Galactomannan detection for invasive aspergillosis in immunocompromized patients

Mariska M. Leeflang; Yvette J Debets‐Ossenkopp; Caroline E Visser; Rob JPM Scholten; Lotty Hooft; Henk A Bijlmer; Johannes B Reitsma; Patrick MM Bossuyt; Christina M Vandenbroucke‐Grauls

doi:10.1002/14651858.CD007394

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Figure 1

Inclusion process

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Figure 2

Methodological quality graph: Review authors' judgments about each methodological quality item presented as percentages across all included studies.

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Figure 3

Methodological quality summary: Review authors' judgments about each methodological quality item for each included study.

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Figure 4

Forest plot of the included studies. TP = True Positive; FP = False Positive; FN = False Negative; TN = True Negative. Between brackets the 95% confidence intervals (CI) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% confidence interval (black horizontal line).

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Figure 5

Plot of sensitivity versus specificity for all 30 studies, irrespective of cut‐off value. The width of the blocks is proportional to the inverse standard error of the specificity in every study and the height of the blocks is proportional to the inverse standard error of the sensitivity.

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Figure 6

Forest plots of sensitivity and specificity. The squares represent the sensitivity and specificity of one study, the black line its confidence interval. Studies are grouped by reported cut‐off value. If a study reported accuracy data for more than one cut‐off, its results are included in more than one subgroup. TP = True Positive; FP = False Positive; FN = False Negative; TN = True Negative.

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Figure 7

Summary ROC plots of sensitivity and specificity for cut‐off value of 0.5 ODI. The width of the rectangles is proportional to the number of patients with possible or without IA; the height of the blocks is proportional to the number of patients with IA (proven or probable). The solid line is the summary ROC curve; the thick black spots are the mean values for sensitivity and specificity; the ellipses around the black spots represent the 95% confidence intervals around the summary estimates.

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Figure 8

Summary ROC plots of sensitivity and specificity for cut‐off value of 1.0 ODI. The width of the rectangles is proportional to the number of patients with possible or without IA; the height of the blocks is proportional to the number of patients with IA (proven or probable). The solid line is the summary ROC curve; the thick black spots are the mean values for sensitivity and specificity; the ellipses around the black spots represent the 95% confidence intervals around the summary estimates.

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Figure 9

Summary ROC plots of sensitivity and specificity for cut‐off value of 1.5 ODI. The width of the rectangles is proportional to the number of patients with possible or without IA; the height of the blocks is proportional to the number of patients with IA (proven or probable). The solid line is the summary ROC curve; the thick black spots are the mean values for sensitivity and specificity; the ellipses around the black spots represent the 95% confidence intervals around the summary estimates.

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Figure 10

Distribution of studies that included only patients with unresponsive fever (black diamonds), studies that included all consecutive patients (grey squares), and patients that used other inclusion criteria (starts) for cut‐off values of 0.5 ODI (10a), 1.0 ODI (10b), and 1.5 ODI (10c).

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Figure 11

This is a summary ROC plot for all cut‐off values combined and for studies that included a representative patient spectrum, a non‐representative patient spectrum or a patient spectrum of which it is unclear whether it is representative or not. Cut‐off value 0.5 ODI: all studies included a representative patient spectrum (black squares, solid black summary curve). Cut‐off value 1.0: eight studies included a representative patient spectrum (filled blue squares, dark blue summary curve), two did not (filled yellow diamonds, no summary curve) and of two studies it was unclear whether they did or not (filled pink spots, no summary curve). Cut‐off value 1.5: nine studies included a representative patient spectrum (light blue squares with cross in it, light blue summary curve), one did not (red circles with cross in it, no summary curve) and of eight studies it was unclear whether they did or not (black diamonds with cross inside, red summary curve).

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Test 1

Platelia ‐ all cutoffs.

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Test 2

Platelia ‐ cutoff 0.5.

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Test 3

Platelia ‐ cutoff 1.0.

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Test 4

Platelia ‐ cutoff 1.5.

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Test 5

In‐house Platelia.

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Test 6

Platelia in children.

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Summary of findings 1. Summary of results table: different cut‐offs.

What is the diagnostic accuracy of the galactomannan ELISA for invasive aspergillosis for different cut‐off values?

Patients/population: immunocompromized patients, mostly hematology patients.

Prior testing: varied, mostly underlying disease or symptoms (fever, neutropenia).

Setting: mainly hematology or cancer departments, mainly inpatients.

Index test: a sandwich ELISA for galactomannan, an Aspergillus antigen.

Importance: depends on the time‐gain the test may give.

