Abstract
Introduction
Antigenic stimulation is a proposed aetiologic mechanism for many haematological malignancies. Limited evidence suggests that community-acquired infections may increase the risk of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). However, associations with other myeloid malignancies including chronic myeloid leukaemia (CML) and myeloproliferative neoplasms (MPNs) are unknown.
Material and Methods
Using the Surveillance, Epidemiology and End Result (SEER)-Medicare database, fourteen community-acquired infections were compared between myeloid malignancy patients [AML (n=8,489), CML (n=3,626) diagnosed 1992–2005; MDS (n=3,072) and MPNs (n=2,001) diagnosed 2001–2005; and controls (200,000 for AML/CML and 97,681 for MDS/MPN]. Odds ratios (ORs) and 95% confidence intervals were adjusted for gender, age and year of selection excluding infections diagnosed in the 13 month period prior to selection to reduce reverse causality.
Results
Risk of AML and MDS respectively, were significantly associated with respiratory tract infections, bronchitis (ORs 1.20 [95% CI: 1.14–1.26], 1.25 [95% CI: 1.16–1.36]), influenza (ORs 1.16 [95% CI:1.07–1.25], 1.29 [95% CI: 1.16–1.44]), pharyngitis (ORs 1.13 [95% CI: 1.06–1.21], 1.22 [95% CI: 1.11–1.35]), pneumonia (ORs 1.28 [95% CI: 1.21–1.36], 1.52 [95% CI: 1.40–1.66]), sinusitis (ORs 1.23 [95% CI: 1.16–1.30], 1.25 [95% CI: 1.15–1.36]) as was cystitis (ORs 1.13 [95% CI: 1.07–1.18], 1.26 [95% CI: 1.17–1.36]). Cellulitis (OR 1.51 [95% CI: 1.39–1.64]), herpes zoster (OR 1.31 [95% CI: 1.14–1.50]) and gastroenteritis (OR 1.38 [95% CI: 1.17–1.64]) were more common in MDS patients than controls. For CML, associations were limited to bronchitis (OR 1.21 [95% CI: 1.12–1.31]), pneumonia (OR 1.49 [95% CI: 1.37–1.62]), sinusitis (OR 1.19 [95% CI: 1.09–1.29]) and cellulitis (OR 1.43 [95% CI: 1.32–1.55]) following Bonferroni correction. Only cellulitis (OR 1.34 [95% CI: 1.21–1.49]) remained significant in MPN patients. Many infections remained elevated when more than 6 years of preceding claims data were excluded.
Discussion
Common community-acquired infections may be important in the malignant transformation of the myeloid lineage. Differences in the aetiology of classic MPNs and other myeloid malignancies require further exploration.
Keywords: Infection, Myeloid Malignancy, SEER-Medicare
Introduction
Myeloid malignancies are a heterogeneous group of diseases including acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukaemia (CML) and myeloproliferative neoplasms (MPNs) that are characterised by overproduction of one or more myeloid lineages resulting in an excess of mature and immature blood cells. These malignant diseases have an incidence rate of 4.00, 4.98, 1.64 and 2.76 per 100,000 for AML, MDS, CML and MPNs, respectively[1], reflecting the rarity of these neoplasms in the general population. Incidence is higher in males than females[1]. Approximately 1,660,290 new cases of cancer will be diagnosed in the USA in 2013 with the proportion of AML, MDS, CML and MPNs accounting for 0.9%, 1.2%, 0.36% and 0.55%, respectively[1]. The aetiology of this group of neoplasms remains largely unknown. AML is preceded by MDS in approximately 30% of cases [2] and is characterised by an abnormal blast cell count in the bone marrow with atypical cell morphology[3]. CML and MPNs are genetically categorised by the presence or absence of the Philadelphia chromosome, respectively [3], with MPNs subdivided into the following disease entities: polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF)[4].
