EAL

H/A: Caloric Needs (2007)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To explore the systemic inflammatory response and the energy expenditure response in HIV-infected patients with active secondary opportunistic infections.

Inclusion Criteria:

Existence of signs or symptoms of active opportunistic infections at the time of study.

Exclusion Criteria:

Those patients who presented with Kaposi's sarcoma, lymphoma or any other neoplastic disease
Presence of diabetes, kidney failure, nephrotic syndrome, active hepatitis or cirrhosis
Body temperature above 38°C at the time of the metabolic measurement
Use of corticoids
Hormone replacement
Any other drug known to affect energy expenditure.

Description of Study Protocol:

Recruitment

AIDS patients with active opportunistic infections
Clincially healthy and weight-stable volunteers at low risk of HIV infection were recruited from among from hospital staff to serve as a control group.

Design

Case-control study.

Blinding Used

Implied for measurements.

Statistical Analysis

Prevalences were compared using the contingency table chi-square test
Differences in mean values between control subjects and HIV-infected groups were assessed by Mann-Whitney non-parametric test
Groups of patients were compared using the Kruskal-Wallis test
Regression analyses were conducted for quantitative variables and regression coefficients were derived
To allow for comparisons among subjects with different body composition

The unexplained residual of REE values in each subject was calculated by the general linear model procedure, introducing FFM as a covariate
Adjusted REE values for each individual were calculated by adding the individual's residual REE value to the mean REE value of the whole study population or to the mean REE value of the AIDS patients, when this group was analyzed separately
Same procedure was used to adjust REE for differences in body weight.

Multiple stepwise regression analysis was conducted to identify factors affecting REE: Age, gender, BMI, previous weight losses, albumin, prealbumin, CRP, TNF-alpha, aTNF-R1, IFN-gamma, IL-6, B2M, CD4 and viral load.

Data Collection Summary:

Timing of Measurements

Blood samples were drawn and body composition and energy expenditure measurements were performed at 8:00 a.m., after an overnight 12-hour fast.

Dependent Variables

Height and weight were used to calculate BMI
Body composition: Tetrapolar bioelectrical impedance analysis with estimation of FFM
Serum albumin, prealbumin, total iron-binding capacity, ferritin and erythrocyte sedimentation rate were measured using standard in-house methods
C-reactive protein: Immunoturbidimetric assay
Fibrinogen: Spectrophotometry
TNF-alpha and sTNF-R1: ELISA
CD4 and CD8 lymphocyte subset counts, by flow cytometry
Viral load: Reverse transcriptase-polymerase chain reaction, using commercial kits
B₂-microglobulin: Quantitative enzyme immunoassay
Energy expenditure: Open-circuit indirect calorimetry.

In the multiple stepwise regression analyses to identify factors affecting REE, most of these variables were entered as independent variables; REE was the dependent variable in the regression.

Independent Variables

AIDS patients
Control.

AIDS patients were also categorized into inflammation categories: No Inflammation (CRP under six mg per liter); Moderate Inflammation (CRP six to 37mg per liter), Severe Inflammation (CRP at least 37mg per liter); the inflammation group was subdivided on the 50th percentile.

See note above regarding regression analyses and variables.

Control Variables

Age
Gender
Previous weight losses
IFN-gamma
IL-6 were also included in the regression analyses along with variables mentioned previously.

Description of Actual Data Sample:

Initial N: 52 AIDS patients with active opportunistic infections related to the AIDS (42 men, 10 women); 19 clinically healthy and weight stable volunteers at low risk for HIV infection as controls (14 men, five women)
Attrition (final N): 52 and 19
Age: 24 to 56 years HIV patients; 27 to 44 years for controls
Ethnicity: Not given
Other relevant demographics: Not given
Anthropometrics
- Height and weight were not presented; BMI information is given in Results.
- Disease information: all were seropositive for HIV infection by enzyme-linked immunosorbent assay, confirmed by Western blot analysis and met criteria for AIDS classification according to CDC
Location: Internal Medicine Wards of Hospital Sant Joan de Reus (17 patients) and the rest at the Nutrition Unit wards of Hospital Virgen del Rocio.

Summary of Results:

Table One: Energy Metabolism Parameters in Control Subjects and AIDS Patients

Variables	Control Subjects (N=19)	AIDS Patients (N=52)	Statistical Significance of Group Difference
REE; Observed (kJ/Day)	6,884.1±863.3	6,762.04±1190.8	NS
REE; Adj. FFM (kJ/Day)	6,290.3±432.8	6,978±846.9	P<0.005
REE; Adj. Weight (kJ/Day)	6,213.1±526.3	7,007.2±966.5	P<0.005
REE_o/REE_p; Percentage of Predicted	99.9±6.7	115.0±15.3	P<0.001
RQ	0.84±0.003	0.83±0.007	NS

