Home care versus hospital care of patients with hematological malignancies and chemotherapy-induced cytopenia

F. H. van Tiel1,*, M. M. Harbers1, A. G. Kessels2 and H. C. Schouten3

1 Department of Medical Microbiology, 2 Department of Clinical Epidemiology and Medical Technology Assessment, 3 Department of Internal Medicine, Division of Hematology/Oncology, University Hospital Maastricht, The Netherlands

* Correspondence to: Dr F. H. van Tiel, Department of Medical Microbiology, University Hospital of Maastricht, P. Debyelaan 25, 6202 AZ Maastricht, The Netherlands. Tel: +31-43-3874643; Fax: +31-43-3876643; Email: fvt{at}lmib.azm.nl


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background: The purpose of this review study is to examine the accumulating evidence of safety of home care, with regard to infection-related morbidity and mortality, for patients with chemotherapy-induced cytopenia, in light of previous studies on the necessity of protective isolation (PI).

Patients and methods: The existing literature on PI, and home care of cytopenic patients after chemotherapy, published in the English language, based on a Medline search, is reviewed.

Results: The studies published so far on home care versus hospital care are all non-randomized studies and confirm that home care of cytopenic patients is safe, in terms of morbidity and mortality due to infections. On the other hand, the majority of studies on the comparison of PI with standard hospital care conclude that an infection-preventive effect of PI exists. The pooled statistics performed confirmed that such an effect of PI exists regarding the occurrence of severe infections, although no benefit to mortality has been shown.

Conclusions: Regarding home care, only the results of a prospective, randomized study of sufficient power will enable definitive conclusions to be drawn as to whether home care is equally safe as hospital-based care with PI.

Key words: chemotherapy, cytopenia, home care, infection prevention, protective isolation


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Infection is a frequently occurring and serious complication in patients with hematological malignancies, due to periods of cytopenia following chemotherapy. Protective isolation (PI) of the patient from the hospital environment, and measures to eliminate potentially pathogenic microorganisms from the gastrointestinal tract have been common practice for the care of granulocytopenic patients for decades [1Go–6Go]. These measures appeared reasonable since studies have suggested that infectious episodes caused by facultative aerobic Gram-negative rods and yeasts in granulocytopenic patients, derived either from the gastrointestinal tract of the patient [7Go], or from the environment of the hospital, could be prevented by the use of PI [8Go]. In addition, based on present knowledge on the routes of transmission of Aspergillus fumigatus, infections due to this fungus and other non-yeast-like fungi are preventable by the use of protective environment (PE), such as HEPA-filtered environment, besides the use of antifungal prophylaxis.

Because of infection-related morbidity, mortality and costs, preventive measures are generally accepted to be a standard of care, and differ between medical centers. Usually, a combination of preventive measures is taken, since it is assumed that each measure contributes to the overall protective effect. Whether this assumption is true or not is a matter of debate; the fact is that since the introduction of these measures more intensive chemotherapy has been applied, without an increase in the infection rate [1Go].

Although protective (reverse) isolation, to prevent infections, has long been the accepted standard of care for nursing patients with cytopenia after intensive chemotherapy, there has been a recent drive for home-based treatment of these patients. This idea is inspired by the desire to improve the quality of life, but also, possibly more so, by the necessity of cost saving. Over the past years several reports on the treatment of patients after hematopoietic stem cell transplantation (HSCT) have cast doubt on the presumed necessity of PI during leukopenia, in highly susceptible patient categories [9Go–14Go].

It therefore appears appropriate to critically review the existing literature on home care and compare with that on PI in the hospital care of these patients. This study will focus on (i) the evidence for the safety of home care, compared to hospital care and (ii) the evidence for infection-preventive effectiveness of PI of patients treated in hospital, with, in both cases, colonization and infectious episodes by Gram-negative rods and/or fungi, and mortality as outcome parameters.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Literature search and inclusion
The literature published since 1965, in the English language, on home care of cytopenic patients after chemotherapy, and on protective isolation, based on a Medline search, was reviewed. For this search ‘isolation’, ‘isolator’, ‘laminar airflow’, ‘air filtration’, ‘protected unit’, ‘protected environment’, ‘protective isolation’, ‘infection prevention’, ‘infection control’, ‘home management’, ‘home care’, ‘cancer’, ‘marrow transplant’, ‘leukemia’, ‘leukaemia’, ‘hematological’, ‘granulocytopen’ were used as key words. Only comparative studies were included for the analysis of studies on protective isolation of patients treated in hospital, whereas for the analysis of studies on home care all studies were included, because of the lack of comparative studies.