Reference standard: gold standard is autopsy, but that is nearly never done; so in most studies the reference standard is composed of clinical and microbiological criteria.

Studies: patient series or case‐control studies, not using an in‐house test and not excluding possibly infected patients. Studies had to report cut‐off values that were used (n = 29). Each study can be present in more than one subgroup.

Subgroup

Effect

(95% CI)

No. of participants

(studies)

Prevalence

(median, range)

What do these results mean?

Cut‐off 0.5

Sensitivity 0.79

(0.61‐0.93)

Specificity 0.82

(0.71‐0.92)

901

(7)

Median 9.9%

(0.8 to 34%)

With a prevalence of 8%*, 8 out of 100 patients will develop IA.

Of these, 2 will be missed by the Platelia test (22% of 8), but will be tested again.

Of the 92 patients without IA, 17 will be unnecessarily referred for CT scanning.

In children (1 study, 71 participants), the sensitivity was higher (92%) and the specificity was lower (60%).

Cut‐off 1.0

Sensitivity 0.71

(0.61‐0.81)

Specificity 0.90

(0.87‐0.94)

1744

(12)

Median 12.4%

(0.8% to 44%)

With a prevalence of 8%*, 8 out of 100 patients will develop IA.

Of these, 2 will be missed by the Platelia test (29% of 8), but will be tested again.

Of the 92 patients without IA, 9 will be unnecessarily referred for CT scanning.

In children (1 study, 32 participants), the sensitivity was higher (80%) and the specificity was higher (98%).

Cut‐off 1.5

Sensitivity 0.62

(0.45‐0.79)

Specificity 0.95

(0.92‐0.98)

2600

(17)

Median 7.4%

(0.8% to 34%)

With a prevalence of 8%*, 8 out of 100 patients will develop IA.

Of these, 3 will be missed by the Platelia test (36% of 8), but will be tested again.

Of the 92 patients without IA, only 5 will be unnecessarily referred for CT scanning.

In children (1 study, 17 participants), the sensitivity was higher (100%) and the specificity was lower (50%).

*Prevalence over all 28 studies (children‐studies excluded): 4501 participants; median 7.7 (IQR 4.6 to 14%)

Summary of findings 1. Summary of results table: different cut‐offs.

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Summary of findings 2. Summary of results table: factors influencing accuracy

What factors influence the diagnostic accuracy of galactomannan for invasive aspergillosis?

Patients/population: immunocompromized patients, mostly hematology patients.

Prior testing: varied, mostly underlying disease or symptoms (fever, neutropenia).

Setting: mainly hematology or cancer departments, mainly inpatients.

Index test: a sandwich ELISA for galactomannan, an Aspergillus antigen.

Importance: depends on the time‐gain the test may give.

Reference standard: gold standard is autopsy, but that is nearly never done; so in most studies the reference standard is composed of clinical and microbiological criteria.

Studies: patient series or case‐control studies, not using an in‐house test and not excluding possibly infected patients. Studies had to report cut‐off values that were used (n = 29). The analyses were done with cut‐off value as first covariate and additional characteristics as second covariate.

Subgroup

Second Covariate

Sensitivity

(95% CI)

Specificity

(95% CI)

Comments

Cut‐off 0.5 ODI

None

0.79 (0.64 to 0.93)

082 (0.71 to 0.92)

For none of the covariates added to cut‐off value 0.5 ODI, sensitivity or specificity exceeded 90%.

The studies that selected only patients with unresponsive fever reported a significantly lower sensitivity than the other two groups (P = 0.0093). Antifungal prophylaxis significantly decreased specificity (P = 0.029). Antifungal therapy significantly increased specificity (P = 0.047). Using the EORTC criteria was associated with a significantly lower sensitivity (P = 0.03).

No selection

Unresponsive fever

Other selection

0.73 (0.54 to 0.92)

0.68 (0.45 to 0.90)

0.89 (0.79 to 0.99)

0.83 (0.69 to 0.96)

0.88 (0.77 to 0.99)

0.82 (0.67 to 0.96)

Antifungal prohylaxis

No prophylaxis

0.82 (0.69 to 0.96)

0.71 (0.51 to 0.92)

0.88 (0.80 to 0.96)

0.77 (0.65 to 0.89)

Antifungal therapy

No therapy

0.82 (0.70 to 0.95)

0.64 (0.39 to 0.90)

0.89 (0.80 to 0.98)

0.78 (0.67 to 0.90)

EORTC criteria used

Other criteria used

0.69 (0.52 to 0.86)

0.86 (0.76 to 0.97)

0.85 (0.75 to 0.95)

0.82 (0.70 to 0.95)

Cut‐off 1.0 ODI

None

0.71 (0.61 to 0.81)

090 (0.87 to 0.94)

Sensitivity varies from 54% to 83%, depending on the subgroup tested.