Infectious diseases, both viral and bacterial in origin, are aetiologically associated with a number of haematological malignancies, especially those of the lymphoid lineage[5]. Chronic antigenic stimulation has been suggested as an underlying mechanism for myeloid malignancies [6] with allergies and autoimmune conditions associated with an increased risk[7–10]. Infectious pathogens possess numerous virulence mechanisms permitting the synthesise of pathogenic virulence factors including M proteins, fever inducing cytokines and super antigens to induce pathogenicity in immunocompromised individuals by inhibiting or impairing natural immune function through genetic adaptation and evolution[11–13]. Exposure to common community-acquired infections in childhood and seasonal influenza epidemics have been suggested as risk factors for the development of AML and CML[7,8,14].
Few studies have investigated community-acquired infections in adulthood and subsequent risk of the myeloid malignancies[6–8]. Recently, Kristinsson et al, using data from the linked Swedish inpatient registry found an overall 30% increased risk of developing both AML and MDS following investigation of eighteen infections including the common community-acquired infections pneumonia, influenza and herpes zoster[6]. Although antigenic stimulation could be a potential causal mechanism driving development of myeloid malignancies, the findings could indicate a compromised immune system at an early stage during the process of malignant transformation[15]. To our knowledge no studies have reported on the association between antecedent community-acquired infections in adulthood and the development of CML or MPNs.
Using the United States of America (USA) Surveillance, Epidemiology and End Results (SEER)-Medicare database we sought to clarify the relationship between common community-acquired infections and subsequent risk of myeloid malignancies.
Material and Methods
Data on myeloid malignancies was obtained from the SEER-Medicare database, which has been described previously[16]. Briefly, SEER was established in 1973 to collect information on cancers diagnosed in the USA from state and metropolitan cancer registries. Currently 20 cancer registries covering approximately 28% of the US population provide demographic and clinical information[17]. Medicare is a federally funded insurance provider for individuals aged 65 years and over, covering approximately 97% of the US population[18]. Medicare comprises part A coverage (free hospital inpatient care) and part B coverage (physician and outpatient services subscribed to by 96% of beneficiaries). So AML and CML cases were available from 1992–2005 whereas MDS and MPN data was only available from 2001 to 2005 when classification was modified by the World Health Organisation[19]. Cases were defined as an individual with a primary diagnosis of a myeloid neoplasm using the international classification of morphology codes (ICD-03): AML 9896/3, MDS 9989/3, CML 9875/3 and MPN (PV 9950/3, ET 9962/3, PMF 9961/3)[18]. Controls were obtained from a 5% random sample of Medicare recipients who were alive, had at least 13 months of part A, part B and non-health maintenance organisation (HMO) coverage, who were malignancy free and previously selected to be frequency matched to larger group of all cancer types in SEER by age, gender and year of diagnosis. Cases and controls were excluded if they had less than 13 months part A, part B or HMO coverage preceding diagnosis or were aged <66 years to allow sufficient time for exposure assessment. Persons with HMO coverage were excluded as claims for individual service submissions are not required by SEER-Medicare leading to missing clinical information[17]. To avoid ascertainment bias and reverse causality, Medicare claims in the 12 months before selection were excluded. Controls may have been selected more than once in different calendar years or later as a case if they developed a myeloid malignancy[17]. Exposure ascertainment was established from one Medicare claim for a common community-acquired infection (bronchitis, common cold, influenza, pharyngitis, laryngitis, pneumonia, sinusitis, cellulitis, herpes zoster, cystitis, prostatitis, pyelonephritis, gastroenteritis and gingivitis) using physician, outpatient and/or inpatient files. Infections were chosen having a prevalence of at least 0.5% in the control population ensuring adequate power to detect differences between cases and controls.
To enable comparison of antecedent common community-acquired infections between cases and controls, odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated using unconditional polytomous logistic regression adjusted for age (66–69, 70–74, 75–79, 80–84, and 85–99 years old), gender and year of selection. Due to multiple comparisons (14 infections across 4 myeloid malignancies) Bonferroni correction (p<0.00089) was used to reduce the possibility of a chance finding and to identify the most prominent associations. Accommodation for controls who later developed a malignancy or who were reselected as a control in different calendar years were considered in the variance computation [9]. Analyses were performed over four time periods with infection claims occurring 13–30, 31–48, 49–72 or >72 months before selection. Linearity of the relationship was tested using tests for trend (ptrend). Analyses excluding individuals with human immunodeficiency virus showed similar findings (data not shown) and hence these patients were included in this report. We investigated associations by gender but not by age as data were adjusted by age and due to a small sample size the categories utilised would be too small.