The main outcome parameters for this review were colonization with Gram-negative rods and/or fungi, infectious morbidity and mortality.

Statistical analysis
For the statistical analysis of pooled data on morbidity only the randomized studies on PI, which presented their data at a patient level, were included. For each of the outcome parameters in this analysis (Aspergillus infections, major, local fungal infections/candidemia, severe infections/major, local infections and bacteremia/septicemia) the odds ratios (ORs) of the two interventions, i.e. PI and antibiotic prophylaxis (AP), were pooled separately by calculating the weighted average, with weights that are inversely proportional to the variances [15Go], and tested for heterogeneity. We called this analysis ‘separate model’, for which in one study a full factorial design was used [16Go]. To pool the OR of one intervention, the two strata, as created by the other intervention, were treated as two different studies. With the separate model it is not possible to use the information from studies in which the study arm and control arm contrast in isolation as well as antibiotic prophylaxis. Therefore, in an additional analysis, ORs were determined using a logistic regression analysis with PI, AP and the categorical variable study center as independent variables. In this combined analysis, which we called ‘combined model’, the ORs of both interventions could be determined simultaneously. To summarize the morbidity end points the (log) hazard ratios were pooled [17Go].

Definitions
In the four controlled studies on home care, patients were eligible for the home care cohort after stem-cell reinfusion, provided there were no contra-indications [10Go, 11Go, 13Go, 14Go]. ‘Home care’ implied discharge to the private home or, as mentioned in the study by Westermann et al., to the private home or to a residential facility, near the hospital, without medical services [10Go]. District nurses visited the patients daily. The outpatient cohort was defined as patients discharged to the private home or to a residential facility near the hospital. These patients were seen and treated daily, in the hospital, by transplant physicians and nurses [10Go].

Of the studies on home care (Table 3) only one study by Russell et al. defines an infection, based on one or more of the following criteria: fever, a clinical or radiologic focus, or positive cultures [12Go]. The remaining studies presented their data without defining infection-related morbidity [9Go–11Go, 13Go, 14Go]. For the end point mortality (Table 3) the follow-up varied from 6 months after entry of the last patient [9Go], the aplastic period, defined as the period starting on the day of stem-cell reinfusion and ending with the day of neutrophil recovery to 0.5 x 109/l [10Go], not defined and unknown [11Go], not defined, but measured as observation time [13Go, 14Go], to 100 days [12Go],


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Table 3. Morbidity and mortality/survival: the comparison of patients in home care versus hospital-based care

 
Regarding the studies on protective isolation (Table 4) an episode of septicemia was defined as a single positive blood culture associated with signs and symptoms of infection (documented local site of infection or fever) or at least two consecutive positive blood cultures with the same organism [16Go, 18Go], or as the finding of one or more blood cultures that were positive for an organism considered to represent a pathogen [19Go]. Severe infections were defined as septicemia or organ invasion, such as pneumonia, or cellulitis or mucositis associated with extensive tissue necrosis and deep cutaneous abscesses [20Go], or as infections involving significant tissue invasion, such as sepsis, pneumonitis, pyelonephritis, peritonitis, meningitis and extensive abscesses [21Go], or as definite symptoms and signs of infection in association with microbiological documentation of the causative agent, together with organ invasion (usually pneumonia) or septicemia or both [22Go], or as infectious episodes involving bacteremia and organ invasion (lower respiratory infection, urinary tract infection, abscesses, miscellaneous infections such as peritonitis, meningitis, otitis, sinusitis), identified by definite clinical signs and symptoms of infection, by radiologic findings, and/or by positive microbiological culture [23Go]. Major local infections, which were potentially life-threatening and always required systemic therapy as well as appropriate local treatment [18Go], were urinary tract infections, mucosal infections and septicemia [24Go], or included both fungal and bacterial infections with documentation of the microbiological cause and the need for systemic antimicrobial therapy and/or surgical intervention [16Go]. Finally, pneumonia was considered to consist of either a new pulmonary radiodensity arising within 1 week of an otherwise unexplained rise in temperature, or of infection proved histologically [20Go].