Specificity varies from 86% to 94%.

No selection

Unresponsive fever

Other selection

0.61 (0.38 to 0.83)

0.54 (0.34 to 0.75)

0.82 (0.73 to 0.91)

0.89 (0.87 to 0.98)

0.93 (0.87 to 0.99)

0.89 (0.82 to 0.95)

Antifungal prohylaxis

No prophylaxis

0.77 (0.64 to 0.89)

0.64 (0.47 to 0.80)

0.93 (0.90 to 0.97)

0.86 (0.80 to 0.92)

Antifungal therapy

No therapy

0.76 (0.66 to 0.87)

0.56 (0.34 to 0.77)

0.94 (0.90 to 0.98)

0.88 (0.83 to 0.93)

EORTC criteria used

Other criteria used

0.63 (0.51 to 0.75)

0.83 (0.73 to 0.93)

0.90 (0.85 to 0.95)

0.88 (0.81 to 0.95)

Cut‐off 1.5 ODI

None

0.62 (0.45 to 0.79)

0.95 (0.92 to 0.98)

Although a cut‐off value of 1.5 ODI results in the highest specificity, sensitivity may be below 50% in some situations.

No selection

Unresponsive fever

Other selection

0.47 (0.16 to 0.78)

0.40 (0.17 to 0.64)

0.72 (0.58 to 0.87)

0.94 (0.87 to 1.00)

0.96 (0.91 to 1.00)

0.93 (0.89 to 0.97)

Antifungal prohylaxis

No prophylaxis

0.55 (0.34 to 0.77)

0.70 (0.51 to 0.89)

0.96 (0.94 to 0.99)

0.92 (0.87 to 0.97)

Antifungal therapy

No therapy

0.69 (0.52 to 0.86)

0.46 (0.21 to 0.71)

0.97 (0.95 to 0.99)

0.93 (0.90 to 0.97)

EORTC criteria used

Other criteria used

0.57 (0.40 to 0.74)

0.79 (0.65 to 0.94)

0.93 (0.89 to 0.97)

0.92 (0.86 to 0.98)

The second includes the variables that were used as covariate next to cut‐off value and that had a significant effect (P < 0.05) on either sensitivity or specificity.

Summary of findings 2. Summary of results table: factors influencing accuracy

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Table 1. EORTC/MSG Criteria

Proven IA	Histopathologic or cytopathologic examination showing hyphae from needle aspiration or biopsy specimen with evidence of associated tissue damage; or positive culture result for a sample obtained by sterile procedure from a normally sterile and clinically or radiologically abnormal site consistent with infection.
Probable IA	At least 1 host factor criterion; and 1 microbiological criterion; and 1 major (or 2 minor) clinical criteria from abnormal site consistent with infection.
Possible IA	At least 1 host factor criterion; and 1 microbiological or 1 major (or 2 minor) clinical criteria from abnormal site consistent with infection. This category is not recommended for use in clinical trials of antifungal agents
Host factor criteria are for example neutropenia, persistent fever, predisposing conditions, prolonged use of corticosteroids. Microbiological criteria are positive culture from sputum, broncheoalveolar lavage fluid (BAL) samples or from sinus aspirate specimen; positive result for Aspergillus antigen in specimens of BAL, cerebrospinal fluid or two or more blood samples. Major clinical criteria are, for example, new infiltrates on CT imaging (e.g. halo sign), suggestive radiological findings. Minor clinical criteria are suggestive symptoms and signs. The exact definitions of the EORTC/MSG criteria and their host factor, microbiological or clinical criteria can be found here (Ascioglu 2002).

Table 1. EORTC/MSG Criteria

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Table 2. Effect cut‐off value

