A Retrospective Analysis of Prognostic Factors of Nursing and Healthcare-Associated Pneumonia

Objective: Nursing and healthcare-associated pneumonia (NHCAP) is similar to healthcare-associated pneumonia (HCAP) a category of pneumonia proposed by the Japanese Respiratory Society (JRS). This study aims to determine the thus far unclear prognostic factors of NHCAP patients, and to clarify the relevance and effectiveness of the selection of antimicrobial agents in accordance with the NHCAP guidelines proposed by the JRS. Materials: A retrospective observational study of NHCAP patients hospitalized at Juntendo University Shizuoka Hospital between January, 2010 and December, 2012 was undertaken. Methods: Clinical data were obtained from clinical records, and subjects were assigned to a group which included survived patients at 30 days after admission, and a group which included patients who died within 30 days. The groups were compared regarding baseline characteristics, vital signs, laboratory data, performance status, determination of the severity of the pneumonia (such as with the A-DROP scoring system proposed by the JRS in cases of community-acquired pneumonia), microbiological examinations, and the antimicrobial agents used initially. Results: 151 NHCAP patients in total were evaluated. A score of 3 or more in the A-DROP scoring system is a factor that has an independent influence on NHCAP patientsʼ prognoses. There were no statistically significant differences in the use of broad-spectrum antimicrobials between the two groups, even those where the use of broad-spectrum antimicrobials was recommended. Conclusion: The results suggest that the severity of the pneumonia is an independent prognostic factor of NHCAP patients, for whom using broad-spectrum antimicrobials does not contribute to improving their prognoses.


Introduction
Nursing and healthcare-associated pneumonia (NHCAP) is a category of pneumonia proposed by the Japanese Respiratory Society (JRS) in 2011 1) .It is thought that NHCAP is a variant of healthcare-associated pneumonia (HCAP), proposed by the American Thoracic Society (ATS) and the Infectious Disease Society of America (IDSA) in 2005 1) , based on the Japanese healthcare and social health-insurance system 2) .NHCAP generally develops in patients with various complications or in bedridden elderly patients 2) .It has both the clinical characteristics of community-acquired pneumonia (CAP) and those of hospital-acquired pneumonia (HAP) 2) .Predicting the prognosis of NHCAP uniformly is considered difficult, because NHCAP is a clinically heterogeneous disease.Therefore, the NHCAP guidelines recommend selecting empirical antimicrobial agents in accordance with the concepts of"treatment classification" , which are based on risk factors of having drugresistant pathogens, and do not mean only the severity of the pneumonia 1) ."Treatmentclassification"of NHCAP is as follows 1) : Group A: patients who do not require hospitalization Group B: patients who require hospitalization without the risk factors of having drug-resistant pathogens Group C: patients who require hospitalization with the risk factors of having drugresistant pathogens, and Group D: patients who require intensive care.The risk factors of having drug-resistant pathogens are: using antimicrobials for 2 days or more within the previous 90 days and using tubefeeding 3) .It is recommended that patients in Groups C and D be administered antimicrobials effective against drug-resistant pathogens as empirical therapy 1) .This study is aimed to determine the prognostic factors of hospitalized NHCAP patients, and to clarify whether administration of antimicrobial in accordance with the guideline improves the prognosis.

Subjects and study design
We conducted a retrospective observational study of NHCAP patients hospitalized at Juntendo University Shizuoka Hospital (a university hospital in Nagaoka, Izunokuni City, Shizuoka, Japan) between January, 2010 and December, 2012.Data for this study were obtained from the clinical records of these patients.NHCAP was defined according to the criteria of the NHCAP guidelines proposed by the JRS as follows: 1) residence in a nursing home or an extendedcare ward 2) patients discharged from a hospital in the preceding 90 days 3) elderly or handicapped patients needing longterm care with grade 3 or 4 of performance status (PS), as defined by the Eastern Cooperative Oncology Group, and 4) patients regularly requiring hemodialysis, antimicrobial treatment,chemotherapy, or immunosuppressive therapy as outpatients 1) In the NHCAP guideline, the necessity of hospitalization is determined by attending physicians according to underlying disease, nutrition condition, physical activity and degree of home assistance 1) .Therefore, patients who were comprised in Groups B, C and D of NHCAP classification were intended for this study.
All subjects belonging to Groups B, C and D were assigned to the category which included survived patients at 30 days after admission (Category I S) and the category which included patients who died within 30 days (Category I NS) respectively.Category I S and I NS were compared with reference to baseline characteristics, vital signs, laboratory data, PS, probable aspiration, the severity of the pneumonia, microbiological examinations, performing and positive rate of blood culture, and antimicrobial agents which were used initially.Probable aspiration was determined by episodes of choking after dietary intake based on medical records.
Furthermore, subjects in Groups C and D defined by the NHCAP guidelines were assigned to the categories which included survived patients at 30 days after admission (Category II S) and the group which included patients who died within 30 days (Category II NS).Broad-spectrum antimicrobials are recommended to be administered in the NHCAP guidelines in Category II, so Category II S and II NS were compared to evaluate the effectiveness of the empirical use of antimicrobial agents considering drug-resistant pathogens.