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Table 4. Morbidity and mortality/survival due to infections: randomized studies on protective isolation versus standard ward care of patients with cytopenia after chemotherapy

 
For the end point mortality in the studies on protective isolation (Table 4) the follow-up was defined differently between studies as: 100-day survival [20Go, 21Go], 30-day survival [23Go], median survival [22Go, 24Go, 25Go], survival on discharge [19Go] or as mortality until the day of departure from hospital or the day of engraftment, whichever occurred first [16Go]. In one study, mortality was defined for both the study and the control group as death during the first 50 days, or longer when persistent granulocytopenia, until the granulocyte level of >500/mm3 occurred, and additionally for the study group as death during the first 50 days, or longer when active graft-versus-host disease or other illness that precluded discharge from hospital occurred [18Go].


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Home care
All six published studies on the feasibility of the management of patients at home, after intensive chemotherapy and SCT have been included [9Go–14Go] (Table 1). The total number of included patients was 585, the median number was 90 patients/study, with a range of 22 to 288 (Table 1). Details of the preventive measures are shown in Table 2. Four of these studies were comparative, non-randomized cohort studies [10Go, 11Go, 13Go, 14Go]. Although these studies claim the successful treatment of SCT recipients at home, some issues need attention.


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Table 1. The studies and number of included patients

 

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Table 2. Summary of protective isolation measures, diets and prophylactic antibiotics and antimycotics

 
Study population
First of all, the study populations differed. The study by Westermann et al. included patients after high-dose chemotherapy with autologous stem-cell support for hematological and non-hematological malignancies [10Go]. Herrmann et al. studied patients receiving high-dose chemotherapy and peripheral blood stem cell rescue for lymphoma and multiple myeloma [11Go]. The studies performed by Svahn et al. observed patients after high-dose chemotherapy and allogeneic stem-cell transplantation for hematological malignancies [13Go, 14Go].

Study design
Second, the study designs differed. In the study of Westermann et al. on 42 patients, allocation and inclusion to the three study groups was performed consecutively: first the inpatient cohort, then the outpatient cohort, and finally the home-care cohort. Herrmann et al. [11Go] performed a study of 51 patients receiving clinical care in the peri-transplant period at home in comparison to 88 patients with the same diagnoses, cared for as inpatients in a HEPA-filtered bone marrow transplant unit. Allocation to treatment group was ‘based on choice, geographic accessibility, availability of educated care given at home and a clean home environment, and comprehension of the concepts of infection and aseptic techniques.’ The studies by Svahn et al. [13Go, 14Go] describe patients treated at home and treated in conventional single rooms with protective isolation.

Colonization data
Only the study by Westermann et al. presents colonization data [10Go]. In all patients receiving antibiotic prophylaxis (AP), Gram-negative rods were suppressed. However, itraconazole-resistant Candida glabrata and Candida species were isolated from surveillance cultures of stool and throat washings in 50 of 81 courses.

Morbidity data
With regard to morbidity, the data are presented in various ways, precluding a comparison between the studies (Table 3). Westermann et al. [10Go] present the median number of days with fever >38°C: 3.5 days for home-care patients, 5 days for outpatients and 4 days for the inpatient cohort. The study by Herrmann et al. [11Go] presents the percentages of patients with fever >38.5°C, and the mean number of days with fever >38.5°C: a comparable proportion of patients in the home care and hospital cohorts remain free of fever (20/51, 39% versus 37/88, 42%, respectively). Finally, the studies by Svahn et al. [13Go, 14Go] show data only on the occurrence of bacteremia, suggesting a lower rate of bacteremia for patients treated at home. This difference was deemed statistically not significant in the larger, and more recent, study [14Go].