Cut‐off Value and Analysis	Proven and Probable versus Possible and no IA			Proven versus Probable, Possible and no IA			Proven, Probable and Possible versus no IA
Cut‐off Value and Analysis	n	sensitivity (95% CI)	specificity (95% CI)	n	sensitivity (95% CI)	specificity (95% CI)	n	sensitivity (95% CI)	specificity (95% CI)
0.5 ODI subgroup	7	0.78 (0.61 to 0.89)	0.81 (0.72 to 0.88)	5	0.90 (0.57 to 0.99)	0.76 (0.61 to 0.86)	4	0.41 (0.24 to 0.60)	0.98 (0.95 to 0.99)
0.5 ODI as covariate	7	0.78 (0.64 to 0.91)	0.84 (0.75 to 0.93)	5	0.90 (0.75 to 1.00)	0.73 (0.60 to 0.85)	4	0.58 (0.28 to 0.88)	0.87 (0.76 to 0.98)
1.0 ODI subgroup	12	0.75 (0.59 to 0.86)	0.91 (0.84 to 0.95)	12	0.84 (0.50 to 0.97)	0.86 (0.76 to 0.92)	11	0.60 (0.32 to 0.83)	0.96 (0.92 to 0.98)
1.0 ODI as covariate	9	0.72 (0.63 to 0.82)	0.89 (0.85 to 0.93)	9	0.80 (0.66 to 0.94)	0.85 (0.81 to 0.90)	9	0.55 (0.39 to 0.71)	0.94 (0.91 to 0.97)
1.5 ODI subgroup	17	0.64 (0.50 to 0.77)	0.95 (0.91 to 0.97)	15	0.66 (0.55 to 0.76)*	0.92 (0.87 to 0.96)	15	0.41 (0.24 to 0.60)	0.98 (0.95 to 0.99)
1.5 ODI as covariate	12	0.67 (0.51 to 0.83)	0.93 (0.89 to 0.97)	10	0.64 (0.37 to 0.90)	0.93 (0.89 to 0.96)	11	0.52 (0.30 to 0.74)	0.98 (0.96 to 0.99)
Table 2 shows the results of the bivariate analyses for sensitivity and specificity for each cut‐off value. The effects of cut‐off value are analyzed in two ways: by means of subgroup analysis or by means of an univariable regression analysis with cut‐off value as covariate. Column 2 to 4 show the results for proven and probable patients versus possible and non‐IA patients. Column 5 to 7 show the results for proven patients versus probable, possible and non‐IA patients. Column 8 tot 10 show the results of the proven, probable and possible patients versus non‐IA patients.

Table 2. Effect cut‐off value

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Table 3. Effect of definition of test positivity

Cut‐off	Analysis	Studies (n)	Sensitivity (95% CI)	Specificity (95% CI)
0.5		7	0.78 (0.61 to 0.89)	0.81 (0.72 to 0.88)
	single sample	1	0.94 (0.82 to 1.00)	0.61 (0.30 to 0.91)
	subsequent samples	6	0.74 (0.60 to 0.88)	0.83 (0.77 to 0.90)
	P value		0.15	0.09
1.0		12	0.75 (0.59 to 0.86)	0.91 (0.84 to 0.95)
	single sample	6	0.83 (0.70 to 0.95)	0.84 (0.74 to 0.94)
	subsequent samples	6	0.61 (0.51 to 0.81)	0.95 (0.91 to 0.98)
	P value		0.07	0.02
1.5		17	0.64 (0.50 to 0.77)	0.95 (0.91 to 0.97)
	single sample	10	0.62 (0.44 to 0.81)	0.92 (0.87 to 0.98)
	subsequent samples	7	0.68 (0.49 to 0.87)	0.97 (0.94 to 0.99)
	P value		0.65	0.15

Table 3. Effect of definition of test positivity

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Table 4. Effect of reference standard

Cut‐off	Reference Standard	Studies (n)	Sensitivity (95% CI)	Specificity (95% CI)
0.5	EORTC criteria	4	0.69 (0.52 to 0.86)	0.85 (0.75 to 0.95)
	Other criteria	3	0.86 (0.76 to 0.97)	0.82 (0.70 to 0.94)
1.0	EORTC criteria	6	0.63 (0.51 to 0.75)	0.90 (0.85 to 0.95)
	Other criteria	4	0.83 (0.73 to 0.93)	0.88 (0.81 to 0.95)
1.5	EORTC criteria	9	0.57 (0.40 to 0.74)	0.93 (0.89 to 0.97)
	Other criteria	4	0.79 (0.65 to 0.94)	0.92 (0.86 to 0.98)
'Other' means that the authors used either modified EORTC criteria with 3, 5 or 6 categories or that they used their own reference criteria, which resemble the EORTC criteria.

Table 4. Effect of reference standard

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Table 5. Effect of age group

Cut‐off	Subgroup	studies (n)	Sensitivity (95% CI)	Specificity (95% CI)
0.5	All studies	7	0.78 (0.64 to 0.91)	0.84 (0.75 to 0.93)
	Adults only	6	0 .79 (0.64 to 0.93)	0.82 (0.71 to 0.92)
	Children only	1	0.80 (0.28 to 0.99)	0.98 (0.88 to 1.00)
1.0	All studies	12	0.72 (0.63 to 0.82)	0.89 (0.85 to 0.93)
	Adults only	11	0.71 (0.61 to 0.81)	0.90 (0.87 to 0.94)
	Children only	1	0.92 (0.62 to 1.00)	0.60 (0.36 to 0.81)
1.5	All studies	17	0.67 (0.51 to 0.83)	0.93 (0.89 to 0.97)
	Adults only	16	0.62 (0.45 to 0.79)	0.95 (0.92 to 0.98)
	Children only	1	1.00 (0.05 to 1.00)	0.50 (0.25 to 0.75)
The results of the 'adults only' analyses are calculated with all studies in that subgroup except the study that contained (a subgroup) of children.

