycosis Cryptococcosis Histoplasmosis PJPHerpes zoster PMLToxoplasmosis300/100 000
JIA cohort*
125/100 000 Cohort without JIA
Baddley 201312
USA/Administrative databases/1998–2007
RA, AS, PsO, PsA, IBD/Anti-TNFLegionellosis Listeriosis SalmonellosisActinomycosis Nocardiosis NTM disease TBAspergillosis Blastomycosis Coccidioidomycosis Cryptococcosis ‘endemic fungal infection’† Histoplasmosis
None‡Toxoplasmosis270/100 000
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-TNFDiphtheria Meningococcal disease Pertussis Syphilis and other venereal diseases¶ TetanusLeprosy NTM disease TBMycoses¶Poliomyelitis/other non-arthropod viral diseases of central nervous system¶ Viral hepatitis**NR820/100 000 Anti-TNF in last 90 days
Salmon-Ceron 201114 ††
RA, IBD, AS, PsO, PsA, JIA‡‡/anti-TNFListeriosis Non-typhoid bacteraemic salmonellosisNocardiosis NTM disease TB§§‘Invasive’ aspergillosis¶ Cryptococcosis PJP‘Disseminated’ CMV¶ ‘Extensive’ herpes simplex¶ ‘Severe’ herpes zoster¶ Varicella with visceral involvementLeishmaniasis151.6/100 000 Anti-TNF
OR 17.6 (4.3 to 72.9) Infliximab vs etanercept
10.28 (2.35 to 44.94) Adalimumab vs etanercept
Greenberg 201015 ¶¶
RA/Anti-TNFListeriosisTBCryptococcosis Histoplasmosis
Varicella zosterNR3000/100 000 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/infliximabLegionellosis Listeriosis Salmonellosis
S pneumoniae‡‡‡
TBCoccidioidomycosis Cryptococcosis HistoplasmosisCMV
HBV reactivation HCV** Zoster
Leishmaniasis ToxoplasmosisNR
OR 8.0 (2 to 50) first year of infliximab
Marehbian 200917 §§§
USA/administrative claims database/2002–2005
Crohn's/anti-TNFNRNRNRNRNR3767/100 000 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/infliximabE coli Streptococcal infectionNTM disease TBBlastomycosis Candidiasis Cryptococcosis HistoplasmosisCMV
Herpes simplex Herpes zoster VZV
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 anakinraNRMycobacterial¶ NocardiosisBlastomycosis Coccidioidomycosis Histoplasmosis
PJP ‘Other opportunistic mycoses’†††
Systemic candidiasis
NRNR65.9/100 000* RA patients
23.0/100 000 Patients without RA
Schneeweiss 200720
USA Medicare and/Pharmacy database/1995–2003
RA/anti-TNFListeriosisNTM disease ‘Pulmonary’ TBAspergillosis Cryptococcosis¶¶¶ Histoplasmosis
NRLeishmaniasis200/100 000* Patients with RA
Dixon 200621 †††,****
RA/anti-TNFLegionellosis Listeriosis SalmonellosisTB
NTM disease
NRNRNR200/100 000 ‡‡‡‡
  • 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.