Mortality data
Mortality/survival data for all studies are presented in Table 3 [9Go–14Go]. In the study by Herrmann et al. no deaths were reported among the control patients, but mortality reached 2/52 for the home care cohort.

Protective isolation
Thirteen studies on PI were found, nine of which were randomized [16Go, 18Go–25Go]. The total number of included patients was 6438, the number of patients per study ranging from 37 to 5065, with a median of 100. The measures taken in PI, including AP and diet, are summarized in Table 2. Initially, plastic-tent isolators with HEPA-filtered air [1Go, 20Go, 21Go, 23Go, 25Go–27Go], and laminar airflow rooms with HEPA filtration of air [16Go, 18Go, 20Go–23Go, 25Go, 28Go, 29Go] were employed. In later years standard single rooms with HEPA or without HEPA [19Go], and laminar airflow rooms without HEPA filtration [30Go] were described as protective environments.

Study design
Nine prospective, randomized studies on PI have been published, of which only four allow the comparison of PI and standard ward care, both without additional preventive measures such as AP [16Go, 19Go, 21Go, 23Go] (Table 1). Of the five remaining randomized studies, three compare patients in PI and on AP with patients on AP only [20Go, 22Go, 25Go], whereas the other studies compare patients in PI and on AP, with patients in standard ward conditions without AP [18Go, 24Go].

Colonization data
Data on colonization with facultative aerobic Gram-negative rods and yeasts were presented in six studies [18Go, 19Go, 23Go, 24Go, 27Go, 28Go], four of which were randomized studies [18Go, 19Go, 23Go, 24Go]. Limited to patients without AP, the comparison from patients with and without PI can be derived from the data of only two studies [19Go, 23Go]. The study of the EORTC working group [23Go] indeed measured an enhanced rate of acquisition and colonization of hospital-acquired strains of Gram-negative rods for patients nursed in standard ward care, compared with those in PI.

The mean colonization rate per patient per week was 0.1, 0.41 and 0.6 for patients in PI and on AP, for patients in PI without AP, and for patients in standard ward care, without protective measures, respectively. Buckner et al. [18Go] report that 12 of 46 patients retained their antibiotics throughout their stay in PI, and that in one of these 12 patients the suppression of all fecal flora was partial, and that in two patients the suppression was absent. In a third randomized study [19Go] cultures were positive for Staphylococcus aureus and/or Pseudomonas aeruginosa in 3.4% of the isolated patients and in 4.4% of patients given standard care.

Morbidity data
Two out of the four randomized studies comparing PI with standard ward care, without AP, demonstrate a preventive effect of PI regarding infection-related morbidity [16Go, 21Go] (Table 4), the two other studies fail to show such an effect [19Go, 23Go]. All remaining randomized studies claim an effect of the preventive measures [18Go, 20Go, 22Go, 24Go, 25Go] (Table 4). In summary, seven out of nine randomized studies conclude that PI has a infection preventive effect [16Go, 18Go, 20Go–22Go, 24Go, 25Go].

As described in Methods, Aspergillus infections, major, local fungal infections/candidemia, severe infections/major, local infections and bacteremia/septicemia were distinguished as separate end points for further analysis. Only one study [19Go] presented the data specifically for Aspergillus. Since no infections occurred in the study arm with PI, the effect was tested with a Fisher exact test (P=0.5). For the remaining end points the pooled ORs, calculated by weighting with the inverse variance (separate model) and by the logistic regression model (combined model) are shown in Table 5. All tests for heterogeneity of the ORs were negative (all P-values indicated non-significance).


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Table 5. Odds ratios of protective isolation and antibiotic prophylaxi for different outcome parameters, pooled with the inverse variances (‘separate model’ including 2–4 studies) and logistic regression model (‘combined model’ including 5–6 studies)

 
Regarding PI as an intervention, statistically significant differences were found for severe/major, local infections and, to a lesser degree, for bacteremia/septicemia as an outcome parameter, but not for fungal infections. With regard to AP as intervention, a significant difference was shown only for bacteremia/septicemia.