Table 5. Effect of age group

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Table 6. Effect of prevalence

Cut‐off	Prevalence	n	Sensitivity (95% CI)	Specificity (95% CI)
0.5	>10%	4	0.78 (0.62 to 0.96)	0.78 (0.66 to 0.90)
	≤10%	2	0.81 (0.63 to 0.99)	0.88 (0.78 to 0.97)
1.0	>10%	6	0.70 (0.56 to 0.84)	0.87 (0.80 to 0.93)
	≤10%	3	0.74 (0.59 to 0.89)	0.93 (0.89 to 0.96)
1.5	>10%	3	0.60 (0.37 to 0.83)	0.92 (0.87 to 0.98)
	≤10%	9	0.65 (0.45 to 0.84)	0.96 (0.94 to 0.98)

Table 6. Effect of prevalence

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Table 7. Effect of patient selection

Cut‐off	Selection	n	Sensitivity (95% CI)	Specificity (95% CI)
0.5	No selection	3	0.73 (0.54 to 0.92)	0.83 (0.69 to 0.96
	Unresponsive fever	2	0.68 (0.45 to 0.90)	0.88 (0.77 to 0.99)
	Other selection	1	0.89 (0.79 to 0.99)	0.82 (0.67 to 0.96)
1.0	No selection	1	0.61 (0.38 to 0.83)	0.89 (0.87 to 0.98)
	Unresponsive fever	1	0.54 (0.34 to 0.75)	0.93 (0.87 to 0.99)
	Other selection	7	0.82 (0.73 to 0.91)	0.89 (0.82 to 0.95)
1.5	No selection	2	0.47 (0.16 to 0.78)	0.94 (0.87 to 1.00)
	Unresponsive fever	3	0.40 (0.17 to 0.64)	0.96 (0.91 to 1.00)
	Other selection	7	0.72 (0.58 to 0.87)	0.93 (0.89 to 0.97)

Table 7. Effect of patient selection

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Table 8. Effect antifungal prophylaxis

Cut‐off	Antifungal prophylaxis	n	Sensitivity (95% CI)	Specificity (95% CI)
0.5	no or unclear	2	0.71 (0.51 to 0.92)	0.88 (0.80 to 0.96)
	yes	4	0.82 (0.69 to 0.96)	0.77 (0.65 to 0.89)
1.0	no or unclear	4	0.64 (0.47 to 0.80)	0.93 (0.90 to 0.97)
	yes	5	0.77 (0.64 to 0.89)	0.86 (0.80 to 0.92)
1.5	no or unclear	7	0.55 (0.34 to 0.77)	0.96 (0.94 to 0.99)
	yes	5	0.70 (0.51 to 0.89	0.92 (0.87 to 0.97)

Table 8. Effect antifungal prophylaxis

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Table 9. Effect antifungal therapy.

Cut‐off	Antifungal therapy	n	Sensitivity (95% CI)	Specificity (95% CI)
0.5	no or unclear	2	0.64 (0.39 to 0.90)	0.78 (0.67 to 0.90)
	yes	4	0.82 (0.70 to 0.95)	0.89 (0.80 to 0.98)
1.0	no or unclear	1	0.56 (0.34 to 0.77)	0.88 (0.83 to 0.93)
	yes	8	0.76 (0.66 to 0.87)	0.94 (0.90 to 0.98)
1.5	no or unclear	6	0.46 (0.21 to 0.71)	0.93 (0.90 to 0.97)
	yes	6	0.69 (0.52 to 0.86)	0.97 (0.95 to 0.99)

Table 9. Effect antifungal therapy.

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Table Tests. Data tables by test

Test	No. of studies	No. of participants
1 Platelia ‐ all cutoffs Show forest plot	30	4792

2 Platelia ‐ cutoff 0.5 Show forest plot	7	901

3 Platelia ‐ cutoff 1.0 Show forest plot	12	1744

4 Platelia ‐ cutoff 1.5 Show forest plot	18	2777

5 In‐house Platelia Show forest plot	3	251

6 Platelia in children Show forest plot	4	366

Table Tests. Data tables by test

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