Crohn’s disease (CD) is a relapsing and progressive condition characterized by diarrhea, abdominal pain, weight loss, and hematochezia that results in serious complications such as perforations, fistulas, and abscesses. Various medications, interventions, and surgical treatments have been used to treat CD. The Korean guidelines for CD management were distributed in 2012 and revised in 2017 by the Inflammatory Bowel Disease (IBD) Research Group of the Korean Association for the Study of Intestinal Diseases. Substantial progress in mucosal immunologic research has elucidated the pathophysiology of IBD, leading to development of biological agents for treatment of CD. The first developed biologic agent, tumor necrosis factor-α agents, were shown to be efficacious in CD, heralding a new era in management of CD. Subsequently, vedolizumab, a monoclonal antibody against integrin α4β7, and ustekinumab, a human monoclonal antibody that inhibits the common p40 subunit of interleukin-12 and interleukin-23, were both approved for clinical use and are efficacious and safe for both induction and maintenance of remission in moderate-to-severe CD patients. Moreover, a recent study showed the non-inferiority of CT-P13, an infliximab biosimilar, compared with infliximab in CD patients. The third Korean guidelines for CD management provide updated information regarding treatment of moderate-to-severe CD patients with biologic agents.
Crohn’s disease (CD) is a chronic inflammatory intestinal disease of the digestive tract characterized by severe diarrhea, abdominal pain, weight loss, fatigue, and hematochezia [
Up-to-date management options for CD focus on inhibition or regulation of mucosal inflammation based on the mucosal immune pathway [
Clinical management guidelines for CD were published in 2012 by the members of the IBD Research Group of the Korean Association for the Study of Intestinal Diseases (KASID) [
The IBD research group of the KASID decided to develop the third guidelines for the management of CD in October 2020, to update the previous guidelines published in 2017. To establish the guidelines, the KASID selected a panel of 9 IBD experts (Seong-Joon Koh, Sung Noh Hong, Byong Duk Ye, Jeong Eun Shin, Kyeong Ok Kim, Hong Sub Lee, Soo-Kyung Park, Sung Hoon Jung, and Chang Hwan Choi) and 1 IBD surgeon (Yong Sik Yoon) supported by a methodologist (Miyoung Choi). The first meeting was held on October 5, 2020. Several novel biologic agents and biosimilars have been approved for management of moderate to severe CD in Korea. Diverse classes of biologics with different efficacies and safety profiles are available and therefore the third Korean guidelines focus on management of CD with biologic agents.
The key questions were gathered and selected from those raised in the clinic by the board members. All questions were solved using adaptations. Each question regarding management of CD identified the population (P), intervention (I), comparison (C), and patient-important outcomes (O). The committee members performed a systematic search and review to assess the relevant data in order to address the clinical questions.
The committee members selected 516 articles published between January 1, 2015, and October 1, 2020, by searching MEDLINE, Embase, the Guidelines International Network, and Korean Medical Guideline Information Center using keywords including “Crohn,” “Crohn’s disease,” and “CD.” The selected guidelines were assessed by 2 independent committee members using Appraisal of Guidelines for Research & Evaluation II (AGREE II). Finally, we identified 6 guidelines that were evidence-based, peer-reviewed, and nationally or internationally appraised (
Recommendations from the 6 guidelines selected by AGREE II from 2015 to 2020 were reviewed to formulate a statement for the 18 clinical questions. Recent studies published after the 6 reference guidelines were identified via a PubMed search and included as evidence for our guidelines. References for each PICO question were evaluated for quality by 2 independent members of the CD guideline committee using RoB 1.0 (randomized controlled trials, RCTs) and RoBANS 2.0 (observational studies) and then presented in the technical review. However, the guideline committee for CD made no recommendation for some clinical questions because of the knowledge gap.
The evidence was assessed for quality and classified into 4 categories, from high to very low, based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification (
The draft was peer-reviewed by IBD experts among members of the KASID. All comments were collected, reviewed, and addressed by the guidelines committee.