Mortality data
The described effects on infectious morbidity did not translate to a difference in mortality. Table 4 demonstrates mortality or survival data for the randomized studies comparing patients in PI versus patients with standard ward care. The heterogeneity in description of the mortality/survival data hindered the extraction of summary statistics to be used for the pooling method, as proposed in the Methods section. Therefore, we only present a descriptive analysis here.

Eleven out of 13 comparative studies on PI included survival/mortality data [16Go, 18Go–20Go, 22Go–26Go, 30Go]. In these studies mortality was presented in different ways, such as 100-day survival, median survival in weeks, 30-day survival, survival on discharge and survival rate. Survival data of the four studies comparing patients in PI with control patients without additional protective measures [16Go, 19Go, 21Go, 23Go] showed that the survival of patients in PI did not differ significantly from that of control patients (Table 4). Two studies conclude that the fatality rate from severe infection [25Go] or deaths from infection [24Go] was statistically reduced among the patients treated in PI.

Sequence of publication
The time sequence of the published reports is depicted in Table 6, according to whether or not home care is equally safe as hospital care or, in the less recent studies, whether a protective effect had been claimed for PI of patients treated in hospital, in comparison with standard ward care.


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Table 6. Sequence of publication of comparative studies

 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
An important factor to encourage home care has been the desire to achieve a higher quality of life during the cytopenic period after intensive chemotherapy. In addition, ever since the necessity of reducing health care costs has been felt, the exploration of the possibilities of treating cytopenic patients at home and the cost-effectiveness of this strategy have been of interest. To the best of our knowledge, an exhaustive critical review on neither of these subjects has been published.

With respect to the safety of home care of cytopenic patients after chemotherapy, four non-randomized, cohort studies describe successful treatment of HSCT recipients at home, but differ in several respects, including study population, and design of the study [10Go, 11Go, 13Go, 14Go]. These studies confirm that home care of cytopenic patients is safe, with similar morbidity and mortality in comparison with hospital care. However, these studies are non-randomized and therefore prone to selection bias, and they are too small to allow statistically valid conclusions to be drawn with regard to infectious morbidity. Moreover, these four studies also lack the necessary power, due to the low numbers of patients included, and three of the studies did not present colonization data [11Go, 13Go, 14Go].

The recently published guidelines for preventing opportunistic infections among HSCT recipients state that all allogeneic recipients should be placed in rooms with >12 air exchanges/hour and HEPA filters, but also admit that isolation and barrier precautions in HSCT recipients have not been evaluated [31Go]. In contrast, one report indicates that allogeneic stem-cell recipients can be treated in hospital without the use of protective isolation [10Go].

Colonization data would have provided us with valuable information as to whether or not AP is capable of suppressing the pre-existing aerobic Gram-negative flora, as well as preventing acquisition of strains from the environment, e.g. the diet. For future studies we advocate the evaluation of colonization by aerobic Gram-negative rods, yeasts and non-yeast-like fungi, as an additional end point.

Regarding studies on PI of patients treated in hospital, seven out of nine randomized studies concluded that PI has an infection-preventive effect [16Go, 18Go, 20Go–22Go, 24Go, 25Go]. The pooled statistics performed for this review reveal an effect of PI regarding the occurrence of infections, although no benefit related to mortality was shown.

With respect to mortality, again the differences between the studies in presenting the data are formidable. This fact alone precludes a fair comparison, even when other factors are taken into consideration, such as type of PI, underlying malignant disease, type of chemotherapy, type of HSCT and the use of growth factors. Nevertheless, a clear statistically significant survival benefit has not been demonstrated by the reviewed studies.

Summarizing, the safety of home care, claimed by four recently published comparative studies, appears to contradict the conclusions of earlier studies on PI of cytopenic patients treated in hospital, the majority of which have shown an infection-preventive effect of PI. Therefore, we conclude that only the results of a prospective, randomized study of sufficient power will enable definitive conclusions to be drawn as to whether home care is equally safe as hospital-based care, with PI.

Received for publication January 20, 2004. Revision received September 8, 2004. Accepted for publication September 10, 2004.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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