research paper on ulcer

• Research article
• Open access
• Published: 10 February 2022

The global, regional and national burden of peptic ulcer disease from 1990 to 2019: a population-based study

• Xin Xie 1 , 2 ,
• Kaijie Ren 1 ,
• Zhangjian Zhou 3 ,
• Chengxue Dang 1 , 4 &
• Hao Zhang   ORCID: orcid.org/0000-0001-8986-3854 1 , 4  

BMC Gastroenterology volume  22 , Article number:  58 ( 2022 ) Cite this article

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Peptic ulcer disease (PUD) is a common digestive disorder, of which the prevalence decreased in the past few decades. However, the decreasing tendency has plateaued in recent years due to changes in risk factors associated with the etiology of PUD, such as non-steroidal anti-inflammatory drug use. In this study, we investigated the epidemiological and the sociodemographic characteristics of PUD in 204 countries and territories from 1990 to 2019 based on data from the Global Burden of Disease, Injuries and Risk Factors (GBD) Study.

Demographic characteristics and annual prevalence, incidence, mortality, disability-adjusted life years (DALYs) and age-standardized death rate (ASR) data associated with PUD were obtained and analyzed. According to the sociodemographic index (SDI), the numbers of patients, ASRs, estimated annual percentage changes and geographical distributions were assessed with a generalized linear model and presented in world maps. All evaluations of numbers and rates were calculated per 100,000 population with 95% uncertainty intervals (UIs).

In 2019, the global prevalence of PUD was approximately 8.09 [95% UI 6.79–9.58] million, representing a 25.82% increase from 1990. The age-standardized prevalence rate was 99.40 (83.86–117.55) per 100,000 population in 2019, representing a decrease of 143.37 (120.54–170.25) per 100,000 population from 1990. The age-standardized DALY rate in 2019 was decreased by 60.64% [74.40 (68.96–81.95) per 100,000 population] compared to that in 1990. In both sexes, the numbers and ASRs of the prevalence, incidence, deaths and DALYs were higher in males than in females over 29 years. Regionally, South Asia had the highest age-standardized prevalence rate [156.62 (130.58–187.05) per 100,000 population] in 2019. A low age-standardized death rate was found in the high-income super-region. Among nations, Kiribati had the highest age-standardized prevalence rate [330.32 (286.98–379.81) per 100,000 population]. Regarding socioeconomic status, positive associations between the age-standardized prevalence, incidence, death rate, DALYs and SDI were observed globally in 2019.

Conclusions

Morbidity and mortality due to PUD decreased significantly from 1990 to 2019, while a gradual upward inclination has been observed in recent 15 years, which might be associated with changes in risk factors for PUD. Attention and efforts by healthcare administrators and society are needed for PUD prevention and control.

Peer Review reports

Peptic ulcer disease (PUD), a common disorder of the digestive system, is defined as digestive tract injury that results in a mucosal break greater than 3–5 mm, with a visible depth reaching the submucosa [ 1 , 2 ]. Mainly occurring in the stomach and proximal duodenum, PUD accounts for an estimated lifetime prevalence of 5–10% and an annual incidence of 0.1–0.3% in the general population in Western countries [ 2 , 3 ]. Due to nonspecific symptoms, PUD assessment and treatment requires clinical caution due to severe complications such as bleeding, perforation, penetration into adjacent organs and gastrointestinal obstruction, all of which could require acute endoscopic or surgical treatment [ 1 , 4 , 5 ].

Similar to several digestive disorders, the prevalence of PUD initially increased and then subsequently decreased. Jennings et al . analyzed PUD epidemiological data spanning 150 years and found that the incidence of and mortality due to PUD increased markedly during the nineteenth century and then decreased steadily due to improvements in environmental hygiene and medical therapeutic strategies [ 6 ]. During the first 50 years of the twentieth century in the United States, PUD affected approximately 10% of the adult population [ 7 ]. Several studies which were conducted in the past 20–30 years indicated a sharp decreasing tendency in the PUD prevalence, PUD-related hospital admissions and PUD-associated mortality due to new anti-PUD therapies application, such as Helicobacter pylori ( H. pylori ) eradication and proton-pump inhibitors (PPIs) using [ 8 , 9 , 10 , 11 ]. However, the widespread use of nonsteroidal anti-inflammatory drugs (NSAIDs), histamine 2 receptor antagonists, and selective serotonin reuptake inhibitors, as well as increased physiological stress, have been reported as risk factors and have changed the landscape of PUD in recent years [ 12 , 13 ]. The details of the epidemiological changes caused by these relatively new risk factors are still controversial.

In this study, we analyzed PUD burdens in 204 countries or territories from 1990 to 2019 based on data from the Global Burden of Disease, Injuries and Risk Factors (GBD) Study, which is updated in 2020 and contains epidemiological and socioeconomic data of 354 diseases globally, allowing evaluations of the burdens, distributions and trends of PUD in different regions. Our study aims to investigate the current landscape and changes in the epidemiological characteristics of PUD to support healthcare-associated policy makers in developing improved PUD prevention strategies.

Data acquisition

The GBD study provides comprehensive epidemiological estimates of the prevalence of, incidence of, disability-adjusted life years (DALYs) due to, and mortality associated with diseases and injuries across specific groups of countries and territories by sex, age and year. Annual (inclusive dates: Jan 1st, 1990 to Dec 31st, 2019) prevalence rates, incidence rates, DALYs and deaths and the corresponding age-standardized rates (ASRs) were extracted from the Global Health Data Exchange (GHDx) database ( http://ghdx.healthdata.org/ ). These data were socioecologically classified into seven GBD super-regions, 21 GBD regions and 204 countries/territories by sociodemographic index (SDI) quintiles, which is a composite indicator of lag-distributed income per capita, ranging from 0 (less developed) to 1 (most developed). SDI value reflects the degree of social development and correlates with total fertility, per capita income, and average years of education [ 14 ]. All countries and territories were classified into five quintiles based on the SDI ( http://ghdx.healthdata.org/record/ihme-data/gbd-2019-sociodemographic-index-sdi-1950-2019 ). Besides, super-regions and regions in GBD database are groups of countries rather than geological concepts for analysis ( http://www.healthdata.org/sites/default/files/files/Data_viz/GBD_2017_Tools_Overview.pdf ).

Statistical analyses

ASRs and numbers were analyzed to compare PUD prevalence and mortality trends among different cohorts. DALYs refer to the years lived with disability and years of life lost [ 15 ]. Estimated annual percentage changes (EAPCs) indicate ASR trends during a defined period. The specific EAPC was calculated using a generalized linear model (GLM) considering a Gaussian distribution for the ASR. Under the assumption of linearity on the log scale, which is equivalent to a constant change assumption, the EAPC was calculated. An EAPC estimation greater than zero indicates an increasing ASR trend, while an estimation less than zero indicates a decreasing ASR trend. If the 95% confidence interval (CI) of the EAPC crossed zero, the change in ASR was not obvious over time.

World maps and graphs were generated to display the distribution and change trends in global, regional, and national disease burdens attributable to PUD. Uncertainty was incorporated by sampling 1,000 draws combining uncertainty from a number of sources, including input data, corrections of measurement errors and estimates of residual nonsampling errors. The 2.5th and 97.5th centiles of the ordered draws were defined as uncertainty intervals (UIs). All calculations and figures were performed and made in EXCEL 2019 (Microsoft Corporation) and R software (version 4.0.0) with the “Rcan”, “ggplot2” and other packages.

Global burden and demographic profiles of PUD

Our study indicated that there were approximately 8.09 million (95% UI 6.79 to 9.58 million) prevalent cases of PUD in 2019, which represented an increase of 25.82% from 1990 [6.43 million (95% UI 5.41 to 7.63 million)]. Moreover, the age-standardized prevalence rate in 2019 was 99.40 per 100,000 (95% UI 83.86 to 117.55 per 100,000) population, which represented a decrease from 1990 [143.37 per 100,000 (95% UI 120.54 to 170.25 per 100,000) population](Additional file 1 : Table S1). Between 1990 and 2019, the number of incident cases of PUD increased from 2.82 million (95% UI 2.36 to 3.30 million) to more than 3.59 million (95% UI 3.03 to 4.22), representing an increase of 27.3% in the global incident cases of PUD. However, the global age-standardized incidence rate of PUD showed a decreasing trend, at 63.84 (95% UI 54.09 to 75.54) per 100,000 population in 1990 and 44.26 (95% UI 37.32 to 51.87) per 100,000 population in 2019 (Additional file 1 : Table S2). At the global level, nearly 6.03 (95% UI 5.59 to 6.64) million DALYs were attributable to PUD, with an age-standardized rate of 74.40 (95% UI 68.96 to 81.95) DALYs per 100,000 population in 2019. The age-standardized rate of DALYs decreased by 60.64% from 1990. Similar trends were also found in PUD-related deaths (Additional file 1 : Tables S3, S4).

Both the number of prevalent cases and age-standardized prevalence rate were higher in males than in females in all years from 1990 to 2019. However, the difference between the two groups decreased, mainly because the number of prevalent cases and age-standardized prevalence rate in males decreased faster than those in females. Overall, in 2019, 3.92 (95% UI 3.29 to 4.64) million prevalent cases occurred in females, whereas 4.17 (95% UI 3.49 to 4.97) million prevalent cases occurred in males. The proportion of prevalent cases between males and females was 1:0.94. The age-standardized prevalence rate was 94.23 (95% UI 79.10 to 111.93) per 100,000 population in females and 104.98 (95% UI 88.26 to 124.10) per 100,000 population in males in 2019 (Fig.  1 a).

Prevalence rates and deaths with age-standardized rate changes in all years from 1990 to 2019. a The numbers of prevalent cases and age-standardized prevalence rates in males and females. b The numbers of deaths and age-standardized death rates in males and females

From Jan.1st, 1990 to Dec 31st, 2019, the number of PUD-related deaths has shown a gradual, fluctuating decreasing trend in females and a relatively significant decreasing trend in males. Moreover, the age-standardized death rates in both groups showed downward trends. Among males, there were 127,522.08 (95% UI 115,260.65 to 143,079.71) PUD-related deaths and 3.57 (95% UI 3.23 to 4.00) per 100,000 population PUD-related age-standardized deaths in 2019, whereas there were 164,933.87 (95% UI 146,881.12 to 180,422.89) deaths and 9.58 (95% UI 8.62 to 10.43) age-standardized deaths in 1990. Among females, there were 108,617.41 (95% UI 96,020.68 to 120,954.17) PUD-related deaths and 2.50 (95% UI 2.21 to 2.79) per 100,000 population PUD-related age-standardized deaths in 2019, whereas there were 114,044.63 (95% UI 99,995.18 to 128,749.67) death and 5.56 (95% UI 4.91 to 6.22) age-standardized deaths in 1990. The number of PUD-related deaths was lowest in 2012 [102,041.21 (95% UI 92,732.31 to 111,554.31)]. This may be related to a variety of factors, such as the age distributions of the different sexes and the proportions of aging populations around the world (Fig.  1 b). The patterns of incidence (Additional file 1 : Figure S1) and DALYs (Additional file 1 : Figure S2) by sex and year were relatively similar to those of prevalence and death, respectively.

The global prevalence of PUD was higher in females than in males on both ends of the age spectrum (more than 70 and less than 24 years old). The PUD prevalence rates peaked in 65- to 69-year-old females [330,974.81 (95% UI 223,943.66 to 485,784.86)] and 55- to 59-years-old males [391,973.56 (95% UI 259,447.97 to 569,117.47)] in 2019. In addition, the age-standardized prevalence rates increased with age, peaking at 80–84 years in both males [393.04 (95% UI 275.22 to 537.73)] and females [385.16 (95% UI 270.52 to 525.41)] and then decreased until patients reached the oldest age group in 2019. Age-standardized prevalence rates were also higher in females than in males at both ends of the age spectrum (more than 85 and less than 24 years old) (Fig.  2 a). However, the age-standardized incidence rates were higher in males than in females and increased with age, peaking in the more than 95-year-old group in both males and females in 2019 (Fig.  2 b). For the age-standardized death rates (Additional file 1 : Figure S3), there was a sharp increase in those aged more than 70 years, and the trend in males increased more than that in females; there was a similar trend in DALYs (Additional file 1 : Figure S4). PUD-related deaths peaked in 80- to 84-year old female patients; at this point, the number of deaths in female patients exceeded that in male patients, which peaked in 75- to 79-year-old males.

Prevalent and incident cases with age-standardized rate changes in 2019. a The numbers of prevalent cases and age-standardized prevalence rates in males and females. b The numbers of incident cases and age-standardized death rates in males and females

Regional burden of PUD

For 30 years, the age-standardized prevalence rate in South Asia [156.62 (95% UI 130.58 to 187.05) in 2019] was highest among all the GBD super-regions. However, it showed a sharp decreasing trend. The super-regions with lowest age-standardized prevalence rates were Latin America and the Caribbean [41.77 (95% UI 35.53 to 49.29) in 2019] (Additional file 1 : Figure S5). Moreover, the age-standardized incidence rate trends of the 7 super-regions were similar to the prevalence rate trends from 1990 to 2019 (Additional file 1 : Figure S6). The high-income super-region had the lowest age-standardized death rate from 1990 to 2019 [1.08 (95% UI 0.96 to 1.19) in 2019]. South Asia presented the largest decreasing trend in the age-standardized death rate during the study period. The percent change from 1990 to 2019 was 66.92% (95% UI 59.25% to 73.22%). Central Europe, Eastern Europe, and Central Asia experienced a fluctuating but gradually decreasing trend (Additional file 1 : Figure S7, S8). Among the 21 GBD regions, the prevalence (Additional file 1 : Figure S9) and incidence cases (Additional file 1 : Figure S10) were highest in South Asia [2.52 (95% UI 2.09 to 3.01) million for prevalence in 2019] and East Asia [1.49 (95% UI 1.22 to 1.82) million for prevalence in 2019], with increasing trends. Although the numbers of PUD-related DALYs (Additional file 1 : Figure S11) and deaths (Additional file 1 : Figure S12) in South Asia and East Asia accounted for the largest proportions, the number of DALYs showed a decreasing trend. The number of deaths in East Asia showed a slight but fluctuating decrease.