Results
Comparisons between 8,489 AML and 3,626 CML cases and 200,000 controls and 3,072 MDS and 2,001 MPN cases and 97,681 controls were made. As cases were compared to controls matched to all cancer cases, for all myeloid malignancy categories, cases were more likely than controls to be older, have longer duration of Medicare coverage and more likely to be of white race, Table 1.
Table 1.
Characteristics of Cases and Controls.
| Controls 1992–2005 | Controls 2001–2005 | AML 1992–2005 | MDS 2001–2005 | CML 1992–2005 | MPN 2001–2005 | |
|---|---|---|---|---|---|---|
| Sex | ||||||
| Males | 106172 (53%) | 51591 (52%) | 4525 (53%) | 1642 (53%) | 1968 (54%) | 918 (46%) |
| Females | 93828 (47%) | 46090 (48%) | 3964 (47%) | 1430 (47%) | 1658 (46%) | 1083 (54%) |
| Age (Years) | ||||||
| 67–69 | 33780 (16.9%) | 16211 (15.8%) | 1078 (12.7%) | 277 (7.4%) | 478 (13.2%) | 308 (15.4%) |
| 70–74 | 52008 (26.0%) | 23878 (23.2%) | 1941 (22.9%) | 500 (16.3%) | 758 (21.0%) | 438 (21.9%) |
| 75–79 | 50440 (25.2%) | 24691 (24.0%) | 2146 (25.3%) | 783 (25.5%) | 885 (24.4%) | 544 (27.2%) |
| 80–84 | 36097 (18.1%) | 18671 (18.2%) | 1839 (21.7%) | 784 (25.5%) | 791 (21.8%) | 405 (20.2%) |
| 85–99 | 27675 (13.8%) | 14230 (13.9%) | 1485 (17.5%) | 778 (25.3%) | 714 (19.7%) | 306 (15.3%) |
| Race | ||||||
| White | 166827 (83.4%) | 81434 (79.3%) | 7433 (87.6%) | 2692 (87.6%) | 3200 (88.3%) | 1723 (86.1%) |
| Black | 13949 (7.0%) | 6788 (6.6%) | 453 (5.3%) | 184 (6.0%) | 220 (6.1%) | 145 (7.3%) |
| Asian | 8097 (4.1%) | 4042 (4%) | 227 (2.7%) | 91 (3.0%) | 79 (2.5%) | 57 (2.9%) |
| Hispanic | 5199 (2.6%) | 2697 (2.6%) | 127 (1.5%) | 46 (1.5%) | 53 (1.5%) | 29 (1.5%) |
| Other/Unknown | 5927 (2.9%) | 2720 (2.6%) | 249 (2.9%) | 59 (1.9%) | 74 (1.6%) | 47 (2.2%) |
| Diagnosis (selection Year) | ||||||
| 1992–1994 | 31364 (15.7%) | NA | 1130 (13.3%) | NA | 570 (15.7%) | NA |
| 1995–1998 | 39843 (19.9%) | NA | 1685 (19.9%) | NA | 772 (21.3%) | NA |
| 1999–2005 | 128793 (64.4%) | 97681 (100.0%) | 5674 (66.8%) | 3072 (100.0%) | 2284 (63.0%) | 2001 (100.0%) |
| Duration of Medicare (Months) | ||||||
| 13–60 | 57440 (28.7%) | 29730 (28.9%) | 1970 (23.2%) | 631 (20.5%) | 873 (24.1%) | 599 (30.0%) |
| 61–120 | 97485 (48.7%) | 49247 (47.9%) | 4199 (49.5%) | 1788 (58.2%) | 1794 (50.0%) | 1025 (51.2%) |
| 121–180 | 35805 (17.9%) | 9434 (9.2%) | 1808 (21.3%) | 270 (8.8%) | 757 (20.1%) | 199 (10.0%) |
| 181–240 | 9270 (4.6%) | 9270 (9%) | 512 (6.0%) | 383 (12.5%) | 202 (5.6%) | 178 (8.8%) |
Abbreviations: AML= Acute myeloid leukaemia, MDS = Myelodysplastic Syndrome, CML= Chronic myeloid leukaemia, MPN = Myeloproliferative neoplasms, OR = Odds Ratio.
Following Bonferroni correction, risk of AML was increased in patients with a claim for respiratory tract infections including bronchitis (OR 1.20 [95% CI: 1.14–1.26]), influenza (OR 1.16 [95% CI: 1.07–1.25]), pharyngitis (OR 1.13 [95% CI: 1.06–1.21]), pneumonia (OR 1.28 [95% CI: 1.21–1.36]), sinusitis (OR 1.23 [95% CI: 1.16–1.30]) and cystitis (OR 1.13 [95% CI: 1.07–1.18]) when compared to controls, Table 2. Similarly, MDS was significantly associated with claims for bronchitis (OR 1.25 [95% CI: 1.16–1.36]), influenza (OR 1.29 [95% CI: 1.16–1.44]), pharyngitis (OR 1.22 [95% CI: 1.11–1.35]), pneumonia (OR 1.52 [95% CI: 1.40–1.66]), sinusitis (OR 1.25 [95% CI: 1.15–1.36]) and cystitis (OR 1.26 [95% CI: 1.17–1.36]), as well as cellulitis (OR 1.51 [95% CI: 1.39–1.64]), herpes zoster (OR 1.31 [95% CI: 1.14–1.50]) and gastroenteritis (OR 1.38 [95% CI: 1.17–1.64]), Table 2.
Table 2.
Common community-acquired infections and their associations with AML. MDS, CML and MPNs.
| AML (1992 – 2005) (n=8,489) | (MDS 2001 – 2005) (n=3,072) | CML (1992 – 2005) (n=3,626) | MPN (2001 – 2005) (n=2,001) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| INFECTION | No. of Controls with infection (%) | No. of Cases with infection (%) | OR (95%CI)3 | p-value | No. of Controls with infection (%) | No. of Cases with infection (%) | OR (95%CI)3 | p-value | No. of Controls with infection (%) | No. of Cases with infection (%) | OR (95%CI)3 | p-value | No. of Controls with infection (%) | No. of Cases with infection (%) | OR (95%CI)3 | p-value |
| Respiratory Tract | ||||||||||||||||
| Bronchitis | 45215 (22.6%) | 2308 (27.2%) | 1.20 (1.14–1.26) | <0.001* | 26332 (27.0%) | 1051 (34.2%) | 1.25 (1.16–1.36) | <0.001* | 45215 (22.6%) | 970 (26.8%) | 1.21 (1.12–1.31) | <0.001* | 26332 (27.0%) | 572 (28.6%) | 1.05 (0.95–1.16) | 0.349 |
| Common cold | 7322 (3.7%) | 362 (4.3%) | 1.10 (0.99–1.23) | 0.075 | 4188 (4.3%) | 157 (5.1%) | 1.09 (0.93–1.29) | 0.300 | 7322 (3.7%) | 159 (4.4%) | 1.17 (1.00–1.38) | 0.056 | 4188 (4.3%) | 106 (5.3%) | 1.21 (0.99–1.48) | 0.062 |
| Influenza | 14726 (7.4%) | 760 (9.0%) | 1.16 (1.07–1.25) | <0.001* | 9991 (10.2%) | 427 (13.9%) | 1.29 (1.16–1.44) | <0.001* | 14726 (7.4%) | 322 (8.9%) | 1.19 (1.06–1.34) | 0.003 | 9991 (10.2%) | 241 (12.0%) | 1.17 (1.02–1.35) | 0.022 |
| Laryngitis | 6584 (3.3%) | 330 (3.9%) | 1.12 (1.00–1.25) | 0.054 | 3838 (3.9%) | 167 (5.4%) | 1.27 (1.08–1.50) | 0.003 | 6584 (3.3%) | 124 (3.4%) | 1.01 (0.84–1.21) | 0.908 | 3838 (3.9%) | 76 (3.8%) | 0.92 (0.73–1.16) | 0.495 |
| Pharyngitis | 22472 (11.2%) | 1107 (13.0%) | 1.13 (1.06–1.21) | <0.001* | 12732 (13.0%) | 501 (16.3%) | 1.22 (1.11–1.35) | <0.001* | 22472 (11.2%) | 420 (11.6%) | 1.0 3 (0.92–1.14) | 0.634 | 12732 (13.0%) | 291 (14.5%) | 1.09 (0.96–1.24) | 0.162 |
| Pneumonia | 30201 (15.1%) | 1684 (19.8%) | 1.28 (1.21–1.36) | <0.001* | 16201 (16.6%) | 815 (26.5%) | 1.52 (1.40–1.66) | <0.001* | 30201 (15.1%) | 806 (22.2%) | 1.49 (1.37–1.62) | <0.001* | 16201 (16.6%) | 378 (18.9%) | 1.15 (1.03–1.30) | 0.016 |
| Sinusitis | 36249 (18.1%) | 1867 (22.0%) | 1.23 (1.16–1.30) | <0.001* | 21513 (22.0%) | 828 (27.0%) | 1.25 (1.15–1.36) | <0.001* | 36249 (18.1%) | 748 (20.6%) | 1.19 (1.09–1.29) | <0.001* | 21513 (22.0%) | 463 (23.1%) | 1.03 (0.92–1.14) | 0.628 |
| Skin | ||||||||||||||||
| Cellulitis | 34426 (17.2%) | 1927 (22.7%) | 1.31 (1.24–1.38) | <0.001 | 19513 (20.0%) | 943 (30.7%) | 1.51 (1.39–1.64) | <0.001* | 34426 (17.2%) | 871 (24.0%) | 1.43 (1.32–1.55) | <0.001* | 19513 (20.0%) | 510 (25.5%) | 1.34 (1.21–1.49) | <0.001* |
| Herpes Zoster | 8857 (4.3%) | 459 (5.4%) | 1.18 (1.07–1.30) | <0.001 | 5047 (5.2%) | 233 (7.6%) | 1.31 (1.14–1.50) | <0.001* | 8857 (4.3%) | 171 (4.7%) | 1.04 (0.89–1.22) | 0.631 | 5047 (5.2%) | 109 (5.4%) | 1.02 (0.83–1.24) | 0.872 |
| Urinary Tract | ||||||||||||||||
| Cystitis1 | 56813 (28.4%) | 2764 (32.6%) | 1.13 (1.07–1.18) | <0.001* | 31594 (32.3%) | 1270 (41.3%) | 1.26 (1.17–1.36) | <0.001* | 56813 (28.4%) | 1146 (31.6%) | 1.09 (1.01–1.18) | 0.019 | 31594 (32.3%) | 699 (34.9%) | 1.04 (0.94–1.15) | 0.405 |
| Prostatitis2 | 16408 (8.2%) | 766 (9.0%) | 1.04 (0.96–1.12) | 0.379 | 9185 (9.4%) | 337 (11.0%) | 1.05 (0.93–1.19) | 0.428 | 16408 (8.2%) | 358 (9.9%) | 1.16 (1.04– 1.31) | 0.012 | 9185 (9.4%) | 172 (8.6%) | 1.04 (0.88–1.23) | 0.648 |
| Pyelonephritis1 | 3529 (1.8%) | 184 (2.2%) | 1.16 (0.99–1.35) | 0.060 | 1851 (1.9%) | 86 (2.8%) | 1.32 (1.06–1.64) | 0.014 | 3529 (1.8%) | 93 (2.6%) | 1.39 (1.13–1.71) | 0.002 | 1851 (1.9%) | 41 (2.0%) | 1.02 (0.74–1.39) | 0.908 |
| Gastrointestinal | ||||||||||||||||
| Gastroenteritis | 5312 (2.7%) | 272 (3.2%) | 1.13 (0.99–1.28) | 0.065 | 3027 (3.1%) | 148 (4.8%) | 1.38 (1.17–1.64) | <0.001* | 5312 (2.7%) | 127 (3.5%) | 1.26 (1.05–1.51) | 0.013 | 3027 (3.1%) | 70 (3.5%) | 1.08 (0.85–1.38) | 0.517 |
| Gingivitis | 917 (0.5%) | 58 (0.7%) | 1.42 (1.09–1.86) | 0.010 | 525 (0.5%) | 22 (0.7%) | 1.25 (081–1.93) | 0.307 | 917 (0.5%) | 24 (0.7%) | 1.42 (0.94–2.14) | 0.092 | 525 (0.5%) | <11‡ (0.4%) | 0.80 (0.42–1.56) | 0.519 |
Abbreviations: AML= Acute myeloid leukaemia, MDS = Myelodysplastic Syndrome, CML= Chronic myeloid leukaemia, MPN = Myeloproliferative neoplasms, OR = Odds Ratio, CI = Confidence Intervals.
Females only.
Males only.
Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age (66–69, 70–74, 75–79, 80–84 and 85+ years), gender and calendar year of selection.
Statistically significant p-value <0.00089 (Bonferroni corrected).
Observations, in which the number of exposed patients is between one and ten, are listed as ‘<11’ to preserve subjects’ anonymity, in accordance with the SEER-Medicare data use agreement.
For CML, bronchitis (OR 1.21 [95% CI: 1.12–1.31]), pneumonia (OR 1.49 [95% CI: 1.37–1.62]), sinusitis (OR 1.19 [95% CI: 1.09–1.29]) and cellulitis (OR 1.43 [95% CI: 1.32–1.55]) were significantly associated with an increased risk compared to controls following Bonferroni correction, Table 2. Cellulitis (OR 1.34 [95% CI: 1.21–1.49]) was the only infection to remain associated with MPNs, Table 2.
Many associations remained significant when longer latency periods preceding selection were utilised, Table 3. Pneumonia was the only infection to remain significantly associated with AML, MDS and CML across all time points, Table 3. Similarly, sinusitis remained associated with AML across all time points, Table 3. Additionally, bronchitis and cystitis claims were more common in AML cases compared to controls >72 months (6 years) before selection, Table 3. This time frame was also emphasised for MDS patients with cystitis and cellulitis claims which remained elevated in cases compared to controls >6 years before diagnosis. For CML, sinusitis and cellulitis were associated with longer latency periods but no clear trends were demonstrated across time periods, Table 3. Infection associations investigated by gender revealed no statistical significance between males and females.
Table 3.
Latency analysis of statistically significant community-acquired infections.
| INFECTION | 13–30 Months OR (95% CI)2 | 31–48 Months OR (95% CI)2 | 49–72 Months OR (95% CI)2 | >72 Months OR (95% CI)2 | p-value for trend |
|---|---|---|---|---|---|
| AML 1991–2005 | |||||
| Bronchitis | 1.06 (0.97, 1.16) | 1.43 (1.31, 1.57) | 1.24 (1.14, 1.35) | 1.14 (1.04, 1.24) | 0.732 |
| Influenza | 1.23 (1.11, 1.37) | 1.15 (0.95, 1.40) | 1.12 (0.94, 1.33) | 1.04 (0.87, 1.24) | 0.090 |
| Pharyngitis | 1.02 (0.90, 1.17) | 1.27 (1.11, 1.45) | 1.19 (1.05, 1.34) | 1.09 (0.97, 1.23) | 0.611 |
| Pneumonia | 1.30 (1.18, 1.43) | 1.39 (1.25, 1.54) | 1.26 (1.13, 1.40) | 1.19 (1.07, 1.33) | 0.153 |
| Sinusitis | 1.21 (1.10, 1.34) | 1.32 (1.19, 1.47) | 1.23 (1.12, 1.35) | 1.18 (1.08, 1.30) | 0.566 |
| Cystitis1 | 1.04 (0.95, 1.13) | 1.15 (1.06, 1.26) | 1.14 (1.05, 1.24) | 1.17 (1.08, 1.27) | 0.033 |
| MDS 2001–2005 | |||||
| Bronchitis | 1.22 (1.05, 1.41) | 1.50 (1.30, 1.73) | 1.32 (1.17, 1.49) | 1.08 (0.95, 1.22) | 0.002 |
| Influenza | 1.45 (1.27, 1.65) | 1.31 (0.96, 1.79) | 1.14 (0.88, 1.47) | 1.01 (0.79, 1.29) | 0.004 |
| Pharyngitis | 1.21 (0.99, 1.50) | 1.63 (1.35, 1.98) | 1.32 (1.11, 1.57) | 0.96 (0.80, 1.14) | 0.006 |
| Pneumonia | 1.44 (1.24, 1.67) | 1.77 (1.52, 2.07) | 1.72 (1.50, 1.97) | 1.22 (1.05, 1.43) | 0.130 |
| Sinusitis | 1.10 (0.92, 1.31) | 1.56 (1.33, 1.82) | 1.38 (1.21, 1.57) | 1.08 (0.94, 1.23) | 0.226 |
| Cystitis1 | 1.22 (1.06, 1.40) | 1.22 (1.06, 1.40) | 1.42 (1.26, 1.59) | 1.18 (1.05, 1.32) | 0.885 |
| Cellulitis | 1.64 (1.43, 1.88) | 1.52 (1.31, 1.76) | 1.64 (1.44, 1.87) | 1.26 (1.09, 1.45) | 0.016 |
| Herpes zoster | 1.45 (1.13, 1.86) | 1.46 (1.12, 1.92) | 1.24 (0.95, 1.63) | 1.11 (0.84, 1.46) | 0.101 |
| Gastroenteritis | 1.50 (1.08, 2.06) | 1.76 (1.26, 2.46) | 1.36 (0.97, 1.89) | 1.04 (0.73, 1.49) | 0.080 |
| CML 1991–2005 | |||||
| Bronchitis | 1.06 (0.92, 1.22) | 1.43 (1.24, 1.64) | 1.34 (1.18, 1.51) | 1.08 (0.95, 1.24) | 0.942 |
| Pneumonia | 1.41 (1.23, 1.61) | 1.83 (1.58, 2.11) | 1.49 (1.29, 1.73) | 1.28 (1.09, 1.51) | 0.230 |
| Sinusitis | 1.01 (0.86, 1.19) | 1.29 (1.10, 1.52) | 1.24 (1.07, 1.43) | 1.22 (1.06, 1.41) | 0.122 |
| Cellulitis | 1.49 (1.31, 1.70) | 1.47 (1.27, 1.70) | 1.38 (1.20, 1.60) | 1.36 (1.17, 1.59) | 0.281 |
| MPN 2001–2005 | |||||
| Cellulitis | 1.32 (1.10, 1.59) | 1.39 (1.15, 1.67) | 1.54 (1.30, 1.83) | 1.11 (0.91, 1.36) | 0.369 |
Abbreviations: AML= Acute myeloid leukaemia, MDS = Myelodysplastic Syndrome, CML= Chronic myeloid leukaemia, MPN = Myeloproliferative neoplasms, OR = Odds Ratio, CI = Confidence Intervals
Females only.
Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age (66–69, 70–74, 75–79, 80–84 and 85+ years), gender and year of diagnosis selection.
p-value to 3 decimal places.
Discussion
Evidence to suggest an association between AML, MDS and antecedent community-acquired infections is lacking[8,20]. Our findings however, similar to a recent report from Sweden[6], suggest that several infections, particularly those affecting the respiratory tract, are significantly associated with AML and MDS even when they occur many years before diagnosis. Likewise, in both studies an excess risk of AML and MDS was observed with urinary tract and skin infections[6]. We report for the first time on a range of common community-acquired infections potentially associated with the development of CML and highlight the lack of association for most infections (except for cellulitis) with MPNs including PV, ET and PMF.
Consistent with the findings from the Swedish study, laryngitis, cellulitis, herpes zoster, pyelonephritis and gastroenteritis were significantly associated with AML however significance did not remain following adjustment for multiple comparisons[6]. These infections were also more common in MDS patients compared to controls, mirroring the reported association between cellulitis and MDS[6]. Although slightly fewer AML cases were included in this study compared to the Swedish investigation we report on double the number of MDS cases providing greater statistical power. Additionally, utilisation of both inpatient and outpatient data is likely to have enabled enhanced acquisition of diagnoses commonly made in primary care settings reducing selection and information biases associated with hospital-based studies.
There are numerous potential explanations for these reported findings. They could reflect a compromised immune system many years before diagnosis making patients more susceptible to transient infections[21,22]. Alternatively, pathological mechanisms of these infections could influence the development of myeloid malignancies in patients by altering both genetic regulation and immune function[10]. The white cells of the myeloid lineage are components of the innate immune system, the first line of defence against infectious pathogens, and could be susceptible to genetic alteration in myeloblast precursor cells causing clonal expansion[23].
As MDS often precedes AML[2] infections could drive this transformation. However, our results suggest that these infections affect earlier in the disease process as most were similarly associated with both MDS and AML. Population-based studies investigating factors affecting progression from MDS to AML in relation to infectious agents are warranted.
To our knowledge the role of community-acquired infections in the development of CML or MPN has not previously been investigated in population-based datasets. We found that CML, and to a much larger extent MPNs, were associated with fewer infections than AML or MDS mirroring the differing associations reported with autoimmune conditions[8,10]. Pneumonia, sinusitis and cellulitis remained significantly associated with CML following the exclusion of >6 years of claims data. Reflective of their commonality within the community these infections are frequently seen in patients with haematological malignancies[24,25] with sinusitis suggested as an underlying disease [26,27]. The slow progression of CML is often asymptomatic in the early stages of disease progression. The gradual increase in the number of peripheral myeloid cells could be stimulated by infection, in turn encouraging disease progression many years before diagnosis. Infections were not associated with CML closer to diagnosis suggesting that further investigation is warranted. Likewise further investigation of the interrelationship between cellulitis and MPNs is warranted.
The main strengths of this study were the large population-based sample of patients with AML, MDS, CML and MPNs which were available from the SEER cancer registries covering approximately 28% of the US population[18]. However, the under reporting of myeloid malignancies, particularly MDS and MPNs, could reduce case ascertainment[28]. Some studies have reported a lower age of diagnosis for CML[29,30] which may have an impact on the generalisability of these findings to CML patients as a whole. Only data on people aged 66 years and over were available which limited any extrapolation of the association between infections and myeloid malignancies to the elderly population of the USA. Reliance on Medicare claims means that there may be misclassification of exposure status or an under reporting of infections not commonly requiring interaction with health care professionals. However in comparison to other population based studies observing a higher frequency of infection, notably pneumonia[31] and those limited to hospital diagnoses[6], our study should reflect a more accurate ascertainment of exposure. In addition, the non-significant associations with conditions such as the common cold suggest against differences in health seeking behaviour of cases and controls. Due to the multiple comparisons undertaken some associations may have resulted from chance. However, we crudely adjusted for this by using Bonferroni correction with many associations remaining highly significant. Although the Medicare dataset did not facilitate adjustment of potential confounders such as diet, socioeconomic status and smoking habits, it is unlikely that these would have exerted a strong effect as these factors are not strongly associated with disease outcome[32–35].
In conclusion, we found that common community-acquired infections were more common in AML, MDS and to a lesser extent CML patients compared to controls adding strength to the recently reported association between infectious diseases and AML and MDS[7]. This suggests that infections may instigate chronic antigenic stimulation and immune disruption which could be a trigger for chronic development of myeloid malignancies or that underlying immune disturbances may alter genetic regulation of the myeloid lineage driving malignant transformation. Further investigations are needed to improve our understanding of infectious disease mechanisms and the risk of myeloid malignancies. In addition, exploration of the differences in aetiology of classic MPNs and other myeloid malignancies are warranted.
Acknowledgments
Acknowledgements and funding
The authors would like to thank the efforts of the Applied Research Program, NCI; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumour registries in the creation of the SEER-Medicare database. This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. This study was supported, in part, by the Intramural Research Program of the National Cancer Institute. GJT is a PhD candidate at Queen’s University Belfast supported by funding from MPD Voice. CMcS is a PhD candidate at Queen’s University Belfast and is in receipt of a Department for Learning and Employment (Northern Ireland) scholarship.
Footnotes
Conflict of interest
LAA was the principle investigator and takes primary responsibility for the paper; EAE provided access to the dataset and coordinated the research; GJT wrote the paper; EAE, LAA, MFMc, CMMc and MC contributed to the interpretation of the results and writing of the paper. All authors approved the final version of the article. The authors report no potential conflicts of interest.
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