Abstracts

INTRODUCTION

Healthcare-associated infections (HAI) pose a threat to hospitalized patients worldwide.²⁰20. Pittet D, Allegranzi B, Storr J, Bagheri Nejad S, Dziekan G, Leotsakos A, et al. Infection control as a major World Health Organization priority for developing countries. J Hosp Infect. 2008;68(4):285-92. DOI:10.1016/j.jhin.2007.12.013 Their incidence is higher in developing countries, where problems with human resources, technical expertise, and laboratory support hinder infection control policies.¹1. Allegranzi B, Bagheri Nejad S, Combescure C, Graafmans W, Attar H, Donaldson L, et al. Burden of endemic health-care-associated infection in developing countries: systematic review and meta-analysis. Lancet. 2011;377(9761):228-41. DOI: 10.1016/S0140-6736(10)61458-4 Traditionally, the occurrence of HAI has been attributed to patient fragilities, invasive procedures, use of antimicrobials, and other work processes.⁵5. Curtis LT. Prevention of hospital-acquired infections: review of non-pharmacological interventions. J Hosp Infect. 2008;69(3):204-19. DOI:10.1016/j.jhin.2008.03.018 However, recent studies indicate the role of climate and weather as additional epidemiological determinants of HAI incidence and etiology.¹⁶16. Leekha S, Diekema DJ, Perencevich EN. Seasonality of staphylococcal infections. Clin Microbiol Infect. 2012;18(10):927-33. DOI:10.1111/j.1469-0691.2012.03955.x ^{, 20}20. Pittet D, Allegranzi B, Storr J, Bagheri Nejad S, Dziekan G, Leotsakos A, et al. Infection control as a major World Health Organization priority for developing countries. J Hosp Infect. 2008;68(4):285-92. DOI:10.1016/j.jhin.2007.12.013 This novel approach may include those infections in the wide group of seasonal diseases, alongside dengue fever and influenza.¹⁰10. Fisman DN. Seasonality of infectious diseases. Annu Rev Public Health. 2007;28:127-43. DOI:10.1146/annurev.publhealth.28.021406.144128

Summer peaks of gram-negative bacilli (GNB) infections in healthcare settings have been reported in developed countries with temperate climates.⁹9. Eber MR, Shardell M, Schweizer ML, Laxminarayan R, Perencevich EN. Seasonal and temperature-associated increases in gram-negative bacterial bloodstream infections among hospitalized patients. PLoS One. 2011;6(9):e25298. DOI:10.1371/journal.pone.0025298 ^{, 14}14. Kaier K, Frank U, Conrad A, Meyer E. Seasonal and ascending trends in the incidence of carriage of extended-spectrum ß-lactamase-producing Escherichia coli and Klebsiella species in 2 German hospitals. Infect Control Hosp Epidemiol. 2010:31(11):1154-9. DOI:10.1086/656748 ^{, 19}19. Perencevich EN, McGregor JC, Shardell M, Furuno JP, Harris AD, Morris JG, et al. Summer Peaks in the incidences of gram-negative bacterial infection among hospitalized patients. Infect Control Hosp Epidemiol. 2008;29(12):1124-31. DOI:10.1086/592698 These countries have well-defined seasons, and hospitals are artificially climatized.²²22. Richet H. Seasonality in gram-negative and healthcare-associated infections. Clin Microbiol Infect. 2012;18(10):934-40. DOI:10.1111/j.1469-0691.2012.03954.x ^{, 24}24. Schwab F, Gastmeier P, Meyer E. The warmer the weather, the more gram-negative bacteria - impact of temperature on clinical isolates in intensive care units. Plos One. 2014;9(3):e91105. DOI:10.1371/journal.pone.0091105 On the other hand, data on the seasonality of HAI pathogens in developing countries, which generally lack those characteristics, are scarce.²¹21. Ramos GP, Rocha JL, Tuon FF. Seasonal humidity may influence Pseudomonas aeruginosa hospital-acquired infection rates. Int J Infect Dis. 2013;17(9):e757-61. DOI:10.1016/j.ijid.2013.03.002 In a previous study conducted in a Brazilian hospital, seasonality was identified in the incidence of bloodstream infections caused by overall GNB and specific pathogens such as Acinetobacter baumannii.¹¹11. Fortaleza CM, Caldeira SM, Moreira RG, Akazawa RT, Corrente JE, Souza LR, et al. Tropical healthcare epidemiology: weather determinants of the etiology of bloodstream infections in a Brazilian hospital. Infect Control Hosp Epidemiol. 2014;35(1):85-8. DOI:10.1086/674392

In all the above mentioned studies, an ecological approach was applied and aggregate data were analyzed. Therefore, it remains to be identified how and to what extent does the weather influence the likelihood of acquiring HAI on an individual basis.

This study was aimed at evaluating if temperature and humidity influence the etiology of bloodstream infections (BSI) in a hospital from 2005 to 2010.

METHODS

This study was conducted at the Hospital das Clínicas of Faculdade de Medicina de Botucatu (HCFMB). The hospital is located in a semi-urban area in the city of Botucatu, Sao Paulo State, Brazil (22°53′09″S, 48°26′42″W). The hospital has 450 beds, 90.0% of which are distributed among non-climatized units. There are several balconies, large windows, and wide corridors with openings to the external environment. HCFMB is a teaching hospital for medical and nursing graduate students as well as for interns, residents, and postgraduates. It is also a facility for tertiary care for several municipalities in the surrounding area, which comprises a million inhabitants.

The hospital has its own microbiology laboratory and an infection control committee, constituted in accordance with Brazilian sanitary regulations.

The study had a case-referent design, and its sample group consisted of subjects who had a laboratory-confirmed, healthcare-associated BSI (HA-BSI) from 2005 to 2010. For typical bacterial pathogens (e.g., Staphylococcus aureus, Enterococci, Klebsiella spp., A. baumannii) or fungi, a single positive blood culture defined BSI. For coagulase-negative Staphylococci (CoNS), positivity in two blood cultures from the same day was required.¹³13. Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control. 2008;36(5):309-32. DOI:10.1016/j.ajic.2008.03.002 As recommended by the Society for Healthcare Epidemiology of America,³3. Cohen AL, Calfee D, Fridkin SK, Huang SS, Jernigan JA, Lautenbach E, et al. Society for Healthcare Epidemiology of America and the Healthcare Infection Control Practices Advisory Committee. Recommendations for metrics for multidrug-resistant organisms in healthcare settings: SHEA/HICPAC Position paper. Infect Control Hosp Epidemiol. 2008;29(10):901-3. DOI:10.1086/591741 in association with healthcare, the three-midnight rule was applied, i.e., only BSI diagnosed based on culture collection after the third day of admission were defined as HA-BSI.

All cultures were collected based on the attending physicians’ request. Although there was no strict decision-making protocol for requesting microbiological tests, doctors were encouraged to collect blood cultures from patients with suspected HAI. This was in accordance with the United States Centers for Diseases Control and Prevention (CDC) diagnostic guidelines in effect during the study period, including their most recent version.¹³13. Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control. 2008;36(5):309-32. DOI:10.1016/j.ajic.2008.03.002 For the purposes of the present study, primary or catheter-related BSI were not differentiated from those secondary to other sites of infection.

Data from positive cultures were obtained in files from the microbiology laboratory in HCFMB. A database for HA-BSI was created based on the definitions described above. Duplications, defined as positive cultures for the same pathogen in the same subject within a 30-day period, were excluded. All other patient data such as sex, age, hospital unit, and length of stay were recovered from administrative files. Data on temperature and humidity for the city of Botucatu were obtained in the Department of Soil Science and Natural Resources from the Faculdade de Agronomia de Botucatu.

Average temperature and humidity data from the seven days preceding the collection of cultures (comprising the day of collection and the six previous days) were calculated for each case subject. An overall reference was obtained from the moving average of the seventh order of daily weather parameters (i.e., the average for every seven-day period) for the whole study period. In the first phase of this study, the parameters for subjects groups were compared based on etiology [fungi, bacteria, Gram-positive cocci (GPC), GNB, or A. baumannii] with the period reference, using the Student’s t-test. The second study phase consisted of the fitting of logistic regression models, including HA-BSI subjects. The outcomes of interest were etiological agents: bacteria (versus fungi), GNB (versus GPC), and A. baumannii (versus other GNB). The immediate seven-day weather parameters were analyzed in an initial non-adjusted (univariate) step, in multivariable models adjusting temperature and humidity for each other, as well as for subject demographics (age, sex, etc.) and admission data (unit of admission and length of stay previous to BSI diagnosis). All tests, models and graphics were performed or built with SPSS 19.0 (IBM, Armonk, NY, USA). The level of significance was p < 0.05.

The study was approved by the Committee for Ethics in Human Research of Faculdade de Medicina de Botucatu, Brazil, Process 15949613.6.0000.5411, approved in 5/7/2013.

RESULTS

A total of 1,619 HA-BSI were included in the study. Of these, 1,417 had bacterial etiology (55.8% GNB, 44.2% GPC). Among GNB infections, 22.4% were caused by A. baumannii. When all groups were compared to the overall period reference (Table 1, Figures 1 and 2), higher temperature parameters were found for bacteria GNB and A. baumannii, whereas fungi were associated with lower temperatures. Humidity parameters were higher than the reference for bacteria and GPC and lower for fungi and A. baumannii. On the other hand, lower temperatures were identified in the days preceding HA-BSI of fungal etiology.

Table 2 presents the results from logistic regression models aimed at identifying weather predictors of HA-BSI etiology. Temperature was positively associated with bacterial etiology as well as with infections caused by GNB as a whole or A. baumannii. The recovery of overall bacteria was likely to occur in periods of greater relative humidity. However, humidity was negatively associated with GNB and A. baumannii. These results were unaffected by the adjustment for subject demographics and admission parameters.

DISCUSSION

There is now compelling evidence that the incidence of HAI caused by GNB is increased during warm seasons. However, although results from ecological studies have a value of their own, they should be complemented by an analysis conducted on an individual basis. This is an important strategy to address the “ecological fallacy”, i.e., the possibility that findings that are valid for aggregated data do not reflect relations on the individual level.⁸8. Dufault B, Klar N. The quality of modern cross-sectional ecologic studies: a bibliometric review. Am J Epidemiol. 2011;174(10):1101-7. DOI:10.1093/aje/kwr241 In epidemiological studies, the assessment of ecological fallacy is of practical importance for the recommendation of interventions targeting both the collectivity and individuals. This study focused on individual outcomes as a means of reducing bias that could arise from ecological fallacy.¹¹11. Fortaleza CM, Caldeira SM, Moreira RG, Akazawa RT, Corrente JE, Souza LR, et al. Tropical healthcare epidemiology: weather determinants of the etiology of bloodstream infections in a Brazilian hospital. Infect Control Hosp Epidemiol. 2014;35(1):85-8. DOI:10.1086/674392

Our findings generally corresponded with those from previous ecological studies; higher immediate temperature values were associated with gram-negative etiology. Even higher temperatures were found in the days preceding HA-BSI caused by A. baumannii. These findings echo results from the ecological analysis performed previously. In that analysis, increases of 4.0% and 13.0% were identified in monthly incidences of GNB and A. baumannii HA-BSI for each additional centigrade degree of average temperature.¹¹11. Fortaleza CM, Caldeira SM, Moreira RG, Akazawa RT, Corrente JE, Souza LR, et al. Tropical healthcare epidemiology: weather determinants of the etiology of bloodstream infections in a Brazilian hospital. Infect Control Hosp Epidemiol. 2014;35(1):85-8. DOI:10.1086/674392 Data concerning A. baumannii is of utmost interest. Those agents are particularly common in regions with a tropical climate.²2. Chim H, Tan BH, Song C. Five-year review of infections in a burn intensive care unit: High incidence of Acinetobacter baumannii in a tropical climate. Burns. 2007;33(8):1008-14. DOI:10.1016/j.burns.2007.03.003 ^{, 7}7. Doughari HJ1, Ndakidemi PA, Human IS, Benade S. The ecology, biology and pathogenesis of Acinetobacter spp: an overview. Microbes Environ. 2011;26(2):101-12. DOI:10.1264/jsme2.ME10179 They are widely disseminated among hospitals in Brazil, and recent reports describe an increase in both overall prevalence and resistance to antimicrobials.¹⁸18. Padoveze MC, Assis DB, Freire MP, Madalosso G, Ferreira SA, Valente MG, et al. Surveillance Programme for Healthcare Associated Infections in the State of São Paulo, Brazil. Implementation and the first three years’ results. J Hosp Infect. 2010;76(4):311-5. DOI:10.1016/j.jhin.2010.07.005 ^{, 23}23. Rossi F. The challenges of antimicrobial resistance in Brazil. Clin Infect Dis. 2011;52(9):1138-43. DOI:10.1093/cid/cir120 In addition, they are the nosocomial pathogen for which most evidence of seasonality has been accumulated.⁴4. Christie C, Mazon D, Hierholzer Jr W, Patterson JE. Molecular heterogeneity of Acinetobacter baumanii isolates during seasonal increase in prevalence. Infect Control Hosp Epidemiol. 1995;16(10):590-4. DOI:10.2307/30141099 ^{, 17}17. McDonald LC, Banerjee SN, Jarvis WR. Seasonal variation of Acinetobacter infections: 1987-1996. Nosocomial Infections Surveillance System. Clin Infect Dis. 1999;29(5):1133-7. DOI:10.1086/313441 ^{, 24}24. Schwab F, Gastmeier P, Meyer E. The warmer the weather, the more gram-negative bacteria - impact of temperature on clinical isolates in intensive care units. Plos One. 2014;9(3):e91105. DOI:10.1371/journal.pone.0091105 Hence, A. baumannii was highlighted, and a separate analysis of weather determinants was included for HA-BSI caused by this agent. The results, together with those from previous studies, strongly suggest that infection control policies aimed at controlling the dissemination of A. baumannii within hospitals should give special attention to the increase in its prevalence during warm months.

Although the recognition of seasonality in human diseases dates back to Hippocrates, the mechanisms underlying this epidemiological behavior are not completely understood. Small changes in seasonal behavior of either the pathogen or its host may give rise to significant fluctuations in the incidence of infectious diseases.¹⁰10. Fisman DN. Seasonality of infectious diseases. Annu Rev Public Health. 2007;28:127-43. DOI:10.1146/annurev.publhealth.28.021406.144128 It can be presumed that a similar phenomenon accounts for seasonality of healthcare-associated GNB infections.

Previous studies raised interesting explanatory hypotheses. First, the ability of GNB to invade human tissues may increase in response to temperature because of the expression of virulence factors.⁹9. Eber MR, Shardell M, Schweizer ML, Laxminarayan R, Perencevich EN. Seasonal and temperature-associated increases in gram-negative bacterial bloodstream infections among hospitalized patients. PLoS One. 2011;6(9):e25298. DOI:10.1371/journal.pone.0025298 Second, the increase in bacterial growth in inanimate reservoirs. These findings correspond with the recent recognition of the importance of environmental contamination in the epidemiology of HAI.²⁵25. Weber DJ, Anderson D, Rutala WA. The role of the surface environment in healthcare-associated infections. Curr Opin Infect Dis. 2013;26(4):338-44. DOI:10.1097/QCO.0b013e3283630f04 They are also consistent with the impact of weather in hospitals from tropical countries, including our study hospital. These hospitals generally lack artificial climatization and have several openings to the external environment. However, the findings fail to explain why seasonality of GNB has been reported even in climatized units.²²22. Richet H. Seasonality in gram-negative and healthcare-associated infections. Clin Microbiol Infect. 2012;18(10):934-40. DOI:10.1111/j.1469-0691.2012.03954.x

In our study hospitals, the 24 wards varied widely with respect to location, contact with the external environment, and climatization (which exists only in intensive care units). However, the association of temperature and humidity with the etiology of HA-BSI was not affected when data on the admission ward was included in the multivariable model. Although a more refined subgroup analysis and longer time span of data collection are necessary to clarify this issue, it seems that GNB prevalence increased throughout the hospital in warm periods.

Studies have suggested that environmental reservoirs outside the hospital increase during summer months. According to this hypothesis, healthcare workers are responsible for the introduction of seasonal GNB into the wards.²²22. Richet H. Seasonality in gram-negative and healthcare-associated infections. Clin Microbiol Infect. 2012;18(10):934-40. DOI:10.1111/j.1469-0691.2012.03954.x Some authors reported that A. baumannii recovered from clinical cultures during warm months are likely to be multidrug susceptible and/or present a polyclonal profile on strain typing methods.⁴4. Christie C, Mazon D, Hierholzer Jr W, Patterson JE. Molecular heterogeneity of Acinetobacter baumanii isolates during seasonal increase in prevalence. Infect Control Hosp Epidemiol. 1995;16(10):590-4. DOI:10.2307/30141099 ^{, 12}12. Fukuta Y, Clarke LG, Shields RK, Wagener MM, Pasculle AW, Doi Y. Lack of seasonality in the occurrence of multidrug-resistant Acinectobacter baumannii complex. Infect Control Hosp Epidemiol. 2012;33(10):1051-2. DOI:10.1086/667741 While these findings strengthen the hypothesis of a community-associated origin, other studies found a significant increase in infections caused by multidrug-resistant isolates of both A. baumannii and Pseudomonas a erugino sa during periods of higher temperature.⁹9. Eber MR, Shardell M, Schweizer ML, Laxminarayan R, Perencevich EN. Seasonal and temperature-associated increases in gram-negative bacterial bloodstream infections among hospitalized patients. PLoS One. 2011;6(9):e25298. DOI:10.1371/journal.pone.0025298 Because multidrug-resistance is a proxy of nosocomial origin, those results point to an increased spread of GNB within hospital units.

A particularly puzzling finding from the present study was the negative association between humidity and GNB or A. baumannii etiology. The association was not found in the previous ecological study conducted in the same hospital.¹¹11. Fortaleza CM, Caldeira SM, Moreira RG, Akazawa RT, Corrente JE, Souza LR, et al. Tropical healthcare epidemiology: weather determinants of the etiology of bloodstream infections in a Brazilian hospital. Infect Control Hosp Epidemiol. 2014;35(1):85-8. DOI:10.1086/674392 This aspect of the result emphasizes the differences in the analysis of aggregate and individual data. They may also be due to the paradoxical relation of temperature and humidity during very short time spans.¹⁵15. Kimball JS, Running SW, Nemani R. An improved method for estimating surface humidity from daily minimum temperature. Agric Forest Meteorol. 1997;85(1):87-98. DOI:10.1016/S0168-1923(96)02366-0 Interestingly, the results did not change when the analysis was repeated using only temperature and humidity values from the day of collection of cultures instead of the seven-day average (data not shown).

Finally, another hypothesis that has been raised to explain the summer peaks in GNB infections within hospitals is related to understaffing. Summer vacations can decrease the nurse/patient ratio, thus increasing workload and failure to comply with infection control rules.²²22. Richet H. Seasonality in gram-negative and healthcare-associated infections. Clin Microbiol Infect. 2012;18(10):934-40. DOI:10.1111/j.1469-0691.2012.03954.x Although understaffing has been consistently associated with an increased risk of HAI,⁶6. Daud-Gallotti RM, Costa SF, Guimarães T, Padilha KG, Inoue EN, Vasconcelos TN, et al. Nursing workload as a risk factor for healthcare associated infections in ICU: a prospective study. PLoS One. 2012;7(12):e52342. DOI:10.1371/journal.pone.0052342 no studies have focused on the association between understaffing and seasonal increases of GNB infections in hospitals. Furthermore, in HCFMB, as in many healthcare services in developing countries, understaffing is a phenomenon that persists throughout the entire year.

This study has some limitations. First, it has a retrospective design, and we analyzed data from administrative and microbiology files. Thus, many risk factors for HAI, such as invasive procedures (including central venous catheter) and severity of illness, were not addressed. Second, possible seasonal changes in patient profiles (e.g., demographics, admission diagnosis) or physician behavior were not addressed. Therefore, the selection bias in the study cannot be completely ruled.

However, these analyses were beyond the scope of our objectives, which focused specifically on the impact of environmental factors, including spatial distribution, time of exposure to the hospital environment, and weather data. We did not analyze clonality or antimicrobial resistance among HA-BSI agents. Finally, it was not possible to completely rule out ecological fallacy because the data regarding exposure to weather conditions was measured for the whole city and does not represent the temperature and humidity in each patient room. However, the analysis of individual outcomes increases the consistency of previous purely ecological analyses.¹¹11. Fortaleza CM, Caldeira SM, Moreira RG, Akazawa RT, Corrente JE, Souza LR, et al. Tropical healthcare epidemiology: weather determinants of the etiology of bloodstream infections in a Brazilian hospital. Infect Control Hosp Epidemiol. 2014;35(1):85-8. DOI:10.1086/674392 This study also has strengths, including the number of HA-BSI subjects and the stability of risk factors in all steps of the multivariable analysis.

The results raise new questions regarding GNB seasonality in tropical healthcare settings: what is the relation between seasonality and resistance to antimicrobials? Do specific risk factors (severity of illness, procedures, antimicrobial use, etc.) vary among patients who acquired HAI in different seasons? Is seasonality equal among hospitals located in different regions? We intend to address these questions in future studies.

In conclusion, we found that high temperatures in the seven days preceding the collection of blood cultures were associated with the recovery of bacteria rather than fungi and GNB rather than GPC. Among gram-negatives, higher immediate temperature values were associated with HA-BSI caused by A. baumannii. These findings not only reflect a change in the relative incidence among different pathogens but also result (as shown in previous analyses¹¹11. Fortaleza CM, Caldeira SM, Moreira RG, Akazawa RT, Corrente JE, Souza LR, et al. Tropical healthcare epidemiology: weather determinants of the etiology of bloodstream infections in a Brazilian hospital. Infect Control Hosp Epidemiol. 2014;35(1):85-8. DOI:10.1086/674392) from an absolute increase in the incidence of GNB and A. baumannii during warm seasons, which contrasted with the stability in the occurrence of other pathogens. Together, these findings suggest that infection control policies should be reinforced during periods of high temperature. In addition, guidelines for empirical antimicrobial therapy should consider the higher risk for GNB infections during those periods. Moreover, these findings pose new questions for research to contribute to the elucidation of the complex association between climate, weather and HAI.

REFERENCES

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