Previous Infection Positively Correlates to the Tumor Incidence Rate of Patients with Cancer

Discussion

This study considered the link between increases in infection prevalence and the formation of malignant cancer. Our study indicated a greater rate of infection for influenza, gastroenteritis, hepatitis, and pneumonia before malignant cancer detection. The four studied diseases showed increased rate of infections in eventual cancer patients occur from 6 to 7 years onwards. These findings suggested that the annual assessment of these four infectious diseases could potentially be useful in examining the precancerous status for adults. Likewise, an increase of infection could be a sign of cancer development and inclusion of clinical immune suppression assays may further help early cancer detection. ORs of any infection in the eventual cancer patients were similar between the 2nd and 5th years. These results suggested that better infection-based immune responses are linked to the prevention of cancer. Further study is needed to clarify these trends.

We used the infection status of patients as a surrogate for immune suppression. The patients here likely had equal exposure to common infectious agents; we hypothesized that becoming symptomatic after infection was dependent on an individual's immune status. The lack of change in the infection rate in the control group, for example, in hepatitis and pneumonia, suggested that the number of symptomatic people to each infection was consistent and the increase in the infection rate in eventual cancer patients was due to immune suppression compared with the healthy cohort.

In the 6th year of our study, there were higher ORs for all four infectious diseases in most of cancer sites, suggesting immune suppression during premalignancy for various cancer types. As the number of cases for each cancer site was limited, it was difficult to correlate the occurrence of cancer in a specific area to a specific infection. Infection to hepatitis B and C viruses may cause liver cancer (15); however our limited dataset could not reveal relationships between these infections and cancer at a specific site. For cancers that are relatively rare, such as endocrinal and hematologic, blood, bone, and bone marrow cancers, the calculation of prevalence rate of infection may have been less reliable for making a comparison; thus, further analysis is needed. However, the results suggest that cancer occurrence may be linked to immune suppression.

Larger increases and greater ORs were found in cases with gastroenteritis, hepatitis, and pneumonia infections compared with those with influenza. This may have been because of the difference of infectivity between influenza and these three infectious diseases. Influenza is a common respiratory infection with a high rate of infection within only a few months, thus influenza generally has much larger sensitivity than gastroenteritis, hepatitis, and pneumonia. Thus, subjects tend to be more susceptible to influenza, even in the control group. Likewise, increased infection or increased sensitivity in eventual cancer patients might have been more obvious in gastroenteritis, hepatitis, and pneumonia infections compared with influenza infections. Similarly, less differences in the infection rate of influenza between the eventual cancer patients and healthy patients may appear during low epidemic seasons, for example, the 3rd to the 5th year in this study, when the prevalence of influenza in cases was lower than 0.10. In the 6th year (2009–2010 season), the epidemic of the new swine influenza virus [Pandemic A (H1N1)] occurred, thus the increase of infection might have been more visible than other influenza seasons. As pneumonia case could have been caused by influenza virus, the increased prevalence of pneumonia in cases may have indicated an increase of intensive influenza infections.

Few studies have addressed infection in the precancer period (5–13). Most consider infection in the precancer period of nonsolid tumors such as lymphoma, chronic lymphocytic leukemia (CLL), and myeloma; these studies discuss infection itself as the oncogenic trigger (3, 6–13). One study observed monoclonal (M-) protein, and changes in free and light chains (FLC) and γ-globulin, which are the immune-related compositions of blood and thought to be a byproduct of CLL, for 9.8 years before CLL diagnosis; up to 44% of 109 patients with CLL had M-proteins and different FLC ratios, and 3 years before the CLL diagnosis hypogammaglobulinemia was detected. Infection was suspected as a potential cause of this inflammatory response and associated with CLL formation (1). Respiratory infections, such as influenza and pneumonia, may be linked to oncogenic inflammation (9, 10). CLL was also diagnosed after pneumonia infection (OR, 1.4), and the OR increased to 1.6 during the 4 years before CLL diagnosis. Sinusitis, pharyngitis, bronchitis, cellulitis, tuberculosis, herpes zoster, and other community acquired infection induce tumorigenic inflammation (6, 7, 11–13); increased ORs were found prior to blood, bone, and lymphoma-related cancers. Therefore, further studies are needed for solid tumors to clarify our results.

Owing to the limitations of our data and the absence of any definitive index that could have been used in hematologic experiments and testing, whether infection or immunity is the most likely inflammatory cause for later tumorigenicity remains unclear. Cancer could occur when inflammation becomes chronic. For instance, although people can have HPV infection, the development of cervical cancer through inflammation post-HPV infection is thought to be dependent on immunity (18). Chronic infection only accounts for 20% of cancer causes, and overall, cell-mediated cancer development is still unclear (4). Any innate immunity disruption brought about by exposure to chemocarcinogens such as smoking, drug use, environmental pollution, and chronic or genetic conditions could be a factor that may induce cancerous inflammation (16–18). Our data provided limited information on other comorbidities, that is, exposure, genetics, or lifestyle. There are other possible precancerous indicators that might lead to oncogenesis, such as immune suppression which can be monitored by the composition of immunity-related cells such as Th, Toll-like receptor, and B cells (2, 23–26). In this precancer period, overall infection generally increases as a consequence of immune suppression (4, 5). In addition, aging is also a factor that causes immune suppression (4), which suggests the younger patients that eventually get cancer may potentially have differing levels of immune suppression compared with the healthy cohort.

One limitation of this study is that the disease trends were recorded using ICD-10 codes, thus these characteristics may have been dependent on the clinician's diagnosis for each cause (e.g., the differentiation between hepatitis A and C). We also only extracted the first cancer diagnosis for each patient, and as the observation period was limited to 8 years, we may have missed further cancer diagnoses. In this study, the precancer period was set before diagnosis of cancer; however, if there has been a delay in diagnosis, the precancer and cancer periods may have overlapped. The data also did not include information on the grade or stage of tumors, which might be potentially important to estimate each precancerous period. The study design was set to monitor the June-to-July infection trend to observe the winter-based infections; however, whether there had been any seasonal trend of each cancer formation or other setting of epidemiologic period is unknown. A series of diagnoses of infection over the years may have increased the prevalence rate of infection. Moreover, patients with infection who did not visit the hospital might have been overlooked. Influenza vaccination status may prevent infection, although a patient's influenza vaccination record was not available in our dataset. Patients who feel unwell, potentially because of cancerous status, tend to see doctors more often. Although our study considered four major infections, analysis of other infections and the timing of infection before malignant cancer detection, which can potentially be a factor for later cancer development, remains to be studied. Cancer can occur through a lifespan, thus a longer study is necessary to clarify the relationship between infections, immune suppression, and cancer formation. Our data suggest that immune suppression and increased infection could occur during the precancer period. Further studies are needed to clarify these precancer trends.