Table 1 Summary of case–control studies to support the association between Chlamydia pneumoniae infection and lung cancer

Serology-based investigations

Xu X, Southeast China [9]

Cases- 449

Controls-512

All participants provided a 5 ml fasting peripheral venous blood sample for testing C. pneumoniae-specific IgG and IgA by using micro-immunofluorescence

Compared to those with no evidence of serum C. pneumoniae IgA or C. pneumoniae IgG, those with both C. pneumoniae IgG + and IgA + had 2.00 times the risk (95% CI: 1.34–3.00) of developing lung cancer

C. pneumoniae infection is potentially associated with primary lung cancer in the Chinese Han population and has combined effects with smoking, passive smoking, and a family history of cancer

Chaturv-edi AK [10]

Cases-593, Controls- 671

Assessed C. pneumoniae seropositivity and endpoint antibody titers (IgG and IgA against C. pneumoniae elementary bodies and IgG against CHSP-60). (Chlamydia heat shock protein-60 (CHSP-60) antibodies, a marker for chronic chlamydial infection.)

C. pneumoniae seropositivity by microimmunofluorescence IgG or IgA antibodies was not associated with lung cancer [odds ratio of 0.88 and 95% confidence interval (95% CI) of 0.69–1.13 for IgG; odds ratio of 0.98 and 95% CI of 0.75–1.27 for IgA]. In contrast, individuals seropositive for CHSP-60 IgG antibodies had significantly increased lung cancer risk (odds ratio, 1.30; 95% CI, 1.02–1.67), and risk increased with increasing antibody titers (P = 0.006)

CHSP-60 seropositivity and elevated antibody titers were associated with significantly increased risk for subsequent lung cancer, supporting an etiologic role for C. pneumoniae infection in lung carcinogenesis

Littman AJ [11]

508 pairs of matched cases and controls

Investigate whether IgA antibody titers to C. pneumoniae measured by the microimmunofluorescence test are associated with lung cancer risk after controlling for confounders

Individuals with antibody titers > or = 16 had 1.2 times the risk of lung cancer (95% confidence interval, 0.9–1.6) compared to those with lower titers. There was a significant trend (P = 0.007) of increasing odds ratios with increasing IgA titers primarily due to an odds ratio of 2.8 (95% confidence interval, 1.1–6.7) associated with titers > or = 256. Lung cancer risk associated with IgA titers > or = 16 was more substantial among former smokers

Future studies using precise measures of chronic C. pneumoniae status are needed to determine better the role of this organism in the etiology of lung cancer

Jackson LA [13], western Washington

Cases-143, Controls-147

Serum specimens were tested for C. pneumoniae IgG, IgM, and IgA antibodies

IgA antibody titer 216 was independently associated with risk of lung cancer among subjects < 60 years of age [odds ratio (OR), 2.67; 95% confidence interval (CI), 1.21–5.89] but not among older subjects (OR, 0.69; 95% CI, 0.34–1.43)

Additional studies, including prospective serological evaluations, are needed to assess this association's possible significance further

Laurila AL [14]

230 smoking males and matched pairs

The diagnosis of chronic infection was based on stable levels of positive specific IgA antibody (titer > or = 16) and immune complex (titer > or = 4)

Markers suggesting chronic C. pneumoniae infection were present in 52% of cases and 45% of controls and hence were positively associated with the incidence of lung cancer (OR 1.6; 95% confidence interval [CI] 1.0–2.3)

Before concluding that C. pneumoniae infection is a new independent risk factor for lung cancer, corroboration from other studies with a larger number of cases and longer follow-up is needed

Liu Z [15], China

Cases- 192 adult women, Controls-90

C. pneumoniae IgG antibodies were tested with the use of an enzyme-linked immunosorbent assay

C. pneumoniae IgG seropositivity prevalence was 61.98% of cases and 28.89% of controls (P < 0.05)

C. pneumoniae infection may be a risk factor for lung cancer

Kocazeybek B [16]

Cases- 123smokers, controls-123

Blood samples (5 ml) were withdrawn at the time of diagnosis and one month later. The values between IgG > / = 512 and IgA > / = 40 were set as the criteria for chronic Chlamydophila pneumoniae infections

Chlamydophila pneumoniae IgG antibody titers of > / = 512 and IgA antibody titers of > / = 40 were found at a higher rate than in the control group. This ratio was not significant for female patients. In chronic Chlamydophila pneumoniae infections, Chlamydophila pneumoniae antibody titres with values IgG > / = 512 and IgA > / = 40 were found in a total of 62 (50.4%) cases

Chronic Chlamydophila pneumoniae infections were seen statistically more often in male patients with carcinoma aged 55 years or younger. This study supports the idea that chronic Chlamydophila pneumoniae infection increases the risk of lung carcinoma

Koyi H [17]

Prospective 2 year study of 210 patients. (136 M, 74 F)

Blood specimens for Cpn serology and throat specimens for DNA analysis were taken

Both males and females had a significant prevalence of high antibody titers compared to controls

Molecular-based investigation

Xiong WM [12], China

12 matched pairs

Genomic DNA and RNA were extracted, and DNA methylation and mRNA levels were detected using the Infinium Human Methylation 450 Beadchip array and mRNA + lncRNA Human Gene Expression Microarray

According to the quantitative analysis of DNA methylation, the methylation level of the RIPK3 promoter region was significantly different between Cpn-positive cancerous and adjacent tissues but not between Cpn-negative cancerous and adjacent tissues

Hypomethylation of the RIPK3 promoter region increases RIPK3 expression, leading to regulated programmed necrosis and activation of NF-κB transcription factors, which may contribute to the development and progression of Cpn-related lung cancer