Table Two: Comparisons Between the Inflammation Categories in AIDS Patients

Variables	No Inflammation (CRP <6mg/L; N=23)	Moderate Inflammation (CRP 6-37mg/L; N=13)	^{Severe Inflammation (CRP ≥37mg/L; N=13)}
REE (kJ/Day)	6,313±1,199	6,760±1,008	7,543±1,009*
REE_FFM (kJ/Day)	6,554±676	6,610±975	7,181±806**
REE_o/REE_p (Percentage)	109±15	114±15	124±14*
RQ	0.86±0.08	0.81±0.05	0.78±0.03***
CRP (mg/L)	5.0±1.2	19.95±11.6	104.45±71.8^a
IL-6 (pg/mL)	4.03±9.6	5.1±6.9	20.57±18.4***^,##
TNF-Alpha (pg/mL)	2.1±5.0	6.2±11.8	1.3±4.2
sTNF-R1 (ng/mL)	3.38±1.04	3.77±1.05	5.41±2.6*^,&
IFN-Gamma (pg/mL)	9.0±12.6	4.9±4.7	3.8±4.8
Fibrinogen (mg/dL)	344.6±76.4	466.3 ± 166.4	471.8±174.3^$
ESR	65.23±37.2	72.27±38.7	83.5±36.0
Ferritin (ug/L)	667.4±511.6	597.3±385.0	1,604.6±1,004.3^$,##
Albumin (g/L)	32.0±6.9	25.4±6.3	21.5±5.4***
Prealbumin (g/L)	0.22±0.13	0.12±0.06	0.06±0.05***^,##
Transferrin (g/L)	2.3±0.6	1.8±0.3	1.4±0.3***^,#
CD4	86.1±111.3	116.6±119.3	89.3±145.8
Log Viral Load	5.42±0.69	4.87±1.05	4.82±0.86
B₂ Microglobulin (mg/dL)	4.04±1.7	3.4±1.0	3.0±0.8**

^a Subdivision of group on 50th percentile
^*P<0.005
^**P<0.05
^***P<0.001
^$ P<0.01 vs. group without inflammation
^# P<0.05
^## P<0.01 vs. patients with moderate inflammation
^& P=0.0 vs. patients with moderate inflammation.

Other Findings

AIDS patients were undernourished

BMI: 18.5±2.4 kg/m²
Body fat percentage: 11.1±7.5
Albumin: 27.4±7.8g per liter
Prealbumin: 0.15±0.11g per liter.

All AIDS patients were below self-reported usual weight, pre-HIV infection
Weight losses ranged from 1.6% to 43% of reported body weight
- Approximately 96% of the patients had lost more than 5% of their customary weight
- 78% lost over 10%
- 39% lost over 20%
- Only 7.8% lost more than 30% of their usual body weight
- Mean weight lost in the previous month was 5.14±3.2kg.
Compared with controls, AIDS patients presented higher levels of inflammation markers

CRP: 33.0±57.2 vs. under six mg per liter (P<0.001)
ESR: 73.5±38.4 vs. 5.05±4.01 (P<0.001)
Ferritin: 879.6±769.8 vs. 81.5±76.6ug per liter (P<0.001).

IL-6 was significantly higher in AIDS patients than in control subjects (8.32±13.5 vs. 1.34±3.0pg per ml, P<0.005); IL-6 was undetectable in 14% of the AIDS patients
No significant differences were observed for TNF-alpha and IFN-gamma
sTNF-R1 was increased in HIV-infected patients, compared with controls (4.06±1.8 vs. 1.72±0.3ng per ml, P<0.001)
Only 2% of the AIDS patients (N=1) were hypometabolic (REE_ob/REE_p<90%); 36.5% were normometabolic (REE_ob/REE_p=90-100%); 61.5% (N=32) were hypermetabolic (REE_ob/REE_p≥110%)
Energy expenditure parameters were positively correlated with CRP, ESR, IL-6, sTNF-R1 and ferritin and negatively correlated with albumin, prealbumin and total iron-binding capacity
FFM was the main determinant of REE for the whole study population and explained 46% of the variation observed
In AIDS patients, REE was dependent on FFM (R=0.73; P<0.01) and CRP was an independent predictor of REE_FFM (R=0.50, P<0.001)
No significant relationship between previous weight losses and REE, CRP production or cytokine levels was observed in the HIV-infected patients
A weak but significant correlation between the REE_o and the REE_p was found in the AIDS group (R=0.59, P<0.01)
The predicted REE and CRP values together explained 55% of the variation in the REE_o (R=0.74, P<0.01)
The predictive equation: REE_ob=(1.273 REE_p+ 6.891 CRP)-959.178
No differences in body composition were observed between groups of AIDS patients
Previous weight losses increased and percentage fat mass decreased across the AIDS group from no inflammation to moderate inflammation to severe inflammation, although the differences were not significant
Secondary infections were subsequently diagnosed as

Tuberculosis (N=15)
Pneumocystis carinii pneumonia (N=12)
Recurrent bacterial pneumonia (N=6)
Visceral leishmaniasis (N=6)
Fever of unknown origin (N=6)
Cryptococcal meningitis (N=2)
Disseminated cryptococcosis (N=1)
Systemic mycobacterium avium-intracellulare (N=2)
Cytomegalorvirus colitis (N=1)
Giardiasis (N=1).

No significant differences in REE parameters nor in anthropometrical or nutritional parameters were observed between the groups with opportunistic infections
REE_FFM and REE_o/REE_p were significantly increased in all groups of opportunistic infections, compared with controls, except for those with recurrent bacterial pneumonia, which was the only normometabolic group
Tuberculosis and pneumocystis pneumonia were the more hypermetabolic secondary infections, with respect to adjusted values or as percentages of predicted values.

Author Conclusion:

The type of concurrent active infections in patients with AIDS is associated with a variable systemic inflammatory response, which may in part explain the resting hypermetabolism obeserved in this patient population
Studies comparing larger samples of different HIV-related infections would be required to identify those secondary infections that are associated with the more severe cytokine-driven inflammatory response and as a consequence to a higher degree of hypermetabolism.

Funding Source:

Reviewer Comments:

Limitations from Authors

Methodolgical difficulties linked to the short half-life of TNF-alpha and circumstances of the autocrine and paracrine action of cytokines could account for the lack of difference
Serum measurements of circulating cytokine concentrations are, because of the sites of action (mainly autocrine and paracrine), limited in their value as predictor parameters in standard clinical practice.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	N/A
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	N/A
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	Yes
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	N/A
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	Yes
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	N/A
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	N/A
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	N/A
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes