Short and long term mortality associated with foodborne bacterial gastrointestinal infections: registry based study

Abstract

Objectives

To determine the excess mortality associated with infections with Salmonella, Campylobacter, Yersinia enterocolitica, and Shigella and to examine the effect of pre-existing illness.

Design

Registry based, matched cohort study.

Setting

Denmark.

Participants

48 857 people with gastrointestinal infections plus 487 138 controls from the general population.

Main outcome measure

One year mortality among patients with gastrointestinal infections compared with controls after adjustment for comorbidity.

Results

1071 (2.2%) people with gastrointestinal infections died within one year after infection compared with 3636 (0.7%) controls. The relative mortality within one year was 3.1 times higher in patients than in controls. The relative mortality within 30 days of infection was high in all four bacterial groups. Furthermore, there was excess mortality one to six months after infection with Yersinia enterocolitica (relative risk 2.53, 95% confidence interval 1.38 to 4.62) and from six months to one year after infection with Campylobacter (1.35, 1.02 to 1.80) and Salmonella (1.53, 1.31 to 1.79).

Conclusions

Infections with all these bacteria were associated with an increased short term risk of death, even after pre-existing illnesses were taken into account. Salmonella, Campylobacter, and Yersinia enterocolitica infections were also associated with increased long term mortality.

What is already known on this topic

Foodborne bacterial infections have a major effect on the public health and economy of industrialised countries

Most estimates of mortality are short term and do not take into account coexisting illnesses

What this study adds

Patients infected with Salmonella, Campylobacter, Yersinia, and Shigella had higher 30 day mortality than controls after comorbidity was taken into account

Salmonella, Campylobacter, and Yersinia infections were also associated with increased long term mortality

The number of deaths from foodborne diseases is likely to be underestimated

Introduction

Foodborne bacterial infections have a major and perhaps increasing effect on the public health and economy of industrialised countries.^1–4 It is difficult to determine the exact mortality associated with bacterial infections that are usually foodborne. Pathogen specific surveillance systems rarely collect systematic information on outcomes of illness, and outcome specific surveillance systems (such as death certificates) greatly under-report many pathogen specific conditions.⁵

The quantification of the public health impact of bacterial foodborne infections is further complicated by their interaction with chronic underlying diseases and associated conditions.⁶,⁷ We report new estimates of the excess mortality associated with infections with Salmonella, Campylobacter, Yersinia enterocolitica, and Shigella spp. By using data from Danish population based registries, we determined the long term effect on survival adjusted for coexisting illness.

Methods

We obtained data for the study from the national registry of enteric pathogens, the Danish civil registration system, the national registry of patients, and the cancer registry. Bacterial foodborne infections are diagnosed at our institute and 10 local clinical microbiology laboratories. The institute is notified of positive findings and records them in the national registry of enteric pathogens. If a bacterial species or Salmonella serotype is found more than once from the same person within six months, only the first positive sample is registered.

We included all patients with culture confirmed infections with non-typhoidal Salmonella, Campylobacter spp, Yersinia enterocolitica, or Shigella spp registered between 1 January 1991 and 31 October 1999. To compare the mortality of patients with that of people without known bacterial gastrointestinal infections, we used data from the civil registration system, which assigns a personal identification number to all liveborn children and citizens of Denmark.⁸ For every patient, we randomly selected 10 people matched for age, sex, and county of residence who were alive on the date the sample was received. We obtained information on vital status, date of death or emigration, and county of residence for patients and controls. Finally, we obtained data on all hospital discharges, outpatient attendances (since January 1995), and cancer diagnoses up to five years before entry in the study from the national registry of patients and the cancer registry. This allowed us to control for pre-existing illness (comorbidity).

Statistical methods

We created a comorbidity index using the principles described by Charlson et al.⁹ This index is a sum of weights corresponding to the number and severity of coexisting illnesses. We first calculated the relative mortality associated with different diagnostic groups, using data from the background population. These relative rates served as weights in the further survival analyses. We then created the index by adding log transformed weights, taking into account multiple discharges before entry into the study. We excluded diagnostic groups associated with a relative mortality less than 1.2. We forced this index into the survival analyses, so that any difference between the mortality of patients and the general population quantified mortality beyond that attributable to underlying illness.^10–13

To compare the mortality of patients with that of the general population, we stratified the data so that each stratum contained one patient and 10 controls. We preserved the matching in all analyses by using conditional proportional hazard regression to control for age, sex, and county of residence. The analysis was conducted with SAS software (version 6.12), with proportional hazards regression procedure (PHREG).

Results

During the study, 49 149 patients had bacterial gastrointestinal infections registered, 48 857 (99.4%) of whom could be linked to the civil registry system. Of these patients, 26 974 (55.2%) had Salmonella infection, 16 180 (33.1%) Campylobacter infection, 4045 (8.3%) Yersinia infection, and 1658 (3.4%) Shigella infection. A total of 1071 (2.2%) deaths were registered up to one year after infection compared with 3636 (0.7%) deaths among the 487 138 controls. Patients infected with one of the four enteric pathogens had a 3.1 times higher mortality than controls (95% confidence interval 2.89 to 3.33).

A total of 2645 patients had one or more of the diseases included in the comorbidity index. Table 1 shows the number of patients and the various diagnostic groups used in the index, the weights of the diagnostic groups, and the relative risk of belonging to one of the diagnostic groups compared with the reference group. Underlying conditions were more common among patients than in the control group, particularly AIDS related illness, metastatic cancers, and lymphomas or leukaemia. After we adjusted for comorbidity, the relative mortality fell from 3.10 to 2.56 (95 % confidence interval 2.38 to 2.76).

Table 1.

 Comorbidity in 48 857 patients with Salmonella, Campylobacter, Shigella, and Yersinia infections, Denmark, 1991-9

Diagnostic group (weight in survival analysis)	Salmonella (n=26 974)			Campylobacter (n=16 180)			Shigella (n=1658)			Yersinia (n=4045)
	No of cases	Relative risk* (95% CI)		No of cases	Relative risk* (95% CI)		No of cases	Relative risk* (95% CI)		No of cases	Relative risk* (95% CI)
AIDS related illness (3.68)	54	13.16 (8.76 to 19.75)		44	15.17 (9.49 to 24.25)		6	12.01 (3.66 to 39.41)		4	7.98 (2.14 to 29.74)
Metastatic cancers (1.72)	123	2.49 (2.05 to 1.62)		37	2.29 (1.60 to 3.28)		6	4.00 (1.55 to 10.33)		1	0.28 (0.02 to 2.02)
Liver diseases (1.61)	135	3.64 (2.97 to 4.46)		38	1.55 (1.10 to 2.18)		8	3.34 (1.50 to 7.44)		6	1.71 (0.72 to 4.07)
Lymphoma or leukaemia (1.47)	222	3.42 (2.94 to 3.98)		67	2.72 (2.08 to 3.57)		4	2.66 (0.88 to 8.04)		14	3.04 (1.67 to 5.54)
Asthma or COPD (1.34)	633	1.74 (1.60 to 1.90)		315	1.49 (1.32 to 1.68)		15	0.90 (0.53 to 1.53)		82	1.47 (1.16 to 1.85)
Movement disorders† (1.29)	93	1.42 (1.14 to 1.76)		30	0.99 (0.68 to 1.44)		3	0.88 (0.27 to 2.87)		7	1.13 (0.51 to 2.46)
Diabetes (1.21)	639	2.13 (1.95 to 2.32)		227	1.67 (1.45 to 1.92)		14	1.04 (0.60 to 1.81)		57	1.97 (1.48 to 2.62)
Other diseases‡ (1.16)	5 898	1.91 (1.85 to 1.97)		2 790	1.74 (1.67 to 1.82)		212	1.33 (1.14 to 1.55)		761	1.81 (1.66 to 1.97)
No diagnosis (1)	25 246	0.97		15 485	0.99		1604	0.99		3877	0.99

As some patients had more than one disease, the sum of patients with each type of infection is higher than the total number of patients. 

^*Relative risk of comorbidity in patients with bacterial gastrointestinal infection compared with the general population. 

^†Parkinson's disease, Huntington's disease, and multiple sclerosis. 

^‡Cardiovascular diseases (angina, arrhythmia, cerebrovascular, hypertension, myocardial infarction, peripheral vascular); pulmonary diseases other than asthma and chronic obstructive pulmonary disease; endocrine diseases other than diabetes; rheumatological diseases; infections other than HIV, tuberculosis, and gastroenteritis; gastrointestinal other than hepatic and inflammatory bowel diseases. 

Table 2 summarises the cumulative mortality (Kaplan-Meier estimates) and relative mortality by time since infection. The relative mortality in the 30 days after the episode date ranged from 3.63 to 22.03 for the four bacteria. No excess mortality was seen after 30 days for Shigella and 180 days for Yersinia enterocolitica, but for Salmonella and Campylobacter, we found an excess mortality up to one year after infection.

Table 2.

 Mortality among 48 857 patients with Salmonella, Campylobacter, Shigella, and Yersinia infection compared with matched controls from the general population and adjusted for comorbidity, Denmark, 1991-9

Type of infection	Time after infection (days)
	0-365	0-30	31-180	181-365
Salmonella
Relative mortality (95% CI)	2.85 (2.61 to 3.10)	13.31 (11.05 to 16.04)	2.22 (1.92 to 2.55)	1.53 (1.31 to 1.79)
Cumulative mortality in patients/controls (%)	3.11/0.97	1.23/0.08	1.08/0.42	0.81/0.47
Campylobacter
Relative mortality (95% CI)	1.86 (1.56 to 2.20)	4.99 (3.27 to 7.60)	1.85 (1.43 to 2.41)	1.35 (1.02 to 1.80)
Cumulative mortality in patients/controls (%)	1.18/0.52	0.27/0.04	0.50/0.23	0.41/0.25
Shigella
Relative mortality (95% CI)	1.80 (0.85 to 3.83)	22.03 (4.12 to 117.70)	2.12 (0.58 to 7.80)	0.46 (0.10 to 2.16)
Cumulative mortality in patients/controls (%)	0.66/0.32	0.30/0.01	0.24/0.10	0.12/0.21
Yersinia
Relative mortality (95% CI)	2.10 (1.40 to 3.16)	3.63 (1.28 to 10.26)	2.53 (1.38 to 4.62)	1.43 (0.74 to 2.79)
Cumulative mortality in patients/controls (%)	0.79/0.38	0.17/0.03	0.35/0.15	0.27/0.19

Table 3 shows the relative mortality before and after we adjusted for coexisting illness. After adjusting for comorbidity, we found that mortality in patients infected with Salmonella dublin was more than 12 times higher than in the control group. For other Salmonella serotypes, Campylobacter, and Yersinia enterocolitica mortality was 1.86 to 2.88 times higher than in the control group. Infection with Shigella species was not associated with higher mortality after we adjusted for comorbidity.

Table 3.

 Crude and adjusted relative mortality within one year in 48 857 patients with Salmonella, Campylobacter, Yersinia, and Shigella infection compared with control group matched for age, sex, and county of residence, Denmark 1991-9

	No of patients	No (%) of deaths	Relative mortality (95% CI)
			Crude	Adjusted*
Salmonella (all)	26 974	838 (3.1)	3.44 (3.18 to 3.73)	2.85 (2.61 to 3.10)
S enteritidis	13 967	419 (3.0)	3.34 (2.98 to 3.73)	2.83 (2.51 to 3.18)
S typhimurium	6 988	205 (2.9)	3.63 (3.08 to 4.27)	2.88 (2.42 to 3.44)
S dublin	127	36 (28.3)	17.71 (10.13 to 30.97)	12.35 (6.67 to 22.86)
Other	5 892	178 (3.0)	2.99 (2.52 to 3.55)	2.50 (2.09 to 3.00)
Campylobacter	16 180	190 (1.2)	2.33 (1.98 to 2.73)	1.86 (1.56 to 2.20)
Yersinia	4 045	32 (0.8)	2.16 (1.46 to 3.19)	2.10 (1.40 to 3.16)
Shigella	1 658	11 (0.7)	2.13 (1.11 to 4.08)	1.80 (0.85 to 3.83)

^*Adjusted for comorbidity. 

In all, 288 (0.6%) patients were admitted to hospital within 30 days of infection with a diagnosis of an invasive illness (septicaemia, endocarditis, aneurysm, meningitis, pneumonia, abscesses, pancreatitis, or hepatitis). In the control group, 44 (<0.01%) were admitted. The relative mortality among patients with an invasive illness within one year was 17.46 (95% confidence interval 10.11 to 30.17). Among patients with no known invasive illness, the relative mortality was 2.47 times higher than in the control group (2.29 to 2.67).

Of the 48 857 patients with gastrointestinal infection, 46 212 (94.6%) had no other illness included in the comorbidity index. The corresponding figure for the control group was 472 924 (97.1%). Table 4 shows the relative mortality of this group of patients compared with the control group.

Table 4.

 Relative mortality within one year in 46 212 patients without any known coexisting disease compared with controls

Infection	No of patients	No (%) of deaths	Relative mortality (95% CI)
Salmonella (all)	25 246	465 (1.8)	2.85 (2.56 to 3.17)
S enteritidis	13 146	234 (1.8)	2.81 (2.42 to 3.26)
S typhimurium	6 518	114 (1.7)	3.01 (2.43 to 3.74)
S dublin	85	15 (17.6)	15.55 (6.57 to 36.80)
Other	5 497	102 (1.9)	2.48 (1.98 to 3.10)
Campylobacter	15 485	115 (0.7)	2.06 (1.68 to 2.53)
Yersinia	3 877	24 (0.6)	2.27 (1.44 to 3.59)
Shigella	1 604	7 (0.4)	1.97 (0.87 to 4.46)

Discussion

Most foodborne gastrointestinal infections are self limiting. However, in a subset of patients they can cause severe complications and increased risk of death. Few large systematic studies exist of mortality from foodborne diseases, and the generalisability of the evidence from case reports and outbreaks is questionable. The most recent estimates of mortality were obtained by calculating death rates from the US FoodNet surveillance.⁵ The authors assumed that deaths attributable to the foodborne infections were limited to the acute phase of infection and the confounding effect of comorbidity was not taken into account. We were able to examine long term mortality and control for coexisting illness in a large, unselected group of patients. As we used registries created for other purposes, the data should be unbiased.

Effect on mortality

Overall, patients had a 3.10 times higher mortality than the background population within one year of follow up. This figure reflects both acute and long term consequences of foodborne illness as well as the effect of underlying diseases, and it conceals large differences between the bacterial types.

The acute relative mortality was high for all four bacteria after we adjusted for comorbidity (22 for Shigella, 13 for Salmonella, 5 for Campylobacter and 4 for Yersinia enterocolitica; table 2). The difference in 30 day cumulative mortality between patients and controls, which correlates to the case fatality rate reported by others, was 1.15% for Salmonella, 0.23% for Campylobacter, 0.14% for Yersinia enterocolitica, and 0.29% for Shigella. These figures are in line with the FoodNet case fatality rate for Yersinia enterocolitica (0.14%) but are higher than the rates reported for Salmonella (0.78%), Campylobacter (0.10%) and Shigella (0.05%).⁵

We found significant excess long term mortality up to one year after infection with zoonotic Salmonella serotypes and Campylobacter and up to six months after Yersinia enterocolitica infections. By contrast, Shigella was mainly associated with death in the acute phase. Unfortunately, valid information on causes of deaths was not available.

Comorbidity

After we adjusted for imbalances in comorbidity, patients infected with Salmonella, Campylobacter, or Yersinia enterocolitica continued to have a higher mortality than the control group, although the differences were smaller. The high mortality associated with Salmonella dublin infections probably reflects its more invasive character.^14–16

Our comorbidity index is based on discharge diagnoses and on data from outpatient clinics but did not include data from general practitioners. It could be argued that this weakens the index. However, any patient with a pre-existing disease severe enough to alter the outcome of a foodborne infection is likely to have come into contact with a hospital or an outpatient clinic in the five years before infection. Nevertheless, people with other illnesses may have increased mortality and an independent excess risk of gastrointestinal infection. These people may also be more likely to seek medical attention and have a sample specimen taken than patients without known comorbidity. Among these people, the diagnosis of a gastrointestinal infection may be a marker of excess mortality rather than a contributing cause. However, only a small proportion of patients had a coexistent illness, and the excess mortality was similar in patients with and without underlying illness. Furthermore, there was an excess mortality independent of invasive illness.

Causes of long term mortality

The late excess mortality may have several explanations, including infectious and reactive complications or sequelae, relapses of the initial infection, and reduced efficacy or treatment failure in the case of antimicrobial drug resistance. Complications and sequelae may occur weeks to months after the initial infection and include sequelae of invasive illness (septicaemia, endocarditis, vasculitis, septic arthritis, etc), intestinal perforation, abscesses, and complications of surgery.

The registry did not include multiple diagnoses of the same bacterial species or serotype. We therefore could not examine the importance of relapses. We had only limited data on antimicrobial drug resistance and no information about treatment with antimicrobial drugs and were not able to study this issue. Studies from the United States suggest that treatment with antimicrobials is a risk factor for infection with drug resistant bacteria, and that this interaction may contribute to mortality.¹⁷,¹⁸ We have previously shown that quinolone resistance may be associated with excess mortality.¹⁹

Conclusions

The four foodborne bacterial species we examined were all associated with increased acute mortality. In addition, Salmonella, Campylobacter, and Yersinia enterocolitica were associated with increased long term mortality. Our data suggest that current estimates of the burden of foodborne diseases underestimate the number of deaths from bacterial gastrointestinal infections.