In 2019, the age-standardized prevalence rates in males were higher than those in females in 16 GBD regions, with the exception of Western sub-Saharan Africa, South Asia, North Africa and the Middle East, High-income North America and Central sub-Saharan Africa. The region with the greatest difference in prevalence between males and females was High-income Asia Pacific (male:female, 2.35:1), followed by Central Asia (male:female, 2.13:1)(Additional file 1 : Figure S13). The age-standardized incidence rate showed almost the same trend (Additional file 1 : Figure S14). The age-standardized DALY rate was slightly higher in females than in males in only South Asia; in the rest of the GBD regions, males had a higher DALY rate than females. The region with the greatest difference in DALYs between males and females was Eastern Europe (male:female, 2.97:1), followed by Central Asia (male:female, 2.46:1)(Additional file 1 : Figure S15). The trend of death was similar to that of DALYs in 2019 (Additional file 1 : Figure S16). From 1990 to 2019, the age-standardized prevalence rate in males in all GBD regions decreased to varying degrees, but among females, four regions showed variable increases: Eastern Europe, Southern sub-Saharan Africa, Western sub-Saharan Africa and Central sub-Saharan Africa. The age-standardized death rates decreased among all 21 GBD regions, except in females in Eastern Europe and Central Asia. After estimating the EAPCs in the age-standardized prevalence and DALY rates, only females in Eastern Europe showed a consistent increasing trend (Additional file 1 : Figure S17, S18, S19, S20).

National burden of PUD

The age-standardized prevalence rate estimated for PUD in 2019 ranged from 15.19 to 330.32 per 100,000 population. Kiribati [330.32 (95% UI 286.98 to 379.81)], Vanuatu [247.62 (95% UI 214.30 to 284.91)] and Greenland [209.77 (95% UI 182.50 to 239.31)] had the highest age-standardized prevalence rates in 2019. Israel [15.19 (95% UI 11.83 to 18.85)], Costa Rica [17.28 (95% UI 14.59 to 20.33)] and Panama [19.95 (95% UI 16.25 to 23.98)] had the lowest rates (Fig.  3 a). The EAPCs in the age-standardized prevalence rates from 1990 to 2019 differed substantially between countries and territories. Turkey [1.39 (95% CI 1.01 to 1.77)], Norway [1.27 (95% CI 0.86 to 1.69)] and Ghana [0.84 (95% CI 0.43 to 1.26)] showed the largest increases, and Bangladesh [-6.80 (95% CI − 7.07 to − 6.53)], Brazil [-4.76 (95% CI − 5.16 to − 4.35)] and Bhutan [-4.24 (95% CI − 4.55 to − 3.94)] showed the largest decreases (Fig.  3 b). The countries and territories with the highest age-standardized PUD prevalence rates in 2019 also had the highest age-standardized incidence rates (Additional file 1 : Figure S21). The country with the highest EAPC in incidence rate was Norway [1.08 (95% CI 0.45 to 1.71)] (Additional file 1 : Figure S22).

Distribution of age-standardized prevalence rates and EAPCs in age-standardized prevalence rates of PUD globally. a The age-standardized prevalence rate (per 100,000 population) in both sexes globally in 2019. b The EAPC in the age-standardized prevalence rate in both sexes globally from 1990 to 2019. Maps in Fig. 3 were designed and plotted by ArcGIS (version 9.0). ATG Antigua and Barbuda, BRB Barbados, COM Comoros, DMA Dominica, FJI Fiji, FSM Federated States of Micronesia, GRD Grenada, KIR Kiribati, LCA Saint Lucia, MDV Maldives, MHL Marshall Islands, MLT Malta, MUS Mauritius, SGP Singapore, SLB Solomon Islands, SYC Seychelles, TLS Timor-Leste, TON Tonga, TTO Trinidad and Tobago, VCT Saint Vincent and the Grenadines, VUT Vanuatu, WSM Samoa

Age-standardized PUD-associated death rates in 2019 varied from 0.46 to 22.48 per 100,000 population. Cambodia [22.48 (95% UI 17.42 to 28.98)], Kiribati [21.78 (95% UI 16.38 to 27.96)] and Laos [19.24 (95% UI 14.04 to 26.14)] had the highest age-standardized death rates in 2019. Sri Lanka [0.46 (95% UI 0.32 to 0.64)], Italy [0.58 (95% UI 0.50 to 0.64)] and Israel [0.60 (95% UI 0.48 to 0.74)] had the lowest rates (Additional file 1 : Figure S23a). Only eight of the 204 countries and territories showed potential increasing EAPCs in age-standardized death rates (red regions in Additional file 1 : Figure S23b). Among them, only one country, Lesotho [1.19 (95% CI 0.04 to 2.36)], showed a definite increase, with all 95% CIs greater than zero. Bangladesh [-10.08 (95% CI − 11.83 to − 8.29)], the Republic of Korea [-7.34 (95% CI − 9.61 to − 5.02)] and Spain [-7.24 (95% CI − 10.46 to − 3.91)] had the largest decreases in age-standardized death rates from 1990 to 2010 (Additional file 1 : Figure S23b).

Socioeconomic profiles of PUD

A lower SDI was associated with higher age-standardized prevalence rates, incidence rates, DALYs and deaths associated with PUD, with values that were higher than the global rate in the two highest SDI quintiles and lower than the global rate in the three lowest SDI quintiles. The age-standardized prevalence rates in the high-SDI and low-SDI quintiles were 80.98 (95% UI 68.19 to 95.81) and 145.35 (95% UI 123.83 to 169.90) per 100,000 population in 2019, respectively (Additional file 1 : Figure S24). The high-SDI quintile [1.18 (95% UI 1.04 to 1.29)] was associated with the lowest age-standardized death rate in 2019, while the low-SDI quintile [6.15 (95% UI 5.31 to 7.04)] had the second-highest rate, which was just slightly lower than that of the low-middle-SDI quintile (Additional file 1 : Figure S25). In contrast, the largest decreases in age-standardized prevalence, incidence, DALY and death rates from 1990 to 2019 occurred in the low-SDI and low-middle-SDI quintiles. For the 21 GBD regions, positive associations were found between the age-standardized prevalence (Fig.  4 a), incidence (Additional file 1 : Figure S26), DALY (Additional file 1 : Figure S27) and death (Fig.  4 b) rates and SDI between 1990 and 2019. However, in the Saharan African regions, the downward trend of the prevalence rate associated with increasing SDI was not obvious. In the Southern sub-Saharan African region, the death rate showed an inverted U-shaped pattern; the death rate and SDI were positively correlated when the SDI was < 0.59 and negatively correlated when the SDI > 0.59. Positive associations between age-standardized prevalence, incidence, DALY and death rates and SDI for 204 countries and territories in 2019 were observed. The age-standardized prevalence rate was higher than the expected level in some countries such as Kiribati, Vanuatu and Greenland (Fig.  5 ). The estimated age-standardized DALY rate decreased when the SDI improved. Some countries and territories also had DALY rates that were significantly higher than expected, such as Kiribati, Cambodia and Laos (Additional file 1 : Figure S28).

Trends of age-standardized prevalence and death rates (per 100,000 population) in 21 GBD regions by SDI from 1990 to 2019. a Trends of age-standardized prevalence rates; b trends of age-standardized death rates by SDI

Age-standardized prevalence rates (per 100,000 population) of PUD in 204 countries globally by SDI in 2019. The gray line represents the expected age-standardized prevalence rate based on the SDI in 2019

PUD is usually defined as a greater than 3- to 5-mm rupture of the gastric or duodenal mucosa, which is caused by an imbalance in factors that protect the gastric and duodenal mucosa and factors that can cause damage. In this study, we analyzed the prevalence trends of PUD at the global, regional and national levels from 1990 to 2019, along with PPIs medication use over the span of thirty years. The prevalence of PUD in 2019 was approximately 8.09 million worldwide, and this study exhibited continues increasing tendency in the number of prevalent. Similar to the results of other research reports [ 16 , 17 ], the incidence of PUD showed a slight increase from 2006 to 2019, but the ASR showed a decreasing trend. However, in recent years, this downward trend has plateaued, which may be related to the fact that the main ulcer etiology has shifted in many countries from H. pylori infection to non-steroidal anti-inflammatory drug (NSAIDs) use [ 1 ]. For PUD, which is a chronic disease, it is often necessary to take appropriate drugs for a long period of time, and its recurrent characteristics and potentially serious complications have a significant impact on the social economy and medical and health costs.

PUD may be attributed to many etiologies, such as H. pylori infection, NSAIDs use, gastric bypass surgery, smoking, selective serotonin reuptake inhibitor use, stress, lifestyle habits and genetic characteristics, which have been identified as the main risk factors [ 1 , 2 ]. During the study period, especially in the first 20 years, the incidence of and mortality due to PUD showed significant decreasing trends, which were closely related to PPIs use and the widespread administration of anti- H. pylori treatment, which started in the late 1980s. In the last 10 years of the study period, the incidence of and mortality due to PUD showed relatively stable trends that did not decline with the further promotion of anti- H. pylori treatment. However, there was an increase in the use of NSAIDs, especially aspirin and other drugs, and these drugs often lead to serious complications in patients with PUD. In previous studies, especially in Australia, a country with an inexplicable history of H. pylori , H. pylori infection was associated with 70% to 90% of PUD cases [ 18 , 19 ]. Although these values are lower in some other studies, H. pylori infection is still a key factor in the pathogenesis of PUD [ 20 ]. Despite anti-inflammatory effect, NSAIDs are always used in antipyrexia and analgesic therapy, which makes NSAIDs as most commonly prescribed medicine [ 21 ]. Targeting cyclooxygenases enzymes (COXs), NSAIDs are divided into non-selective NSAIDs and selective COX-2 inhibitors, such as aspirin and celecoxib repectively [ 22 ]. However, NSAIDs could cause gastrointestinal adverse effects including ulcers, bleeding or perforation [ 21 , 23 ]. Drugs such as aspirin and other NSAIDs account for approximately 10% of PUD cases. NSAIDs have a stronger correlation with duodenal ulcers than with gastric ulcers. In recent decades, the use of these drugs has increased dramatically [ 24 , 25 ]. They account for approximately 5% to 10% of all prescription drugs each year and have shown an increasing trend [ 26 ]. In general practice, the prevalence of NSAIDs use in patients over 65 years old is as high as 96% [ 27 ]. A study from Norway indicated that approximately 7.3% of elderly patients over 60 years old took at least one NSAIDs prescription within one year period [ 28 ]. Differ from aspirin, selective COX-2 inhibitors have a weaker association with PUD than nonselective NSAIDs, which suppress COX-1 activity to inhibit gastric mucosa repair [ 29 , 30 ].

For sever obesity patients, bariatric surgery, such as Roux-en-Y gastric bypass (RYGBP) surgery and duodenal switch (DS) surgery, could be a proper therapy to reduce weight and comorbidities [ 31 ]. Due to well-established procedure and nearly 70 years of surgical experience, RYGBP is considered as gold standard for bariatric surgery [ 32 ]. Although overweight and related metabolic symptoms would be reduced after gastric bypass surgery, several complications still might influence the recovery of operated patients, such as marginal ulcer (MU). MU developed at or distal to gastroenteral anastomosis and occurs in approximately 5% of obese patients undergoing gastric bypass surgery [ 31 , 33 ]. In patients with upper gastrointestinal symptoms after gastric bypass surgery, the incidence can reach 27% to 36%, indicating gastric bypass surgery history might contribute to the development of PUD [ 1 , 34 ].

In the vast majority of GBD regions, the incidence of and mortality due to PUD showed significant downward trends with increasing SDI; this is closely related to the awareness of H. pylori treatment and the appropriate management of other chronic diseases. However, in some areas, this relationship is questionable, especially in the southern sub-Saharan African region. The cause of this phenomenon is still controversial and may be related to the epidemiological characteristics and risk factors for PUD in such countries and territories. Although the incidence of H. pylori infection had decreased as SDIs increased in these areas, in some countries, the infection rate remains very high. NSAIDs use rates in these areas were significantly lower than those in developed countries [ 35 , 36 ]. Studies have also shown that the rates of severe PUD-related complications, such as perforation of the digestive tract, are high in these countries and territories and appear to be associated with Khat intake [ 37 ]. When stratified by SDI, the incidence of PUD showed decreasing trends in different groups over time. The decrease was more obvious in low- and low-middle-SDI regions than in high-SDI regions, and the incidence of PUD tended to plateau in high-SDI regions; however, it was still far lower than those in low-SDI regions. PUD-related deaths decreased in all groups. In 2019, in different countries and regions, the prevalence of PUD generally decreased with increasing SDI, but in some Pacific islands, such as Kiribati and Vanuatu, the prevalence of PUD remained abnormally high. This may be related to the high H. pylori infection rate among and the ethnic characteristics of Pacific islanders. Some studies found that Maori and Pacific Island adults and children living in South Auckland had a high rate of infection with H. pylori compared to Europeans from the same area [ 38 ]. Data showed that household crowding involving children in New Zealand contributed to 44% of H. pylori infections in Pacific Islanders, 36% in Maori people and 14% in Europeans [ 39 , 40 ].

The age-standardized incidence rate showed an increasing annual trend with increasing age. This is different from the incidence rate of H. pylori . A multicenter cross-sectional study showed that the positive rate of H. pylori serum antibody increased linearly from the 30- to 39-year-old age group to the 60- to 69-year-old group, while the infection rates of H. pylori in people aged 20 to 29 and over 70 years old were low. The change in the H. pylori infection rate showed a trend of initially increasing and then decreasing with age [ 41 ]. The consistent increase in the age-standardized incidence rate may be associated with an increased incidence of drug-related PUD in older people who are more likely to suffer from other chronic diseases and require other medications, such as NSAIDs. Studies have shown that the use of NSAIDs peaks at approximately 50 years old, and after 70 years old, the use of NSAIDs, especially aspirin, decreases, which is related to the increased incidence of NSAID-related adverse reactions in the elderly population [ 42 , 43 ]. Estrogen can prevent ulcers by inhibiting the synthesis and release of gastrin and reducing the secretion of gastric acid. The decrease in estrogen levels in elderly females may be a protective factor for PUD [ 44 ] and may also cause a slight decrease in the growth trend of the age-standardized incidence rate in elderly women over 80 years old.

Regarding sex, at the end of the twentieth century, the incidence of and mortality due to PUD showed significant decreases, and the trends in males were more obvious than those in females. Over time, the decreasing trends of the age-standardized incidence and mortality rates became less steep, but the rates in males remained higher than those in females. PUD-related deaths and DALYs were significantly lower in females than in males. However, further analysis of PUD-related factors revealed that the incidence in females was slightly higher than that in males aged less than 20 years. In 2019, among the different GBD regions, the incidence rates of PUD in the Oceania, High-income Asia Pacific, Eastern Europe, East Asia and Central Asia regions were significantly higher in males than in females, while in other regions, there was no significant difference in the incidence between the sexes. In some regions, such as Western sub-Saharan Africa, the rate in females was significantly higher than that in males. However, the PUD-related death rate was higher in males than in females, except in Central sub-Saharan Africa. In West African countries, such as Ghana and Nigeria, the incidence of PUD in females accounted for approximately 54–57% [ 35 ]. Research results have shown that there is a sex difference in the influence of acetic acid-induced gastric ulcer formation in rats. After the administration of certain interventions, the natural defensive mechanism in the gastric mucosa was adversely disturbed in male rats but activated in female rats [ 45 ]. This phenomenon is similar to previous clinical and the current research results, although the specific mechanism is not completely clear.

There were increasing trends in the EAPCs in the age-standardized prevalence and DALY rates among only female patients in Eastern Europe (marginally increasing incidence and death rate trends) from 1990 to 2019, mainly due to the increase in the number of females in Russia and the Ukraine. In these two countries, especially in Siberia, the H. pylori infection rates were significantly higher than those in other regions. However, there were no differences in H. pylori infection rates between the sexes and among ethnicities [ 46 , 47 ]. Therefore, the consistently increased risk of PUD among females in these areas may be related to factors such as drugs or bypass surgery [ 48 , 49 ]. These reasons require further study to produce high-level evidence-based medical evidence.

The roles of anti- H. pylori therapy and acid suppression therapy in the treatment and prevention of PUD are clear. Identifying high-risk populations and preventing drug-related complications are particularly important at this stage. Anti- H. pylori treatment can reduce the incidence of PUD and reduce the risk of gastric cancer in high-risk groups. Similar to acid suppression therapy, it will not increase the economic burden of disease treatment. However, there is still some controversy regarding whether to administer anti- H. pylori treatment in all positive patients considering the extensive administration of antibiotics, as it may promote the production of other resistant bacteria, leading to the occurrence of Clostridium difficile -associated diarrhea, and increase the potential risk of cardiovascular disease [ 50 , 51 ]. Acid suppressant drugs, mainly PPIs, seem to be the most effective class of gastroprotectants for the management of PUD [ 52 ]. Especially in recent years, the risk factors for PUD have gradually changed from H. pylori infection to drug-related PUD, so treatment with PPIs has gradually increased in importance. Especially in patients with gastrointestinal bleeding, PPIs can significantly reduce the incidence of adverse outcomes. However, PPIs also have certain medication risks, such as an increased risk of fracture and the development of other infections. These risks still lack strong evidence, and the benefits of PPIs greatly outweigh their associated risks. The current controversy mainly concerns the durations and doses of PPIs and whether oral PPIs have the same effect as intravenous medication in maintenance treatment [ 53 ].

The study has some limitations. First, critical information about disease burden in some countries does not exist or was unavailable, making it difficult to illustrate and understand health trends. Second, compared with other chronic noncommunicable diseases with high mortality rates, the mortality rate associated with PUD is relatively low, but PUD has the characteristic of recurrence. The high prevalence rate also results in a high disease burden. However, compared with that of malignant tumors, diabetes, and cardiovascular and cerebrovascular diseases, evidence indicating that PUD should be considered a high-priority disease is lacking [ 54 ].

In conclusion, this study focused on the epidemiological characteristics of PUD in different countries and territories, different age groups and different sexes. Overall, the risk of morbidity and mortality due to PUD decreased significantly, but with the passage of time for H. pylori eradication, the downward trend gradually weakened, which might be related to the gradual shift in the main risk factors for PUD from H. pylori infection to wide use of NSAIDs. Therefore, additional medical and health-related attention is needed to control the incidence of PUD and the occurrence of adverse events.

Availability of data and materials

The datasets generated and/or analyzed during the current study are available in the Global Burden of Disease, Injuries and Risk Factors Study ( http://ghdx.healthdata.org/ ).

Abbreviations

• Peptic ulcer disease

Proton-pump inhibitor

Nonsteroidal anti-inflammatory drugs

Global Burden of Disease, Injuries and Risk Factors Study

Disability-adjusted life years

Age-standardized rate

Global Health Data Exchange database

Sociodemographic index

Estimated annual percentage change

Generalized linear model

Confidence interval

Uncertainty interval

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We thank the Global Burden of Disease, Injuries and Risk Factors (GBD) Study which provided the free data for this study.

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1 : Table S1 . PUD prevalence in 1990 and 2019 for both sexes and estimated annual percentage change in age-standardized rates by location; Table S2 . PUD incidence in 1990 and 2019 for both sexes and estimated annual percentage change in age-standardized rates by location; Table S3 . DALYs of PUD in 1990 and 2019 for both sexes and estimated annual percentage change in age-standardized rates by location; Table S4 . PUD death in 1990 and 2019 for both sexes and estimated annual percentage change in age-standardized rates by location; Figure S1 . Incident cases with age-standardized incidence rate (per 100,000 population) changes in all years from 1990 to 2019; Figure S2 . DALYs with age-standardized rate (per 100,000 population) changes in all years from 1990 to 2019; Figure S3 . Deaths with age-standardized death rate (per 100,000 population) changes by age in 2019; Figure S4 . DALYs with age-standardized DALY rate (per 100,000 population) changes by age in 2019; Figure S5 . Age-standardized prevalent rate changes in PUD in seven super-regions in all years from 1990 to 2019; Figure S6 . Trends of age-standardized incidence rates (per 100,000 population) in seven super-regions in all years from 1990 to 2019; Figure S7 . Trends of age-standardized death rates (per 100,000 population) in seven super-regions in all years from 1990 to 2019; Figure S8 . Trends of age-standardized DALY rates (per 100,000 population) in seven super-regions in all years from 1990 to 2019; Figure S9 . Trends of prevalent cases of PUD in 21 GBD regions in all years from 1990 to 2019; Figure S10 . Trends of incident cases of PUD in 21 GBD regions in all years from 1990 to 2019; Figure S11 . Trends of DALYs due to PUD in 21 GBD regions in all years from 1990 to 2019; Figure S12 . Trends of PUD-related deaths in 21 GBD regions in all years from 1990 to 2019; Figure S13 . Age-standardized prevalence rates (per 100,000 population) of PUD in males and females in 21 GBD regions in 2019; Figure S14 . Age-standardized incident rates (per 100,000 population) of PUD in males and females in 21 GBD regions in 2019; Figure S15 . Age-standardized DALY rates (per 100,000 population) due to PUD in males and females in 21 GBD regions in 2019; Figure S16 . Age-standardized death rates (per 100,000 population) due to PUD in males and females in 21 GBD regions in 2019; Figure S17 . Estimated annual percentage changes in age-standardized prevalent rates in different regions between 1990 and 2019; Figure S18 . Estimated annual percentages of age-standardized incident rates (per 100,000 population) in 21 GBD regions between 1999 and 2019; Figure S19 . Estimated annual percentages of age-standardized DALY rates (per 100,000 population) in 21 GBD regions between 1999 and 2019; Figure S20 . Estimated annual percentages of age-standardized death rates (per 100,000 population) in 21 GBD regions between 1999 and 2019; Figure S21 . Distributions of age-standardized incidence rates (per 100,000 population) of PUD in different regions in 2019; Figure S22 . Distributions of age-standardized incidence rates (per 100,000 population) of PUD in different regions from 1999 to 2019; Figure S23 . Distributions of age-standardized death rates and EAPCs in age-standardized prevalence rates of PUD globally; Figure S24 . Trends of age-standardized prevalence rates (per 100,000 population) in different SDI regions from 1990 to 2019; Figure S25 . Age-standardized death rates (per 100,000 population) from 1990 to 2019 in different SDI regions; Figure S26 . Trends of age-standardized incidence rates (per 100,000 population) of PUD in 21 GBD regions by SDI; Figure S27 . Trends of age-standardized DALY rates (per 100,000 population) of PUD in 21 GBD regions by SDI; Figure S28 . Age-standardized DALY rates (per 100,000 population) due to PUD globally in 204 countries and territories by SDI in 2019.

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Xie, X., Ren, K., Zhou, Z. et al. The global, regional and national burden of peptic ulcer disease from 1990 to 2019: a population-based study. BMC Gastroenterol 22 , 58 (2022). https://doi.org/10.1186/s12876-022-02130-2

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Rethinking the history of peptic ulcer disease and its relevance for network epistemology

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The history of the research on peptic ulcer disease (PUD) is characterized by a premature abandonment of the bacterial hypothesis, which subsequently had its comeback, leading to the discovery of Helicobacter pylori—the major cause of the disease. In this paper we examine the received view on this case, according to which the primary reason for the abandonment of the bacterial hypothesis in the mid-twentieth century was a large-scale study by a prominent gastroenterologist Palmer, which suggested no bacteria could be found in the human stomach. To this end, we employ the method of digital textual analysis and study the literature on the etiology of PUD published in the decade prior to Palmer’s article. Our findings suggest that the bacterial hypothesis had already been abandoned before the publication of Palmer’s paper, which challenges the widely held view that his study played a crucial role in the development of this episode. In view of this result, we argue that the PUD case does not illustrate harmful effects of a high degree of information flow, as it has frequently been claimed in the literature on network epistemology. Moreover, we argue that alternative examples of harmful effects of a high degree of information flow may be hard to find in the history of science.

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1 Introduction

The early 20th century research on peptic ulcer disease (PUD) is often mentioned as an example of scientific inquiry ‘gone wrong’ (e.g. Thagard, 2000 ; Gilbert, 2000 ; Solomon, 2001 ; Zollman, 2010 ; Wray, 2010 ; Miller, 2013 ; Šešelja & Straßer, 2014 ; O’Connor, 2020). As most accounts of this case report, from the 19th century on there were two major rivaling hypotheses of the disease: the acidity hypothesis, according to which the disease is caused by an excessive acidity of the stomach, and the bacterial hypothesis, which stipulated bacteria as the primary cause of the disease. In the mid-20th century the bacterial hypothesis was abandoned, and the research on PUD proceeded along the lines of the acidity research program. The latter focused on the study of various treatments aimed at achieving a chemical balance in the stomach, from antacid medications to surgical procedures, rather than on the identification of bacteria and their eradication. For three decades the research on PUD was based on a worse of the two hypotheses. It was only in the 1980s that Robin Warren and Barry Marshall discovered Helicobacter pylori, a bacterium which turned out to be the major cause of PUD. This discovery, for which Warren and Marshall received a Nobel Prize in Physiology or Medicine, led to the revival of the bacterial research program.

According to the received view on the history of this episode (originating primarily in Warren and Marshall, 1983 ; Marshall, 2002 ), Footnote 1 the main reason for the abandonment of the bacterial hypothesis was a large-scale study by a prominent gastroenterologist, Palmer ( 1954 ). Palmer examined 1,180 subjects, fifth of whom were healthy individuals, while the remainder of the group were patients with gastrointestinal complaints. The study showed no presence of bacteria in the gastric mucosa of the subjects. As scientists Fukuda et al. ( 2002 ), reflecting on the history of this case, write:

[T]he hypothesis that PUD was caused by bacteria in the mucosa of the human stomach was rejected in 1954 by the major authority in American gastroenterology, [Palmer, 1954] despite consistent information in the preceding 50 years of bacteria that adhered to the gastric musosa \(\dots\) His words ensured that the development of bacteriology in gastroenterology would be closed to the world as if frozen in ice. (p. 17) His study established the dogma that bacteria could not live in the human stomach, and as a result, investigation of gastric bacteria attracted little attention for the next 20 years. (p. 20)

Nowadays we know that Palmer’s study was deeply misleading as it was based on a method unsuitable for detecting spiral bacteria (see Fukuda et al., 2002 ). As a result, this historical episode has become one of the central examples of an inquiry in which everything was done by the book in the sense that each individual scientist had good reasons to abandon the bacterial hypothesis, and yet, the scientific community on the whole was sidetracked towards a false theory for a long period of time (Zollman, 2010 ; Kummerfeld and Zollman, 2016 ; O’Connor, 2020). As such, the PUD case appears to be a nice example of the individual and group rationality coming apart in the sense that rational choices by individual scientists do not sum up to an optimal inquiry at the level of the given community. It also appears to be illustrative of how a wide dissemination of erroneous findings can sidetrack the entire scientific community.

However, such an interpretation of the events leaves some questions open. For instance, if Palmer’s study was that influential, how come nobody in the scientific community noticed potential problems with it? After all, warnings about the unsuitability of the method of staining used in Palmer’s study had previously been pointed out by Freedberg and Barron ( 1940 ), whom Palmer even cited in his paper. This is all the more surprising if we agree with Šešelja and Straßer ( 2014 ) that the bacterial research program (in spite of Palmer’s findings) had promising lines of inquiry in the 1950s, when it was largely abandoned. What is more, the alleged impact of Palmer’s study has never been corroborated by adequate historical evidence. Nor has the widely adopted view of the popularity of the bacterial hypothesis prior to Palmer’s publication ever received a proper evidential support.

In this paper we aim to advance this debate by conducting a critical examination of the received view on PUD, according to which, the main reason for the abandonment of the bacterial hypothesis was Palmer’s study. If the received narrative is correct, the abandonment of the bacterial hypothesis can be ascribed, for instance, to Palmer’s influence, which swayed the entire medical community. As Zollman ( 2010 ) writes: “It was the widespread acceptance of Palmer’s result which led to the premature abandonment of the diversity in scientific effort present a few years earlier.” (p. 21).

However, claims about Palmer’s influence are often asserted without considering the state of the research landscape prior to 1954. Our aim is therefore to examine whether the bacterial hypothesis of PUD had been largely abandoned already before Palmer’s publication. In order to uncover the details of this episode, we have used the method of digital textual analysis applied to the corpus of the English-language literature on PUD published in the decade prior to Palmer’s study. The reason why this point is especially interesting is that, if confirmed, it would have important repercussions for philosophical discussions of this episode.

First of all, the relevance of Palmer’s study would be significantly reduced: even if his claims had discouraged some scientists from pursuing the bacterial hypothesis, they’d be the final nail in the coffin of an already dying theory, rather than the main cause of its abandonment.

Second, explaining the PUD episode in terms of a wide dissemination of Palmer’s results would be undermined. As a result, this case would fail to serve as an example of how a high degree of information flow among scientists can lead to inefficient inquiry. While this point originates in Zollman’s work on network epistemology, it has become widely adopted across the philosophical literature, beyond discussions on formal models of science (e.g. Wray, 2010 ; Douven & Kelp, 2011 ; Nunn, 2012 ; Vickers, 2020 ; Peters, 2020 ; Killin & Pain, 2021 ). Since examples of harmful effects of a dense communication flow are hard to find, PUD has been particularly valuable as an illustration of this phenomenon. Hence, if our hypothesis is confirmed, philosophers need to find other suitable historical case studies in order to illustrate such a socio-epistemic mechanism. But as we shall argue in Sect.  4 , this may be challenging.

Finally, if it turns out that there was hardly any research on the bacterial theory already in the 1940s, then the above question—why was the bacterial hypothesis abandoned in the 1950s?—wouldn’t be puzzling anymore. Instead, we would be confronted with different questions, raised by alternative possible histories of this case. One such possibility is that the bacterial hypothesis used to be popular at the end of the nineteenth century, after which it went through a gradual decline. Another option is that its decline wasn’t gradual, but abrupt and triggered at some point between the end of the nineteenth century and early 1940s. Finally, it is also possible that the bacterial theory had not been popular at any point in the first half of the twentieth century, but had always been a fringe research line. While previous historical discussions of this case had been based solely on a qualitative analysis, new quantitative methods, based on digital tools, could be fruitfully used to acquire new evidence and reveal which of the above scenarios is best corroborated. As we will argue, such new scenarios come with specific philosophical puzzles, which have so far not been considered.

Here is how we will proceed. In Sect.  2 we give a historical overview of this case-study focusing on the question, which factors might have contributed to the abandonment of the bacterial research program. In Sect.  3 we introduce the method of digital textual analysis, which we use to examine the historical claim that the bacterial research program was largely abandoned prior to the publication of Palmer’s study. In Sect.  4 we examine the consequences of our results for philosophical discussions of this episode, with a special focus on the literature in network epistemology. Section  5 concludes the paper.

2 Etiological theories of PUD

In this section we provide a historical overview of the English-language research on PUD in the first half of the twentieth century, focusing on the question as for which factors, besides Palmer’s paper, could have indirectly contributed to the abandonment of the bacterial hypothesis of PUD. To this end, we will primarily rely on secondary sources from history of medicine Footnote 2 and first-hand testimonies from gastroenterologists who were working on PUD during the period of our interest, in Britain (Christie and Tansey, 2002 ) and worldwide (Warren, 2005 ). These primary sources give an insight into personal factors that led researchers away from the correct hypothesis.

Before turning to factors that are relevant in considering the downfall of the bacterial research program (or the ‘germ theory of PUD’), we give a brief overview of different etiological theories of this disease researched in the first half of the twentieth century.

2.1 Theoretical diversity

According to the received view that we engage with (Kidd and Modlin, 1998 ; Zollman, 2010 ; Pollock, 2014 ), two influential hypotheses of what causes PUD developed early on: on the one hand, the so-called acidity hypothesis, according to which the ulcer is caused by gastric juice corroding the stomach, and on the other hand, the bacterial hypothesis, which postulated bacteria as the cause of the disease. Eventually, the story goes, the latter strand of research was brought down by the paper by Palmer ( 1954 ) thus “setting back gastric bacterial research by a further 30 years” (Kidd and Modlin, 1998 , p. 10). Our aim in this section is to show that, contrary to the commonly told story, the question of what causes PUD rarely took shape of a simple choice between the bacterial and the acidity theory.

While the research on PUD draws its origins from the late 16th century, modern gastroenterological study of the disease started in the 19th century. Moving on to the first half of the twentieth century, it is easy to notice a range of insufficiently corroborated etiological theories forming this research landscape (Miller, 2010 , p. 105). For instance, Pollock ( 2014 , Chapter 3) distinguishes eight different factors that were at some point considered important in the genesis of peptic ulcers. These include not only germs and the acid, but also factors related to anatomical pathologies, inborn predispositions (such as e.g. an “ulcer personality type”, see also (Miller, 2010 , p. 102)), or psychological factors, such as stress (see also Jones, 2012 , p. 13). What is more, gastroenterology was slow to develop as a specialized field, partly because there was no general agreement among surgeons and physicians on how to best treat digestive diseases (Miller, 2010 , p. 105). Notably, however, the treatment of PUD–whether pharmacological or surgical—was mainly focused on reducing the acidity in the stomach (Miller, 2010 , p. 105).

The research in the 1940s and the 1950s witnessed an increasing focus on the role of physiological and psychological factors on the development of PUD. The Lancet editorial from the end of the 1940s nicely illustrates this point: it posits that theories of peptic ulceration inevitably center around two possibilities: heightened erosive potency of gastric contents, or lowered anti-acid resistance (“Ætiology of Peptic Ulcer. Editorial”, 1949 , p. 997). At the similar time, a number of editorials from The American Journal of Digestive Diseases Footnote 3 emphasized in turn the psychological causes of PUD, such as anxiety and stress. The appearance of an ulcer was considered to indicate a reduced capability of the body to prevent ulcers, rather than a result of increased external ulcerogenic factors (such as bacteria).

Altogether, the research on PUD shifted away from a mono-causal and towards multi-causal approaches, and away from acidity as the sole etiological factor and towards the overall physiological balance in the stomach, including the failure of its anti-ulcer mechanism (Connell, 1949 ). This reflects the overall trend in medicine at the time. While in the beginning of the 20th century the medical research was largely driven by a mono-causal perspective, closely related to the germ paradigm of disease (originating in the works of Koch and Pasteur), the situation started to change around the 1950s with the emergence of the chronic disease epidemiology (Carter, 2003 ; Šešelja & Straßer, 2014 ). In case of the research on PUD, the multi-causal perspective was already present prior to Palmer’s study.

Some of the earliest indications that the idea of multiple causes was on the table comes from J. Shelton Horsley who commented that an ulcer may be produced by a combination of three factors: hyperacidity, toxic influences (possibly bacterial in nature), and the neurogenic (psychological) factors (Dragstedt, 1935 , p. 579). After WWII, the popularity of multi-causal theories increased. For instance, according to Kirsner and Palmer, ( 1952 , p. 615), “acid is indispensable” as a factor but “apparently not the only one”. In a similar vein, Sullivan and McKell, ( 1950 , p. 14–20) introduced a ‘Theory of Multiple Etiology’, taking a form of a simple mathematical ratio, where the ulcer was a result of imbalance in the ratio of the sum of contributing factors, e.g. personality, precipitating emotional situations, genetic factors, etc., and the overall resistance to ulcers. Relatively strong ulcer-inducing factors, or relatively weak resistance, could both lead to ulceration. Footnote 4 Remarkably, while the presence of acid was deemed essential, the bacteria were not mentioned by Sullivan and McKell. Taken together, the multi-causal approach meant that the etiological search space was more nuanced and complex than a simple choice between an acid theory and a germ theory.

However, the possibility that PUD was considered at the time as a multi-factorial disease is not discussed in the received view literature (e.g., Kidd & Modlin, 1998 ; Zollman, 2010 ). Even Pollock ( 2014 ), who discusses multiple etiological theories, portrays them as if they were pursued one at a time and treated as mono-causal accounts intended to be both sufficient and exhaustive. Thus, the evidence we provide above invites to reconsider the PUD case as that of scientists confronted not with a binary choice but with having to weight multiple factors in terms of their importance, perhaps in a way that the aforementioned theory of Sullivan and McKell from 1950 would suggest.

2.2 Factors that played a role in the demise of the bacterial hypothesis

We now take a closer look at different issues, beside Palmer’s study, which could be explanatory of why the bacterial research program lost its popularity in the mid-twentieth century.

The role of hyperacidity As mentioned above, despite prolific arguments and the lack of agreement about the role of acid in ulceration, the acid theory seemed at the time to be the most fruitful hypothesis in terms of possible treatment (Christie & Tansey, 2002 , p. 20). Therefore, the primary focus for treatment centered on regulating gastric secretion, which was reflected in a widely popular dictum: ‘no acid, no ulcer’, coined by Karl Schwarz in 1910 (Bralow et al., 1950 ).

The significance of acid as an etiological factor was in big part due to the work of Dragstedt (e.g. 1935 ) who demonstrated that a high degree of acidity in the stomach was alone capable of causing ulcers. This immediately led some scientists to consider hyper-acidity as the most immediate cause of ulcer (e.g. Rowland, 1937 ). As Pollock ( 2014 , p. 93) comments, despite the lack of unanimity in the community, hyper-acidity became the main working hypothesis and the efforts towards an effective treatment were largely based on this assumption.

Vagotomy Another factor that played an important role in the decline of the bacterial research program is the success of a surgical procedure known as vagotomy. In order to treat ulcers, Dragstedt and Owens ( 1943 ) introduced a surgical method of cutting the vagus nerve, responsible for the acid secretion. Dragstedt established the viability of this procedure through a series of papers (Dragstedt, 1945 ; Dragstedt & Schafer, 1945 ; Dragstedt et al., 1947 , 1949 ). Vagotomy appeared to work and until late 1970s it remained the most effective and reliable treatment for the condition, with comparatively fewest side-effects (Hobsley, 1994 ). Footnote 5

Problems in early bacteriological research Since the introduction of Koch’s principles Footnote 6 the major challenge for bacteriological theories was finding and identifying the disease-causing organism. Even though bacteria isolated from stomach ulcers were microscopically identified as early as in 1875, it was not clear which of them could play a part in the genesis of ulcers (Pollock, 2014 , p. 85). Moreover, their reported frequency of occurrence in ulcerated stomachs was considerably lower than in other animals (Warren, 2005 , p. 19). In the early 20th century Turck ( 1907 , 1908 ) examined the link between Bacillus coli and PUD, but his findings were not successfully reproduced (Kidd & Modlin, 1998 , p. 8). Soon thereafter, another researcher, Edward Rosenow, hypothesized that a different strand, Streptococci, was “commonly the original cause” of PUD (Rosenow & Sanford, 1915 , p. 226) and attempted to induce ulcers with the aid of bacteria. Rosenow’s findings were influential and well-known (Pollock, 2014 , p. 86) but later researchers again could not replicate the results using Rosenow’s technique (as reported in Ivy et al., 1950 , p. 271). Thus, we can see that the initial studies, despite being based on the germ theory, posited wrong candidate microbes as etiological agents and as a result were not successfully replicated.

What’s more, while Rosenow believed in the etiological role of bacteria in ulceration, he held that it was the bacteria in and around the mouth and away from the abdomen that were to blame. In short, he looked for PUD-related bacteria outside of the stomach. This view was a particular expression of a “focal infection” theory, which posited that local sepsis in the teeth, tonsils, or sinuses, allowed a blood-borne spread of bacteria or toxins to other bodily areas, causing various diseases (Pollock, 2014 , p. 89–98). As a treatment, Rosenow advised the surgical removal of the “loci of infection” (Rosenow, 1916 , p. 359). However, the focal infection theory kept on drawing increasing criticism. It soon became evident that it is both life-threatening and practically impossible to try to remove all the loci of infection, and that one can have focal sepsis and still lead a perfectly healthy life (Pollock, 2014 , p. 92). Eventually, by 1940 Rosenow’s theory was flatly rejected by Grossman ( 1940 ). Because of a misconceived mechanism for infection and unviable treatment, this strand of bacterial research faded away well before Palmer’s study.

Altogether, the significance of microbes in the stomach was not appreciated (Pollock, 2014 , p. 89). Contemporary researchers regarded bacterial presence as “accidental” or at best secondary, following the ulceration but not causing it (Dragstedt, 1917 ; Smithies, 1935 ; Hinton, 1936 ; Winkelstein, 1936 ; Henry, 1942 ). This pattern continued outside of the US, as the presence of bacteria in the stomach kept being reported after the war (Barber and Franklin, 1946 ; Cregan et al., 1953 ) and even after Palmer’s paper (Bishop and Anderson, 1960 ; Franklin and Skoryna, 1966 ). Nevertheless, in each case the researchers did not assign any etiological role to the found microorganisms and maintained their beliefs that healthy stomachs are sterile.

An exception was the research by Freedberg and Barron ( 1940 ), who identified spiral bacteria in patients suffering from PUD. However, their study was small in scale and the results inconclusive. While their findings (subsequently cited by Palmer) provided some argumentative support to the bacterial research program, hardly anyone engaged in its pursuit. Footnote 7

Psychogenic Factors Finally, the idea that gastric problems were in some way related to mental activity was a dominant theme in the North American and British literature on indigestion for centuries (Miller, 2010 , footnote 30). This conjecture had a fertile ground to grow at the beginning of the 19th century, which marked the shift in medicinal practice towards a holistic approach, taking into account not only physical symptoms, but also the psyche, emotions and social environment of a patient (Spiro, 1998 , p. 645; Miller, 2011 , Ch. 5). The role of psychogenic factors was further corroborated by emerging physiological evidence linking brain malfunction and stomach disturbances (Miller, 2010 , p. 101).

Another important development during this time was the rise in influence of Franz Alexander who in 1934 offered a psychogenic hypothesis of ulcer (Spiro, 1998 , p. 645; Miller, 2010 , p. 101). According to Alexander ( 1934 ), ulcer was developed as the result of suppressed subconscious tendencies, such as a desire to be fed, which in turn would trigger a negative somatic response leading to a disease. Furthermore, Robinson ( 1935 ) argued that PUD was found only among slender people of white race who as a result of their body type were supposed to have a disposition for mental instability, thus being at risk of developing ulcer. Inspired by these ideas, Davies and Wilson ( 1937 ) proposed the existence of an “ulcer type” of a person. Their work became highly influential and started a quest to define the “peptic ulcer personality” (Miller, 2011 , p. 111–113). As Davey Smith ( 2005 ) argues, it was the belief in the ulcer-inducing power of stress that shifted the attention away from bacteriological research:

[T]he stress model served to block people from building on this [bacterial theory] and moving towards an answer ... Things may appear clear with hindsight, but people really were directed away from a treatment for peptic ulcers that worked—antibiotics—to ones that did not.

Coincidentally, the outbreak of WWII also boosted the influence of the psychogenic theory (Christie and Tansey, 2002 , p. i). The incidence of peptic ulcer grew at an unprecedented rate, especially among troops internationally, and stomach disorders quickly became a major health complaint (Miller, 2010 , p. 97). The war and the ulcers were associated so strongly that already early into the war, British practitioners began calling PUD a ‘military dyspepsia’ or a ‘war ulcer’. This novel rate of increase in ulcers was a new phenomenon and defied any logic in medical thinking. First, it contrasted with WWI, during which abdominal problems went relatively unnoticed (Miller, 2010 , p. 97). Secondly, on the Eastern Front, few soldiers on the front-line developed ulcers, as opposed to those further back in the supply line (Miller, 2010 , p. 97). Some researchers associated peptic ulcers with poor nutrition in the war-zone (Hoelzel, 1943 ; Steele 1944 ), but even as diet improved, the rate of occurrence kept increasing, reaching its peak in the mid-1950s (Jones, 2012 , p. 1). As a result, in these post-Freudian days of the 1950s the psychosomatic factors, especially stress, in combination with ‘ulcer type personality’, were widely thought to be the main cause of the ulcer (Christie & Tansey, 2002 , p. i). Looking for a connection between the army service and PUD continued in the US after the war and became a focus of several studies (Garbat, 1946 ; Halsted & Weinberg, 1946 ; Barrett, 1953 ; Palmer & Sullivan, 1952 ).

In this section we have provided an overview of developments other than Palmer’s paper, which contributed to the demise of the bacterial theory of the PUD etiology. This summary aimed to be primarily descriptive (rather than normative): while we presented a number of potentially relevant factors in the abandonment of the bacterial theory, we did not evaluate whether such a neglect was epistemically warranted (we will come back to this point in Sect.  4 ). Moreover, we do not claim we have established a definite answer as to what put the germ theory to a pause. However, we hope to have shown that there was a variety of factors that worked against it. In the next section, we will put forward a thesis that by the time Palmer’s infamous study was published, the germ theory had already been marginalized and cast aside by the overwhelming majority of scientists.

3 The status of bacterial research program prior to Palmer’s study: digital textual analysis

In this section we examine the following historical question: to what extent was the bacterial hypothesis of PUD pursued prior to the publication of Palmer’s 1954 study? By answering this question we will be in a better position to judge the significance of Palmer’s result on the abandonment of the bacterial hypothesis.

The motivation for asking this question comes from a few separate considerations. First, as we have seen in the previous section, towards the 1950s, the overall research climate was not very forthcoming to the bacterial hypothesis. Second, assuming that the bacterial research program was active in the early 1950s, it is surprising that nobody noticed the methodological error underlying Palmer’s results. Finally, looking at the articles on the etiology of PUD published in the early 1950s, one can easily encounter articles that do not even mention bacteria as a potentially relevant factor (as noted by Šešelja and Straßer ( 2014 )). Nevertheless, these indicators are insufficient evidential basis for answering the above query, whether Palmer’s paper was indeed a game-changer to PUD researchers. To approach the issue more systematically we turn to digital textual analysis of the relevant literature.

3.1 Methodology

To address the above line of historical inquiry, we have performed a digital textual analysis of a selection of English language articles published in the period from 1943-1953 Footnote 8 . More precisely, we have selected articles in PubMED database that have a MeSH Major Topic “Peptic Ulcer” and a a MeSH Qualifier “etiology”. Footnote 9 Together, the Major Topic and the Qualifier yield a combined search term “Peptic Ulcer/etiology”, which we assumed to be sufficient for picking out the articles that are most likely to feature any significant research on bacteria as an etiological factor in PUD. Our complete search command was:

Our search resulted in 186 hits, but actually consisted of 184 unique and complete papers, out of which we have managed to access 163 manuscripts. One of the papers was mistagged and was therefore removed from the bibliography. Footnote 10 It is also worth mentioning that MeSH terms are either assigned to articles by human reviewers or automatically using natural language processing methods. In our case 80 out of 186 positions have been indexed automatically (without human supervision), making it not implausible that some “germ theory” articles were omitted.

To better understand this output, we will now elaborate on the status of PUD articles in the PubMed database in this time period.

For the period 1943–1953, PubMed lists 172,719 articles belonging to “Diseases Category”. Roughly 10.7% of these (18,477) are articles concerning “Digestive System Diseases”. In comparison, the “Infections” Major Term yields 45,221 articles (26.1%) and “Nervous System Diseases” yields 23,213 articles (13.4%). Within the “Digestive System Diseases”, PUD articles comprise roughly 14% (2579/18,477) making it roughly 1.5% (2659/172,719) of the more encompassing “Diseases Category”. Thus, PUD research appears to be a considerable area of study in this time period. Our selection of manuscripts is narrowed down to those that revolve around PUD’s etiology. Out of these, a substantial amount of articles comes from well-known specialised gastroenterological journals. For instance, there are 16 (out of 184) publications from Gastroenterology —American Gastroenterology Association’s (AGA) flagship journal and 12 from the American Journal of Digestive Diseases —also once the AGA’s flagship journal. Over a dozen of articles comes from non-specialised but equally well-renowned medical journals. For instance, 8 from the Journal of American Medical Association , 4 from The New England Journal of Medicine, 8 articles from the British Medical Journal , and 3, resp. 2 articles from the British journals The Practitioner and Lancet . Overall, our search results are representative exclusively of the English-language publishing in the period 1943–1953 given that they consist mostly of publications from the US (132 out of 184) with the rest of the articles in English from Europe and Southern Asia.

All the manuscripts have been digitally processed via the Optical Character Recognition software (OCR). Footnote 11 To determine the presence of the bacterial research program in this body of manuscripts, we have examined the of occurrences of the following strings: ‘bacter’ and ‘spiroch’ (thereby identifying all the words that include the given string, such as bacteria/spirochetes. Footnote 12 ) To digitally analyze the text in this way we have used pdfgrep , an open source Linux command line tool for searching text in PDF files (see https://pdfgrep.org/ , accessed on July 1, 2021). More precisely, we have used the following command: pdfgrep -R -c “string” , which displays the number of instances of the given string in each file within the given folder. For each occurrence of the string, we have first-hand examined the context in which the string appears in order to determine whether the term is related to the bacterial hypothesis of PUD. In addition, for the sake of comparison, we have searched for the number of occurrences of the strings related to keywords of the acidity hypothesis, such as ‘acid’.

3.2 Results

Among the analyzed manuscripts, we have found hardly any occurrence of the string ‘bacter’, and no occurrence of the string ’spiroch’. Out of 162 analyzed papers, only four mention bacteria as a possible cause of PUD. Out of these four papers, only one mentions bacteria in a more detailed context (Barber & Franklin, 1946 ), while the remaining three list it as one of numerous possible etiological factors (see Table  1 ). In contrast, string ‘acid’ appears in 145 of the analyzed manuscripts.

The average occurrence of string ‘bacter’ in the whole set of examined articles is 0.41 times per article, while the average occurrence of string ‘acid’ is 14.58 times per article. Footnote 13 Such a low average of bacteria-related strings, coupled with roughly a 30-fold disparity in the frequency of occurrence, is indicative of a largely abandoned status of the germ research program.

3.3 Discussion

These results suggest that the bacterial hypothesis was indeed largely abandoned already before the publication of Palmer’s study, at least in the gastroenterological journal literature in English language.

We have further corroborated these findings by conducting an additional search in PubMed. Instead of focusing our search on the above mentioned corpus of articles that include the “Peptic ulcer/etiology” qualifier, we have searched PubMed for the same time period as well as the following decade based on ‘text words’, Footnote 14 displayed in Table  2 . The search command in this case had the following format:

where string stands for the additional search term listed in Table  2 . Footnote 15

The number of hits for the acidity research program (‘acid*’, ‘vagus’, ‘vagotomy’) is again much higher than the number of hits for the bacterial research program. Moreover, the majority of the 10 articles resulting from the search for ‘bacter*’ do not belong to the bacterial research program (e.g. some are related to infections following a perforated ulcer, bacterial diseases that are complicated by the appearance of peptic ulcers, or the reduction of acidity in the stomach via substances of bacterial origin.) We list the number of hits for ‘peptic ulcer’ alone mainly to show the overall number of papers in this research area at the time (for the comparison with other articles in PubMed on digestive diseases see Sect.  3.1 ).

It is also worth mentioning that the number of articles on peptic ulcer available in the database rapidly increases towards the 1950s: out of 2659 hits for ‘peptic ulcer’ more than half are from 1950–1953. This is due to a more general trend in the PubMed database, which includes less than 10,000 articles published 1943–1944, compared to 250,000 in 1945–1949, and ca. 400,000 in 1950–1953. Footnote 16

Finally, let us indicate some limitations of our study. First, one may wonder why we haven’t used citation analysis to examine the extent to which Palmer’s results had been cited at the time. The main reason for this is that the bibliometric data for the period between 1950-1970 is rather sparse. Hence, obtaining reliable information on how many scientists cited Palmer’s paper proved difficult.

Second, our study focused on a specific corpus of the relevant literature in gastroenterology, that is, English language literature on peptic ulcer indexed in PubMed in the period 1943-1953. Future studies may be extended to non-English language sources and further databases and archives. Moreover, looking into other historical sources may bring additional valuable insights into this episode. For instance, it would be interesting to examine funding applications at this time period and check whether those based on the bacterial hypothesis were submitted at the time, whether they were successful, etc.

4 What can philosophers learn from this case-study?

As mentioned in the previous section, our results provide evidence for the claim that bacterial research program was largely abandoned already before 1954, the year when Palmer published his paper. Hence, it is not surprising that the bacterial hypothesis wasn’t investigated after Palmer’s publication: its pursuit had already been inactive for a whole decade. This is also why it is unlikely that the bacterial program was dropped because of Palmer’s study. If anything, the latter may have just assured scientists that the contemporary research community did not miss much by abandoning this line of inquiry.

However, the above conclusion opens a new set of problems and questions. In this section we list some of them, hoping to restart discussion on this historical episode and its role in the philosophical literature.

4.1 Lessons for network epistemology

We first consider the implications of our results for previous employments of this case study in philosophical discussions. Our findings suggest that the given historical narrative, commonly used by philosophers, is unfounded. In particular, the claim alleging Palmer’s role in the premature loss of bacterial hypothesis seems insufficiently supported by historical evidence. However, it is precisely due to Palmer’s role that the PUD case has become one of the most common examples of the tension between the individual and group rationality used by philosophers of science. In particular, as mentioned in Sect.  1 , PUD has been a central case study in the literature on network epistemology, illustrating how erroneous results obtained by one scientist can spread throughout the given scientific community, swaying it to a wrong theory. For instance, according to Zollman ( 2010 ):

In hindsight, Palmer’s study was too influential. Had it not been as widely read or been as convincing to so many people, perhaps the bacterial theory would have won out sooner. It was the widespread acceptance of Palmer’s result which led to the premature abandonment of the diversity in scientific effort present a few years earlier. (p. 21)

More recently, in reference to Zollman’s work O’Connor and Weatherall ( 2020 ) write:

Palmer’s findings were misleading. But they were so influential, that an entire generation of scientists turned away from the bacterial theory of ulcers and focused on treatments for stomach acid. (p. 40)

Our results reveal that such a narrative, rooted in Warren and Marshall’s interpretation of this historical episode, may not be accurate after all. If our findings are correct, the bacterial hypothesis had been largely abandoned already before Palmer’s study, in which case this episode cannot be used as an example of a scenario in which a quick spread of misleading information sidetracks the entire research community. Footnote 17

But why should network epistemologists care about this? After all, they could simply use a different example to illustrate the same point. The problem is, however, that such examples may be rather hard to find. To see why this is the case, note that episodes illustrating the above claim that a high degree of interaction among scientists may lead to a premature abandonment of a fruitful scientific theory, have to satisfy two criteria: a) they should include a scenario in which the given scientific community initially pursues, but then abandons a hypothesis, which is in fact superior to its alternatives; b) such an abandonment should be primarily based on a wide-spread information flow of misleading results (rather than some other factors, such as dogamtism, various kinds of biases, etc.). Altogether, such cases would illustrate that a high degree of interaction among scientists can trigger a premature reduction in ‘exploration’ of different hypotheses, which is replaced by ‘exploitation’ of one of the sub-optimal ones.

Looking at the episodes of prematurely abandoned or ignored hypotheses (criterion a), such cases are already quite rare (the most prominent examples include Mendelian genetics, Wegener’s hypothesis of continental drift and the bacterial hypothesis of PUD). The main reason for this is that in most cases of a premature hypothesis rejection, the given scientific community remains split on the given issue, which then results in a scientific controversy rather than a widely adopted rejection of what is, in fact, a superior theory. Out of the above examples, only PUD has so far appeared to be a suitable case satisfying condition b) as an episode in which the abandonment occurred due to a wide dissemination of misleading results (rather than due to, for instance, dogmatic views of the involved scientists). But if, as we argue, this case does not fit the bill, we are left to wonder what other historical episode could be used as a replacement. After all, any suitable case would have to be such that a high degree of interaction, rather than some other factors, is causally relevant for the development of the given episode. Footnote 18 The upshot is that the PUD case has seemed to be the only suitable candidate of this particular phenomenon modelled in the network epistemological literature, but the novel evidence we provide suggests it cannot play this role.

But couldn’t we still use the received narrative on PUD as a plausible historical scenario (even if inaccurate)? The problem with this idea is that the received narrative is not that plausible. If we assume that Palmer’s erroneous study was widely shared across the scientific community, it seems unlikely that nobody noticed a problem with it. In other words: a wide dissemination of erroneous results doesn’t simply increase the chance of a wide adoption of the given idea, but also of its critical assessment. Footnote 19 It is also unlikely that Palmer’s results would trigger an outright rejection of the bacterial hypothesis, as maintained by the received view, rather than a controversy (which would preserve a theoretical diversity), as it usually happens in such cases.

Nevertheless, using highly idealized models to explain concrete historical episodes is not their only epistemic function. They can also have an exploratory function by providing a proof of possibility of a certain theoretical phenomenon or novel hypotheses about socio-epistemic mechanisms that underlie scientific inquiry (Šešelja, 2021 ). Even if we fail to empirically observe a causal mechanism that has been identified via an idealized model, this alone does not mean the given mechanism is philosophically uninteresting or irrelevant. On the one hand, the mechanism could remain empirically undetected for various reasons, including the possibility that some other empirical factors are typically more dominant, or that the phenomenon in question occurs only under very specific empirical conditions. On the other hand, the given mechanism could be theoretically relevant and explanatory of theoretical phenomena (such as scientific rationality taken in abstracto ). In both cases the model could be motivated by a stylized scenario rather than a concrete historical one. However, this also means that the simulation cannot be considered validated in view of concrete historical episodes and arguably does not result from a properly integrated history and philosophy of science. Consequently, results of such simulations need to be taken with caution when drawing inferences about actual scientific inquiry. An argument that a certain phenomenon could be epistemically harmful because it has proved to be so in the past (where the model explains how and why), hasn’t been established.

Our study thus supports the claim that the results of the above mentioned network epistemological studies still need to be treated as exploratory. In particular, how significant the threat of a high degree of information flow among scientists is (e.g. for the purposes of science policy) remains an open question. While it may turn out that such a threat is indeed relevant under specific conditions of inquiry, which exact conditions these are (when interpreted in terms of actual scientific practice) has remained largely underspecified in the literature. Footnote 20 From a more general point of view, our study provides support to recent calls for a modest treatment of results obtained by highly idealized agent-based models of scientific inquiry unless they have been empirically validated (Martini & Fernández Pinto, 2017 ; Frey & Šešelja, 2018 ; Thicke, 2020 ; Šešelja et al. 2020 ; Šešelja, 2021 ; for a somewhat different viewpoint see Mayo-Wilson & Zollman, 2021 ).

4.2 Some open questions

As mentioned above, it was previously argued that the bacterial theory of PUD was worthy of pursuit in the 1950s, even after the publication of Palmer’s results (Šešelja & Straßer, 2014 ). As the authors point out, the bacterial research program not only had open lines of inquiry, but for each of the major objections directed against it (some of which have been elaborated in Sect.  2 ), there were clear methodological responses available at the time. Beside the objection coming from Palmer’s study, Šešelja and Straßer also examine the objection that the bacteria could not survive in the acid environment of the stomach, as well as the objections coming from the successes of the acidity research line. For instance, in response to Palmer’s results the research community had a counterargument coming from a study by Freedberg and Barron ( 1940 ), which emphasized the importance of using silver staining technique for detecting bacteria rather than hematoxylin-eosin stain, used by Palmer (see Footnote 7).

If we agree with this assessment, then the results presented in the current paper raise a number questions, both of historical and socio-epistemic nature. First of all, how come that a program which was worthy of pursuit in view of the arguments available at the time failed to be actually pursued? Was this just a result of an unfortunate division of labor, resulting from factors discussed in Sect.  2 , or were some additional factors at play? This is particularly interesting in view of the claim by Fukuda et al. ( 2002 ) that prior to Palmer’s work there had been a consistent line of research on the bacterial origin of PUD throughout the first half of the twentieth century (see the quote in Sect.  1 ). Footnote 21 Together with our findings, this would indicate that the bacterial research program declined over this time period. Such a course of events is interesting not only for discussions on the division of cognitive labor, but also for the problem of epistemic responsibility. For instance, we could ask: should anyone be held accountable for the abandonment of the bacterial research program? Answering this question is at the heart of contemporary discussions on collective epistemic responsibility and normative accounts of accountability of scientists as (unorganized) collectives (see e.g. Fleisher & Šešelja, 2021 ). Moreover, this problem is closely related to discussions on scientific pluralism as well (e.g. Longino, 2002 ; Chang, 2012 ) since the PUD case illustrates potential dangers of losing a fruitful line of inquiry.

Finally, the status of the bacterial hypothesis in non-English speaking literature is another open question worthy of further investigation, which may shed additional light on the overall dynamics of the medical community at the time.

5 Conclusion

In this paper we have re-examined the history of the research on PUD, and the role of Palmer’s infamous study, which has long been considered to have played a central role in convincing other scientists that bacteria cannot be an etiological factor in this disease. To this end, we have used digital tools to systematically analyze a scope of journal articles published in English language in the decade before Palmer’s publication. Our results suggest that there had been hardly any active pursuit of the bacterial hypothesis already before Palmer’s publication. This indicates that the impact of a single influential figure on the whole research program is perhaps overestimated in the received view.

Even for those who would rather proceed with caution and who consider our results as just a piece of the puzzle requiring further investigation, our study should at least make them pause. The obtained results indicate that, at the minimum, we need to re-examine the received narrative before we take it to be an accurate historical presentation of the PUD episode. This is all the more important given the lack of historical evidence corroborating the alleged role of Palmer’s work in the history of PUD, as well as the lack of attempts at using quantitative tools for systematic digital analysis of the literature on PUD published throughout the first half of the twentieth century.

We will close by highlighting the methodological relevance of our study. The availability of digital tools makes re-examinations of historical episodes discussed by philosophers of science timely and relevant. In addition to the method of textual analysis employed in this paper, other types of related methods may be even more suitable for similar investigations. In particular, citation analysis in view of bibliometric data may provide insights into social networks characteristic of the scientific community at the time. Footnote 22 As we have mentioned, the reason we have turned to textual analysis rather than to the citation analysis is that the bibliometric data for this time period is rather sparse. Hence, obtaining reliable data (e.g. on how many scientists cited Palmer’s paper) proved difficult. However, for more recent case-studies, bibliometric data may be a valuable additional evidence.

See also Kidd and Modlin ( 1998 ), Fukuda et al. ( 2002 ), Warren ( 2005 , p. 18).

Sources include: two articles on the history of abdominal illness in Britain during WWII by professional historians of medicine (Miller, 2010 ; Jones, 2012 ); an MD thesis in the history of medicine by Pollock ( 2014 ), which comprises a chapter on the history of etiological theories until 1960s; a historical overview of ‘germ theory’ research until Palmer’s paper (Kidd and Modlin, 1998 ); a critique of the biopsychosocial model with PUD as a case study (Davey Smith, 2005 ). The authors of the last two publications are medical practitioners and were included to represent two different interpretations of factors leading to the abandonment of the ‘germ theory’. Moreover, we have included a more recent case study on this topic, written in the field of integrated history and philosophy of science (Šešelja and Straßer, 2014 ).

For example Cornell et al. ( 1944 ), “Editorial” ( 1954b ), “Editorial” ( 1954a ), and “Peptic ulcer and “ordinary” anxiety” ( 1950 ).

Sullivan and McKell summed their theory in the following formula: \(u = \dfrac{a+b+c+d+x}{r}\) , where u = ulcer, a = constitutional and genetic factors, b = personality, c = precipitating emotional situations, d = physical injury, x = unique factors, r = resistance.

This is not to say that vagotomy was harmless: it still had a significant mortality rate. For example, Edwards et al. ( 1963 ) report the operative mortality rate of 2.7 % (see also Šešelja and Straßer, 2014 , p. 437).

In the second half of the 19th century Koch presented a set of postulates for accepting the etiological role of bacteria: (1) The organism must be shown to be constantly present in characteristic form and arrangement in the diseased tissue; (2) the organism must be isolated and grown in pure culture; (3) the cultured organism must be shown to initiate and reproduce the disease when reinoculated into a healthy body; (4) the organism must be re-isolated from the experimentally infected organism (Thagard, 2000 , p. 59).

A particularly interesting aspect of Freedberg and Barron’s study is that they explicitly advise against the employment of hematoxylin-eosin staining technique (later on used by Palmer) for the identification of bacteria, since in contrast to silver staining (subsequently used by Warren and Marshall), it did not reveal the spiral bacteria. Note also that while Palmer cites their paper he does not comment on Freedberg and Barron’s warnings concerning the staining techniques (see also Šešelja & Straßer, 2014 , Sect. 5).

The textual analysis did not consider books published during this period. These resources could be included in futures studies.

Medical Subject Headings (MeSH) Major Topic terms are assigned to articles by the U.S. National Library of Medicine. The MeSH Major Topics classify articles in terms of a disease, a type of an injury, or a pathological condition that a medical article focuses on, and they are usually obtained from the title and/or statement of purpose (see https://www.nlm.nih.gov/bsd/disted/meshtutorial/principlesofmedlinesubjectindexing/majortopics/ accessed on July 14, 2019). MeSH Qualifiers allow to bring together citations focusing on a particular aspect of a subject (which usually is a particular disease). The “etiology” Qualifier is “used with diseases for causative agents including microorganisms and includes environmental and social factors and personal habits as contributing factors”. The above qualifier includes, among others, the “pathogenesis” (see https://www.nlm.nih.gov/mesh/qualifiers_scopenotes.html ) and the “microbiology” Qualifiers (see https://www.nlm.nih.gov/mesh/subhierarchy.html ).

The mistagged paper, unrelated to PUD, is Twiss and Carter ( 1952 ). A paper by Monro ( 1945 ) was published twice, while a paper by Chattopadhyaya ( 1951 ) was split in two. The main reason we couldn’t retrieve all the articles is that they are not available in libraries across Germany, which means that obtaining them would be significantly more costly.

More precisely, we used OCRmyPDF software based on Tesseract, an open source OCR engine, see https://ocrmypdf.readthedocs.io/en/latest/index.html . Our results are based on the 4.1.0 release of Tesseract, see https://github.com/tesseract-ocr (both links accessed on July 1, 2021).

Spirochetes are spiral bacteria discussed by Palmer and others (e.g. by Freedberg and Barron, see Sect.  2 ) in the context of PUD.

We have further validated these results by examining the occurrences of related terms, such as “microbe” and “germ”, which were very scarce and in no instance related to the etiological role in PUD. As a basic test we checked the occurrences of the string “ulcer” which indeed appeared in 100% of the articles.

Text words search includes “all words and numbers in the title, abstract, other abstract, MeSH terms, MeSH Subheadings, Publication Types, Substance Names, Personal Name as Subject, Corporate Author, Secondary Source, Comment/Correction Notes, and Other Terms \(\dots\) ” ( https://pubmed.ncbi.nlm.nih.gov/help/#tw , accessed on July 1, 2021).

In order to stay sufficiently broad in our search we included each decade plus an additional year.

This disparity could be due to multiple reasons: from the increase in the number of post-war publications to a higher coverage by the relevant indexes to medical periodical literature, which were for this time period selective (see https://www.nlm.nih.gov/databases/databases_oldmedline.html , accessed on July 1, 2021).

We are not suggesting that the scientific community at the time was not tightly connected, but rather, that factors other than the connectedness of the community and the structure of its information flow may be more explanatory of the loss of the bacterial hypothesis.

This may be challenging: for example, in case of the continental drift debate, biased outlooks of North American scientists played an important role in their rejection of Wegener’s hypothesis of continental drift, see Oreskes ( 1999 ), Šešelja & Weber ( 2012 ).

Think of Wakefield’s fraudulent study aiming to show an association between the measles-mumps-rubella vaccine and autism, which received primarily critical response from the scientific community (see e.g. Suelzer et al., 2019 ).

For some attempts at specifying such conditions by means of robustness analysis see Rosenstock et al. ( 2017 ), Frey and Šešelja ( 2020 ).

While their claim is based on 15 studies related to the bacterial hypothesis of PUD conducted between 1875 and 1940 (Fukuda et al. 2002 , p. 18), it would be interesting to apply digital textual analysis to this time period as well and reexamine whether this was indeed the case, or whether the bacterial research program had been rather fringe all along.

For examples of using social network analysis in the context of integrated history and philosophy of science see Claveau and Herfeld ( 2018 ), Herfeld and Doehne ( 2018 ). For a more general discussion on digital approaches to philosophy of science see Pence and Ramsey ( 2018 ).

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Acknowledgements

We are grateful to two anonymous reviewers for valuable comments, which helped to improve this paper. We also wish to thank the RTG “Situated Cognition”, the work group led by Tobias Schlicht at Ruhr University Bochum, Philosophy & Ethics Group at TU Eindhoven, and Christian Straßer for valuable comments on an earlier draft of this paper. The research for this paper was partially funded by the Munich Center for Mathematical Philosophy (MCMP) at LMU Munich and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Research Grant HA 3000/9-1; Project number 426833574 (DFG Research Network on Simulations of Scientific Inquiry) and GRK-2185/1, META 2.3 (DFG Research Training Group “Situated Cognition”).

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Bartosz Michał Radomski

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Dunja Šešelja

Munich Center for Mathematical Philosophy, LMU Munich, Munich, Germany

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Radomski, B.M., Šešelja, D. & Naumann, K. Rethinking the history of peptic ulcer disease and its relevance for network epistemology. HPLS 43 , 113 (2021). https://doi.org/10.1007/s40656-021-00466-8

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Pressure ulcers: Prevention and management

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• 1 Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts. Electronic address: [email protected].
• 2 Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts.
• PMID: 30664906
• DOI: 10.1016/j.jaad.2018.12.068

Prevention has been a primary goal of pressure ulcer research. Despite such efforts, pressure ulcers remain common in hospitals and in the community. Moreover, pressure ulcers often become chronic wounds that are difficult to treat and that tend to recur after healing. Especially given these challenges, dermatologists should have the knowledge and skills to implement pressure ulcer prevention strategies and to effectively treat pressure ulcers in their patients. This continuing medical education article focuses on pressure ulcer prevention and management, with an emphasis on the evidence for commonly accepted practices.

Keywords: chronic wounds; debridement; dressings; management; nutrition; pressure injury; pressure sore; pressure ulcer; prevention; repositioning; support surface; surgery; therapy; treatment; wound care; wound healing; wounds.

Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

• Debridement / methods
• Dermatology / methods*
• Evidence-Based Medicine / methods*
• Negative-Pressure Wound Therapy / methods
• Patient Positioning
• Pressure Ulcer / etiology
• Pressure Ulcer / therapy*
• Secondary Prevention / methods*
• Skin Care / methods*

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Review of the Current Management of Pressure Ulcers

Tatiana v. boyko.

1 Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Plastic and Reconstructive Surgery Division, Stanford University School of Medicine, Stanford, California.

2 Department of Surgery, University at Buffalo SUNY, Buffalo, New York.

Michael T. Longaker

3 Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.

George P. Yang

4 Department of Surgery, Stanford University School of Medicine, Stanford, California.

5 Veterans Affairs Palo Alto Health Care System, Palo Alto, California.

Significance: The incidence of pressure ulcers is increasing due to our aging population and the increase in the elderly living with disability. Learning how to manage pressure ulcers appropriately is increasingly important for all professionals in wound care.

Recent Advances: Many new dressings and treatment modalities have been developed over the recent years and the goal of this review is to highlight their benefits and drawbacks to help providers choose their tools appropriately.

Critical Issues: Despite an increased number of therapies available on the market, none has demonstrated any clear benefit over the others and pressure ulcer treatment remains frustrating and time-consuming.

Future Directions: Additional research is needed to develop products more effective in prevention and treatment of pressure ulcers.

George P. Yang, MD, PhD

Scope and Significance

T he fastest growing segment of our population is those over 65 years of age, and there are increased rates of obesity, diabetes, and cardiovascular disease. 1 This combination of factors has resulted in more people needing assistance with activities of daily living due to decreased mobility. 2 A major morbidity of decreased mobility is development of a pressure ulcer. The treatment for pressure ulcers is lengthy and causes a significant financial burden on the healthcare system. In the United States, an estimated $11 billion dollars is spent on pressure ulcers yearly, with $500 to $70,000 being spent on a single wound. 3

Translational Relevance

Despite a number of new dressings and treatments available for the management of pressure ulcers, none has been demonstrated to have a significant benefit over the other. The basic principles of maintaining the wound clean and well perfused remain the hallmarks of therapy. A major target for new therapies would be finding approaches to decrease incidence among susceptible patients, especially given potential penalties in reimbursement for patients who do develop a pressure ulcer.

Clinical Relevance

The prevention and treatment of pressure ulcers are highly relevant to wound care professionals. These patients require prolonged course of treatment to fully heal their wounds. The biomedical burden is tremendous as noted above and healthcare expenditures on this problem are only rising. Penalties now imposed for hospital-acquired pressure ulcers mean we need greater knowledge about causation and prevention.

Pressure ulcers develop as a result of a combination of physiologic events and external conditions. The classic thinking of tissue ischemia induced by prolonged external pressure on tissue being the sole causative factor of pressure ulcer formation has been examined more systematically. Along with localized ischemia and reperfusion injury to tissues, impaired lymphatic drainage has been shown to contribute to injury as well. Compression prevents lymph fluid drainage, which causes increased interstitial fluid and waste build up and contributes to pressure ulcer development. Deformation of tissues has been shown to be a greater indicator of pressure ulcer formation than pressure exerted on tissues alone. 4 The time required to develop a pressure ulcer is dependent on many factors, including the patient's physiology and the degree of pressure and shear force placed on the tissue. 5 Pressure ulcers occur over predictable pressure points where bony protuberances are more likely to compress tissues when the patient is in prolonged contact with hard surfaces ( Fig. 1 ). 6 , 7 For patients unable to move themselves, such as intubated patients in the ICU, positional change every 2 hours has been widely accepted as effective prevention. 8 , 9 Surgeries longer than 4 hours on a standard OR table have been shown to increase the risk of pressure ulcer formation leading to the routine use of gel pads in areas of risk during prolonged surgery. 10

Illustration of locations of pressure ulcers in supine patients. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Pressure ulcer formation is highly influenced by risk factors ( Table 1 ), including all conditions leading to immobility, decreased or lack of sensation, as well as malnutrition. 11 Extrinsic risk factors include being immobilized on a spinal board, OR table, or bed for prolonged periods of time, as well as poorly fitted medical devices in contact with patient tissues. Intrinsic risk factors such as diabetes, malnutrition, and smoking also increase the overall risk for pressure ulcers. The spinal cord injury patient population is at the highest risk (25–66%) of developing a pressure ulcer due to the combination of immobility and decreased sensation. A prospective study of spinal cord patients not only found that sacral and ischial pressure ulcers were very common (43% and 15%, respectively), as might be expected, but also noted that the second most common location was on the heel (19%). 12 , 13 Nursing home patients have a pressure ulcer prevalence of 11% and are most likely to develop pressure ulcers over the sacrum or heels. 14 , 15 Nursing home patients were also found to have contractures at a prevalence of 55%. 16 Contractures are caused by decreased elasticity of the tissue surrounding major joints, and the resulting lack of full mobility in the affected extremities significantly increases the risk of pressure ulcer formation. These data highlight how critical the need is to understand the physical, environmental, and medical risks for development of pressure ulcers in the individual patient to prevent them.

Intrinsic and extrinsic factors influencing the development of pressure ulcers

Risk Assessment

Assessing the risk for the development of pressure ulcers needs to be performed in all patients to institute appropriate prevention measures in those at risk. Risk should be assessed in all admitted patients as well as with any changes in mobility or medical conditions. Several risk assessment scales exist. The Norton scale scores the following five categories from a low of 1 to a high of 4: physical condition, mental condition, activity, mobility, and incontinence. A total score less than 14 indicates high risk for pressure ulcer development. 17 The Braden scale is similar giving up to four points in the categories of sensory perception, moisture, activity, mobility, nutrition, and friction with a higher score indicating lower risk. 18 The exact specific scale used is not as important as simply having regular risk assessment and exercising clinical judgment. 19

Prevention of pressure ulcer formation is directed at alleviating the risk factors for the individual patient, and is primarily focused on minimizing episodes of prolonged pressure either by placing appropriate padding at pressure points or by frequent patient repositioning. All patients using prosthetics or requiring a wheelchair for mobility should be appropriately fitted to ensure that the fit is correct and there is adequate padding. The fitting process should be repeated if there are any significant changes in weight or body habitus that can affect fit. Sweat, urine, and stool can lead to maceration of the skin and the initial skin breakdown can lead to a pressure ulcer if the skin is overlying a pressure point. 20 A significant focus for care of at-risk patients is keeping the skin clean and dry. Even with adequate padding, it is important to make routine positional changes as even relatively low pressures can cause a pressure ulcer with prolonged exposure. 5 , 21

Pressure mapping technologies have been developed to measure the amount of pressure placed on different parts of the sitting or reclining body. These technologies have been used to develop pressure-relieving wheelchair cushions and to study normal weight-shifting behavior. 22 These technologies were also used in determining that 30 degrees of wheelchair tilt is needed to relieve pressure from the ischial and sacral areas. 23 Their use in bed-bound patients has been limited but has great potential for determining pressure points at risk for ulceration and in determining the effect of pressure-relieving positions on established wounds.

Any patient who has been determined to be at risk for development of a pressure ulcer or who already has a pressure ulcer needs to have a plan for repositioning. The plan needs to be individually tailored for each patient to address his or her specific needs. Frequency of repositioning needs to take many factors into account, including the support surface for the patient, general medical condition, and goals of care. Clinicians need to be cognizant of the fact that repositioning itself can create shear forces on skin, and so, the fragility and condition of the patient's skin need to be part of the assessment for how frequently to reposition them. There are a variety of factors to take into account for how to reposition patients depending on whether the patient is supine, prone, or in a wheelchair. Of special note for patients in the acute hospital setting are medical devices. Care must be taken since inadvertent positioning of the device between the patient and the support surface can create a high-pressure zone. While repositioning, lifting instead of dragging patients reduces friction and shear forces on the skin and prevents skin damage. 5 Documentation of repositioning and regular skin condition assessment is key in determining early signs of pressure ulcer formation such as nonblanching erythema. System solutions such as electronic medical record programs, which prompt providers to document results of pressure ulcer screening every shift or day, are of great importance in diagnosing pressure ulcers early and preventing progression. 24

A variety of pads are available, which are designed to specifically cover pressure points such as the sacrum and heels as well as foam pads designed to wrap around body parts at risk (especially feet). 25 However, it is important to note that some pads can actually be detrimental. For example, supports with cutouts can have increased pressure at their edges. There are an equal number of mattress pads (egg crate mattresses, natural sheepskins, etc.) that serve to decrease pressure across a large surface area. 21 Silk-based fabrics have been shown to be superior in pressure ulcer prevention when compared to cotton-based fabrics due to a decrease in friction forces and subsequent damage to skin. 26

Finally, adequate nutrition is very important in preventing pressure ulcer formation. Nutritional supplementation can benefit patients with limited oral intake and enteral or parenteral feeding can become necessary in patients who are not able to safely ingest enough oral nutrients. Protein intake is especially important to maintain a positive nitrogen balance, and vitamin/mineral supplements are recommended in patients lacking a balanced diet. 27 Prealbumin is used as a laboratory test of short-term nutritional adequacy. Albumin is also useful, but its longer half-life means it is more reflective of nutrition over a long period of time.

Diagnosis and Assessment

Once a pressure ulcer is identified, staging and careful documentation of the size of the wound should be performed. Additional assessments of the ulcer include the location, surrounding skin condition, presence of tissue undermining and tunneling, and amount of exudate, odor, and tenderness. Pressure ulcers are classified into six categories ( Fig. 2 and Table 2 ). 7 , 28 Stage I describes intact skin with nonblanchable erythema. Stage II pressure ulcers have partial-thickness skin damage with possible blister formation, but no subcutaneous tissues visible. Stage III pressure ulcers have full-thickness skin loss with subcutaneous fat exposed but no muscles, bones, or tendons visible. Stage IV pressure ulcers have tissue loss with exposure of muscles, bones, tendons, or vital organs. A common hallmark of pressure ulcers is that the area of skin affected typically underestimates the amount of subcutaneous tissue involved. An unstageable pressure ulcer refers to a wound with an undetermined level of tissue injury because the entire base of the wound is covered by slough tissue and/or eschar. A deep tissue injury is a term recently proposed by the National Pressure Ulcer Advisory Panel (NPUAP) to describe a pressure wound that has tissue injury hidden below intact skin. 29 These wounds appear as deep bruises and have high potential for quick deterioration into a high-stage pressure ulcer.

Illustration of different stages of pressure ulcers. From left to right . Top diagram showing pressure ulcers Stage I: skin intact. Stage II: partial skin loss. Stage III: full-thickness skin loss, subcutaneous tissue exposed. Stage IV: muscle, tendon, bone or organs exposed. Bottom diagram showing unstageable pressure ulcer with tissue damage hidden from observer by eschar over entire wound. Deep tissue injury hidden from observer by intact skin appears as a bruise from above.

Table of different stages of pressure ulcers

The pressure ulcer scale for healing (PUSH tool) is a commonly used tool developed by the NPUAP, which grades pressure ulcers based on size of wound, wound bed tissue type, and exudate amount ( Table 3 ). 30 Another commonly used scale is the Bates-Jensen wound assessment tool which scores wounds based on size, depth, wound edges, tissue undermining, type and amount of necrotic tissue, type and amount of exudate, skin color, presence of edema, induration, granulation, and epithelialization. 31 Other similar tools such as the pressure sore status tool and Sessing scale are also of use. 32 It is more important to evaluate and monitor pressure ulcers in a close and consistent manner than the specific tool used to do so.

Pressure ulcer scale for healing (PUSH tool)

Copyright. NPUAP, 2003, reprinted with permission. Points are calculated per category and are added for a total score.

Further workup is sometimes warranted to define the extent of tissue involved. Because the area of skin breakdown is smaller than the total area affected, CT or MRI can be useful in defining the extent of the tissue involved and to determine whether osteomyelitis is present. 33 Wound cultures are not routinely performed, but should be considered with lack of ulcer healing and persistent evidence of infection. If a wound culture is to be performed, tissue culture is more informative than simply performing a swab of the wound. 5 Cultures showing more than 10 5 CFU/g are indicative of active tissue infection. In the extremities, the adequacy of perfusion should be accessed via the ankle–brachial index and vascular studies. 34

The mainstays of pressure ulcer treatment include offloading the offending pressure source, adequate drainage of any areas of infection, debridement of devitalized tissue, and regular wound care to support the healing process.

Pressure relief

The first step in management is offloading pressure from the wound site. All of the measures described above for prevention of pressure ulcers are equally applicable to their treatment. For bedridden patients, this means strict adherence to repositioning the patient regularly. Any methods to pad the area of the pressure ulcer should be instituted if not already in use. Beyond the usual onlays and pads, some patients may require specialty beds to aid in decreasing pressure. These beds typically use air to continually shift pressure points through a variety of approaches. 35 Even with these beds, patients still need to be repositioned regularly. For patients using prosthetics, they may need to go without them for a period of time to allow healing to occur. Any patient developing a pressure ulcer with a prosthetic should be refitted after they have healed to protect against future problems. Wheelchair-bound patients may need to have their mobility limited to allow healing. As with a prosthetic, the wheelchair should be reexamined for proper fit. 36

Infection control

An important part of the initial evaluation of a pressure ulcer is to determine if there is evidence of inadequately treated infection. The pressure ulcer should be examined for the presence of surrounding erythema or fluctuance. The presence of crepitus is more ominous and should result in an expeditious assessment for the possibility of a necrotizing soft tissue infection. If there is a determination that there is inadequate source control, the patient should be taken to the operating room for appropriate abscess drainage and debridement.

Some surgeons elect to treat the wound initially with locally applied antiseptics, including povidone iodine, silver sulfadiazine, hydrogen peroxide, or Dakin's solution (sodium hypochlorite). The theory is that these topical agents serve to kill bacteria in the pressure ulcer to allow for better healing. If these solutions are used, they should only be used in the short term as they can also retard wound healing in the long term through their cytotoxic effects. 37

Intravenous antibiotics should only be used in patients with significant cellulitis, or systemic signs and symptoms of infection, and should be stopped once those signs improve. A clean pressure ulcer, even with some necrotic debris, does not require intravenous antibiotics. Currently, most treatment protocols would recommend the use of intravenous antibiotics when there is evidence of osteomyelitis, but there is actually little evidence for its use. 38 , 39 Generally, osteomyelitis requires debridement of the infected bone and coverage with a well-perfused flap to allow it to heal. 40 Topical antibiotics have little role in the management of pressure ulcers.

Debridement

Debridement of devitalized tissue and biofilm and abscess drainage are necessary in the treatment of pressure ulcers. In cases where there is a significant amount of necrotic tissue, performing the initial debridement in the operating room allows for a more definitive procedure. Subsequent debridements are then more easily managed at the bedside. There are instances where significant debridement is not needed or should not be done. If there is a dry eschar without purulence or fluctuance, and minimal erythema, the eschar can be left in place. If there is little subcutaneous tissue under the eschar, as in the case of the heel, debridement should be done with care. When performing surgical debridement, tissue should be resected until healthy bleeding tissue is encountered. After the initial presentation, repeated debridements are often necessary as the extent of necrosis can be difficult to assess. 41

Other approaches to performing mechanical debridement include the use of acoustic energy in the form of ultrasound. Low-frequency ultrasound has been used to decrease bioburden of the wound and was shown to speed pressure ulcer healing. 5 Hydrotherapy, including whirlpool, pulsed lavage, and vibration therapy are occasionally used for pressure ulcer debridement. There are additional products that perform an autolytic or enzymatic debridement over time when no urgent need for debridement exists. 7 In cases where a patient cannot tolerate surgical debridement, there is an option of undergoing medical maggot debridement, in which maggots remove dead tissue, allowing the wound to heal. 42 The goal of all these approaches is to create a bed of well-granulated tissue throughout the ulcer cavity. Small well-granulated ulcers can heal with re-epithelialization, while skin grafting or a surgical flap may be necessary in larger ulcers.

Dressings and topical agents

Dressings should be chosen depending on the wound being treated ( Table 4 and Fig. 3 ). It should be noted that none of the dressings described below has been shown to have any superiority, and the choice of dressing should depend on the type of wound being treated. 43 Things to be considered include size, depth, shape and location of the wound, presence and volume of exudate, presence of tunneling and tissue undermining, type of tissue in wound bed, and surrounding skin condition. Skin surrounding the ulcer should be protected from excessive moisture and friction to prevent breakdown. Dressings should be changed regularly and as soon as they become soiled with urine or feces to prevent wound contamination. Each dressing change should be accompanied by concurrent wound reassessment.

Algorithm for help in choosing an appropriate class of dressings for pressure ulcer management. *Gauze dressings can be used if limited options available require more frequent dressing changes.

Dressings available for pressure ulcer management with advantages, disadvantages, and ideal use

Gauze dressings

The traditional wet-to-dry method of gauze dressing now has more limited use in the treatment of pressure ulcers. While the materials are inexpensive, they do require frequent changes and the related nursing expense needs to be factored in when determining their true cost. 44 When properly performed, they help maintain a moist wound environment, and the gauze also serves the role of performing a superficial debridement of biofilm and small amounts of necrotic tissue during dressing changes due to its adherent nature. 45 The advent of advanced dressing materials makes gauze dressings a fallback when nothing else is readily available. 46 Dry gauze dressings should not be used to treat pressure ulcers.

Alginate dressings

Alginate is a very absorbent material that is ideal for use in wounds with moderate to high discharge. They can absorb several times their weight in exudate and can conform well to irregular or tunneled wounds. Alginate dressings can be used in the setting of infected wounds and can be left in place longer than most dressings. 47

Foam dressings

Foam dressings are made from polyurethane, a semipermeable material that can accommodate a medium to high amount of wound exudate and can be used in infected pressure ulcers. Foam dressings are often used for prevention of pressure ulcers because they provide some cushion. Silicone is often used in combination with foam dressings (such as Allevyn, Mepilex, and Optifoam) and is helpful in the setting of fragile tissue surrounding pressure ulcers. Dressings with silicone are less likely to cause trauma to skin on removal compared to other adherent dressings. 48

Hydrocolloid dressings

Hydrocolloid dressings are made of a foam or film polyurethane material and contain a gelatin- or sodium carboxymethylcellulose-based gel material, which gives it the ability to absorb some fluids. They are well suited for wounds that have minimal to moderate drainage and are often used on Stage II and Stage III pressure ulcers. 46

Hydrogel dressings

Hydrogel dressings are gel based and are 90% water. These dressings are therefore ideally used in dry or dehydrated wounds and are often used over granulation tissue. In addition to being available in sheet form (where hydrogel is placed over a thin fiber mesh) and in the form of impregnated gauze, hydrogel also comes in its pure form in tubes and can be placed at the base of an uninfected granulating wound. This dressing should be covered by a sturdier dressing to prevent dislocation and dehydration of the hydrogel. 49

Silver-containing dressings

Silver has bactericidal properties and dressings that are impregnated with silver are ideal for use in infected wounds. This dressing should be discontinued after clearance of infection as it can delay wound healing due to its toxicity to keratinocytes and fibroblasts. Silver is often incorporated into foam and alginate dressings. Silver alginate comes in rope and square forms, which are well suited for infected wounds with exudate, and gel form, which is better suited for drier wounds. 50

Honey-containing dressings

There are anecdotal reports of the use of honey in the treatment of wounds since antiquity. In modern times, there is currently low evidence for the use of honey in the setting of pressure ulcers. 28 Medical-grade honey has been shown to have mild antibiotic properties. Medical honey comes in stand-alone forms of gel or paste as well as impregnated into dressings where it is combined with alginate or hydrocolloid materials.

Transparent film dressings

Transparent film dressings are used primarily to protect Stage I or II ulcers where the skin remains intact. They provide a barrier to urine, stool, and other bodily fluids, which can macerate the skin. Because they are transparent and allow for observation of the wound, they can be applied and left in place for days. These dressings should not be applied in any ulcer where there is exudate as they are not porous. Care must be taken to remove these dressings as they can rip skin if removed forcefully. 51

Negative pressure wound therapy

Negative pressure wound therapy (NPWT) consists of a foam dressing, which can be tailored to fit the patient's wound and is covered by a transparent film to enable creation of a vacuum in the wound when the foam is attached to a suction device via tubing. NPWT has been shown to speed wound healing in chronic wounds and the prevailing theory is that the vacuum causes the cells in the wound bed to sense a mechanical force. 52 Mechanical forces stimulate the proliferation of fibroblasts leading to improved healing. The presence of the vacuum continuously eliminates exudate making it ideal in wounds where there is heavy exudate. Before application of the NPWT device, the wound must be adequately debrided. The foam dressing is easy to conform to wounds with unusual shapes, tunneling, and undermining. Because of the transparent film required for the vacuum to hold, NPWT is useful for preventing additional wound contamination. Randomized controlled trials showed no advantage of NPWT over other dressings. 53 As with any dressing, its use is dictated by its properties. Wounds with a heavy exudate are readily managed with NPWT. It has been found to be helpful in wounds adjacent to fecal flow where its seal prevents wound contamination. Contraindications to NPWT use include uncorrected coagulopathy, exposed vital organs or large vessels. 53 A nonadherent dressing can be placed below the foam to decrease pain on removal of foam dressing and during suctioning over the wound bed.

Other therapies

Biophysical treatments, including direct electric stimulation, pulsed electromagnetic field, and pulsed radio frequency energy, have been used to promote wound healing. Phototherapy treatment of pressure ulcers has been performed using laser, infrared, and ultraviolet waves. Studies have shown equivocal evidence concerning laser and infrared treatments, but ultraviolet C light therapy has been shown to decrease the bacterial burden and can be used following wound debridement in persistently infected wounds. 54 Hyperbaric oxygen therapy and topical oxygen therapy have been used for pressure ulcer treatment with equivocal results. 55

Biologic dressings describe a group of products derived from skin structures that have been purported to speed healing. They can be derived from nonhuman and human sources and are applied to noninfected, well-granulated wounds. The products range from decellularized human and porcine skin to dressings containing human fibroblasts and keratinocytes. Collagen is the main connective tissue fiber and application of collagen to uninfected granulating wound base can theoretically stimulate wound healing by providing a matrix network for cells to migrate into. These biologic dressings are typically used when an ulcer has fully granulated in, but still has a significant area of un-epithelialized wound. The dressings can be used in lieu of skin grafting to prevent having a second wound that needs attention. Growth factors have also been used by themselves to increase wound healing by stimulating angiogenesis and matrix deposition. 56

Patient optimization

In addition to treatment of the pressure ulcer itself, it is important to treat the overall patient as well. Physical measures to relieve pressure have already been described. Hyperglycemia will retard wound healing and diabetics should be aggressively treated to maintain glycemic control. The immune system has been shown to have a vital role in wound healing and immunosuppression will slow healing. Attention should be directed to any therapy that can cause immunosuppression, and these medications should be optimized to provide appropriate therapy without excessive immunosuppression. Proper wound healing requires adequate blood supply. For any pressure ulcer in the extremities, perfusion should be assessed and vascular surgery consulted if it is determined to be inadequate to support proper healing. 5 , 7 Finally, we will stress once again the need to provide adequate nutrition. Periodic assessments of adequate nutrition should be performed by checking serum markers of nutrition such as albumin and prealbumin. Dietary intake should be adjusted to ensure the patient is in positive nitrogen balance. 27

Control of contamination

By default, any open pressure ulcer is superficially contaminated with environmental flora. However, it is important to prevent added contamination if the wound is near the fecal stream as in ischial or sacral pressure ulcers. An added concern is that stool and urine can be irritating to the skin, causing further skin breakdown and extension of the ulcer. Because a large number of patients with pressure ulcers are incontinent of both bowel and bladder, it is important to consider how to deal with this. At the very least, these patients require frequent changes of their diapers to minimize skin contact with urine and stool. Consideration should be given to placement of a urinary catheter with the understanding that discomfort and complications, including urinary tract infection, are possible. Rectal tubes can be used but are rarely useful due to solid stools. 57

Diversion of the fecal stream through surgical placement of a colostomy can be undertaken in those cases where it is felt to be necessary to allow proper healing. Any discussion of fecal diversion should include consideration of the likelihood that the colostomy will be permanent. Many of the patients who develop severe sacral and ischial pressure ulcers are incontinent or require a bowel program due to underlying conditions such as dementia or spinal cord injury. In these patients, having a permanent colostomy can actually be beneficial in their long-term care. 58

Surgery for reconstruction

Although the majority of pressure ulcers will heal following debridement and conservative treatments outlined above, sometimes surgery will allow more rapid resolution of the ulcer. It should be noted that patients with poorly healing wounds should first be assessed for why the wound is not closing as those same factors could risk failure of surgical reconstruction. There are a variety of techniques available ranging from a simple skin graft to pedicled or, rarely, microvascular flaps for coverage. The appropriate candidate for surgical reconstruction has a wound that is without purulence, well-granulated and well-protected from soilage. The patient should be adequately nourished as assessed by nitrogen balance, albumin, and prealbumin, and without acute medical problems separate from the wound. Any intrinsic problems that can delay healing should be optimized, that is, well-controlled blood sugars in diabetics. In the appropriate patient, reconstruction will speed healing. Composite local tissue flaps are most frequently used to provide adequate tissue protection and perfusion. There are innumerable approaches to tissue coverage and the plan for each patient needs to be individualized. The flaps are planned so that suture lines remain away from pressure sites to ensure the best chance for healing. 59 Microvascular tissue transfer is rarely used but indicated when local options for creating a flap are exhausted. 60 Careful surgical planning is required to assure options for future reconstructions in cases of flap failure or pressure ulcer recurrence.

Among the indications for using surgical reconstruction are very large wounds, wounds with exposed organs and vessels, chronically nonhealing wounds, and wounds with osteomyelitis. Chronically infected bone will not allow appropriate healing of the overlying tissue. Prolonged antibiotics are often inadequate in curing the infection. A surgical approach to healing the ulcer requires debridement of the infected bone and placement of a well-vascularized flap to cover the area can allow the infection to be cured.

Pressure ulcer prevention remains the most important step in the management of these wounds. However, despite best efforts, pressure ulcers may develop if enough risk factors are present. Treatment of pressure ulcers is necessary for patient comfort and to decrease risk of systemic infection. The mainstays of treatment as outlined above include debridement of devitalized tissue, control of remaining infection with antibiotics, medical and nutritional patient optimization, appropriate dressing selection, and frequent monitoring of progression of wound evolution. If standard approaches are not adequate, additional therapies can be pursued, including biophysical modalities. Finally, in large ulcers, ulcers where wound healing is not adequately progressing, or ulcers where chronic osteomyelitis is present, reconstructive surgery can be considered.

Take-Home Messages

• • Pressure ulcers represent a large and growing biomedical burden to society.
• • Understanding prevention and treatment is necessary for wound care specialists.
• • Novel dressings and therapies have not shown increased benefit over others, but they have utility based on specific patients.
• • A major target for research should be improved prevention, given penalties now in place of hospital-acquired pressure ulcers.

Abbreviations and Acronyms

Acknowledgment and funding sources.

The authors acknowledge generous support from the Hagey Laboratory for Pediatric Regenerative Medicine.

Author Disclosure and Ghostwriting

No competing financial interests exist. The content of this article was expressly written by the authors listed. No ghostwriters were used to write this article.

About the Authors

Tatiana V. Boyko, MD, is a general surgery resident at the University at Buffalo currently performing a postdoctoral research fellowship at Stanford University. Michael T. Longaker, MD, MBA, is the Deane P. and Louise Mitchell Professor of Surgery at Stanford University School of Medicine. He is the Director of the Hagey Laboratory for Pediatric Regenerative Medicine and the Co-Director of the Institute of Stem Cell Biology and Regenerative Medicine. George P. Yang, MD, PhD, is an Associate Professor of Surgery at Stanford University School of Medicine.