The severity of the disease
The severity of the pneumonia was evaluated using the A-DROP scoring system for CAP proposed by the JRS.The system comprises the following parameters: (1) age (men: ≧ 70 years, women: ≧ 75 years) (2) dehydration (concentration of blood urea nitrogen (BUN) ≧ 21 mg/dl) (3) respiratory failure (oxygen saturation measured by pulse oximeter ≦ 90%) (4) disturbance of orientation (5) low blood pressure (systolic blood pressure ≦ 90 mmHg) 4) Patients were defined as serious if they scored 3 or more in the A-DROP scoring system.To evaluate the severity in the chest X-ray findings, the predictive factors for prognosis of HAP proposed by the JRS were used.We defined patients as serious if their chest X-ray films showed pneumonic shadows occupying 2/3 of all pulmonary fields or more.

Microbiological evaluation and antimicrobial agents
Samples obtained from respiratory tracts were investigated.These samples were cultured in a semiquantitative manner.In this study, Pseudomonas aeruginosa, Acinetobacter species, Enterobacteriaceae with extended-spectrum β-lactamase (ESBL), stenotrophomonas maltophilia, and methicillin-resist-ant Staphylococcus aureus (MRSA) were considered drug-resistant pathogens according to the NHCAP guidelines.Staphylococcus haemolyticus and Enterococcus faecium were classified into drug resistant pathogens because in this study those were susceptible only for anti-MRSA drugs.
Initial antimicrobial agents were evaluated in this study.Broad-spectrum antimicrobials were defined as antimicrobial agents effective against drugresistant pathogens except for MRSA, according to the NHCAP guidelines, e.g.tazobactam/piperacillin, cefepime, carbapenems and fluoroquinolones.

Statistical analysis
Data were analyzed using the SPSS software

Ethical declaration
This study has been approved by the Ethics Committee in our hospital on 10th May 2015, approval number 452.It confirms with the provisions of the Declaration of Helsinki.

Results
A total of 151 NHCAP patients were evaluated.Comparisons between Category I S and I NS are presented in Table-1.The proportion of Groups B, C D patients were not significantly different between Category I S and I NS.The proportion of patients who scored 3 or more in the A-DROP scoring system was significantly high in Category I NS.The proportion of patients was also high in Category I NS in each of the A-DROP score factors; age, dehydration, respiratory failure, disturbance of orientation, low blood pressure.The proportion of patients whose chest X-ray showed that the pneumonic shadow occupied 2/3 of all pulmonary fields or more, was significantly high in Category I NS.
The broad-spectrum antimicrobials were used  Variables significantly different in univariate analysis (p < 0.05) and known risk factors of mortality (drug resistant pathogens, use of broad spectrum antimicrobial, serum albumin) were taken forward to multivariate models.A score of 3 or more in the A-DROP scoring system was an independent factor associated with the prognosis of NHCAP patients (p = 0.002).
The comparison of Groups C and D with Group B was performed.As shown in Table -  62.7% of the patients.Tazobactem/piperacillin was the most frequently used antimicrobial, followed by sulbactam/ampicillin. Which were used more than those in Group B (52.6%, p = 0.21).Table-5 shows the detailed comparison of the survivors and non-survivors in Groups C and D (Category II S and Category II NS), for both of which broad-spectrum antimicrobials are recommended as empirical therapy in the NHCAP guidelines.There was no significant difference of empirical use of broad-spectrum antimicrobial between Category II S and II NS (Table -5).And the rate of empirical antimicrobial therapy with susceptibility for cultured pathogens were not significantly different between Category II S and II NS.The proportion of the patients with three or more A-DROP scores was also significantly high in Category II NS (p = 0.015)

Discussion
NHCAP is a category of pneumonia proposed by the JRS in 2011 1) .It is thought that NHCAP is a variant of HCAP, proposed by the ATS and the IDSA in 2005, on the basis of the Japanese system of healthcare and social health insurance 2) .According to previous reports, patients with HCAP have tendency toward having poor prognoses because they were more likely to have drug-resistant pathogens and to have been initially administered inappropriate antimicrobial than the patients with pneumonia who do not meet the criteria for HCAP 3) 5) 6) .Therefore, empirical therapy using broad-spectrum antimicrobials is recommended for all patients in the HCAP guidelines 7) , and for patients with risk factors of drug-resistant pathogens in the NHCAP guidelines 1) 2) .However, several reports state that routine use of broadspectrum antimicrobials for patients with HCAP or NHCAP may lead to excessive antibiotic treatment for many patients 8) -10) .We have empirically treated NHCAP patients without using strict criteria in the selection of antimicrobials.In this study, there was no statistically significant difference in the proportion of the patients administered with broad-spectrum antimicrobials between the category which included survived patients at 30 days after admission and the category which included patients who died within 30 days.Furthermore, there was no statistically significant difference in the proportion of the patients administered broad-spectrum antimicrobials between the category which included survived patients at 30 days after admission and the category which included patients who died within 30 days even in Groups C and D for whom the use of broad-spectrum antimicrobials was recommended in the NHCAP guidelines.These results may indicate that broad-spectrum antimicrobials are not necessarily for all NHCAP patients in Groups C and D.
Although drug resistant pathogens were cultured in 23.4% of the survived patients, most of them made improvement without empiric use of susceptible antimicrobials for cultured pathogens (Table -1).This fact is consistent with previous reports 7) 9) 10) .Several studies indicate that aspiration pneumonia is one of the major causes of NHCAP, and anaerobe is a major causal microorganism in aspiration pneumonia 9) 11) 12) .Anaerobe is not detected by usual sputum culture, so sputum culture cannot detect actual causal microorganisms of pneumonia but sometimes simply detects bacterial colonization in the airway in HCAP patients 13) .Antimicrobials against anaerobe (e. g. sulbactam/ ampicillin, tazobactam/piperacillin) were used for many patients in this study, so effectiveness of treatment of NHCAP might be dependent on coverage of aspirated anaerobes, not on the coverage of drug-resistant pathogens.Some reports also stated that the HCAP patients who were treated with broad-spectrum antimicrobials had a high risk of an adverse outcome 10) 14) .Therefore, broad-spectrum antimicrobials might not have to be routinely used for NHCAP patients.Even now, the most appropriate criteria for identifying patients who should be administered empirical broad-spectrum antimicrobials are unclear.A recent prospective multicenter study identified six risk factors for drug-resistant patho-gens in CAP and HCAP 15) , as follows: prior hospitalization, immunosuppression, previous use of antimicrobials, use of gastric acid-suppressive agents, tube feeding and no ambulatory status.Being conscious of these risk factors, restriction of the use of broad-spectrum antimicrobials may lead to appropriate treatment for NHCAP patients, resulting in preventing the increase of multidrug-resistant pathogens.Further study is necessary to identify patients who truly need empirical broad-spectrum antimicrobials.
The results show that the severity of pneumonia is an independent prognostic NHCAP factor.The results support prior reports that mortality in NHCAP patients depends on their backgrounds, such as their nutritive state or the severity of the disease itself rather than the presence of multidrug-resistant microorganisms or the administration of broad-spectrum antimicrobials 8) 10) .
Our study has several limitations.First, the data were retrospectively collected from a single institution.The population of patients and distribution of causative NHCAP pathogens are thought to be different in each region 4) 6) 7) 16) 17) , so these results may not apply to other facilities.Second, evaluation for identified microorganisms was insufficient.Because the results of gram staining were not evaluated and the cultures were semiquantitative, the identified microorganisms included colonization in the airway and were not definitive causes of pneumonia.Third, atypical pathogens such as mycoplasma pneumonia and chlamydophila pneumonia were not evaluated in this study.
In conclusion, this study demonstrates that the severity of pneumonia is an independent prognostic factor of NHCAP patients, with no statistically significant difference in the proportion of the patients treated with broad-spectrum antimicrobials between the survived patients at 30 days after admission and the dead patients within 30 days, even in the patient Groups C and D recommended for broad-spectrum antimicrobials in the NHCAP guidelines.Our results suggest that using broad-spectrum antimicrobial for NHCAP does not contribute to improving the prognosis of NHCAP patients.

Contributions
Munechika Hara and Shin-ichiro Iwakami have reviewed the clinical data and equally contributed to this manuscript.Kazuhisa Takahashi, Shinichi Sasaki and Mitsuhiro Fujii have supervised this manuscript.All authors have read and approved the final document.

Table - 1
Patient characteristics and outcomesprogram version 20.0 (SPSS Inc., Chicago, IL, USA).A p-value of < 0.05 was considered to be statistically significant.The χ-square test was used to compare categorical data.The two-sample t-test IQR: interquartile range SD: standard deviation ＊＜ 0.05

Table - 2
Microbiological resultsmore for the patients in Category I S than for those in Category I NS, although there were no statistically significant differences between the categories.The details of identified microorganisms are shown in Table-2.Staphylococcus aureus including MRSA was the most frequently identified microorganism.

Table - 3
Multiple logistic regression analysis

Table - 4
Initial antimicrobial for Groups C and D

Table - 5
Patient characteristics and outcomes in the Groups C and D