The goal of CD treatment is to prevent complications such as abscesses, strictures, and perforations by inducing and maintaining remission. The “treat-to-target” clinical management strategy has been used for management of IBD [
Conventional treatment with steroids and immunomodulators cannot alter long-term prognosis. However, suppression of TNF-α in IBD is effective for mucosal healing, which reduces the risk of bowel surgery and recurrence after operations [
Biologic agents including anti-TNF biosimilars are available in real-world practice in Korea. Unfortunately, little information is available regarding head-to-head clinical trials comparing the efficacy and safety of biologics for patients with CD. Although network meta-analyses have been performed, limited information exists regarding the choice of biological agents for CD [
The Vienna Classification has been previously used to classify CD [
The Crohn’s Disease Activity Index (CDAI) has been widely used in clinical trials and practice (
Clinical response is defined as a decrease in score to CDAI ≥ 100 (CDAI-100) [
Steroid-refractory CD patients are those in whom remission is not induced or who do not respond to an adequate treatment dosage of 0.75 mg/kg/day prednisolone within 4 weeks. Steroid-dependent CD patients are those who respond to steroid therapy but in whom the dose of prednisolone cannot be reduced to < 10 mg/day or who suffer symptom recurrence within 3 months after steroid discontinuation [
We recommend infliximab, adalimumab, vedolizumab, or ustekinumab for induction of remission in patients with moderate-to-severe CD who are refractory or intolerant to conventional therapy. (Strong recommendation with a moderate level of evidence)
RCTs demonstrated that biologics such as infliximab, adalimumab, vedolizumab, and ustekinumab are more efficacious than placebo for inducing remission in patients with luminal CD who have moderate to severe activity. Infliximab was more efficacious than the placebo for achieving clinical remission in 2 RCTs involving 106 biologic-naïve patients with CD [
In patients with moderate-to-severe CD who achieve a clinical response or remission with infliximab, adalimumab, vedolizumab, or ustekinumab, we recommend maintenance therapy using the same biologic agents. (Strong recommendation with a moderate level of evidence)
Nine RCTs compared the efficacy for maintenance of remission in patients who previously had moderately-to-severely active CD after induction of remission with biologics including infliximab, adalimumab, vedolizumab, and ustekinumab. In the ACCENT-1 trial in which 335 patients with moderately to severely active CD responded to a single infusion of infliximab within 2 weeks, infliximab was more efficacious than placebo to maintain clinical remission at week 30 (odds ratio [OR], 2.7; 95% CI, 1.6–4.6) and at week 54 (OR, 4.2; 95% CI, 1.5–11.5) [
a. We recommend infliximab in combination with thiopurines over infliximab monotherapy for induction of remission in patients with moderate-to-severe CD. (Strong recommendation with a moderate level of evidence)
b. We suggest adalimumab in combination with thiopurines over adalimumab monotherapy for induction of remission in patients with moderate-to-severe CD. (Conditional recommendation with a very low level of evidence)
One RCT (SONIC study) evaluated the efficacy of infliximab plus a thiopurine in patients with moderately-to-severely active CD [
The DIAMOND trial evaluated the efficacy of adalimumab plus azathioprine versus adalimumab monotherapy in patients with moderately-to-severely active CD over 52 weeks [
A double-blind RCT evaluated the efficacy of infliximab plus methotrexate and infliximab monotherapy among 126 patients with CD [
We recommend the use of adalimumab in patients with moderate-to-severe CD who lose their response to infliximab maintenance therapy. (Strong recommendation with a moderate level of evidence)
Treatment failure with TNF-α receptor antagonists includes primary treatment failure and secondary loss of response. Development of immunogenicity is critical for secondary loss of response. There is no evidence of an anti-drug antibody crossreacting with other TNF inhibitors. Based on a systematic review and meta-analysis of the efficacy of a second TNF-α receptor antagonist in patients with IBD in whom TNF-α receptor antagonist treatment has failed, the efficacy of a second TNF-α receptor antagonist in CD patients largely depends on the reason for switching [
The GAIN trial demonstrated the efficacy of adalimumab among patients with moderate-to-severe CD with secondary infliximab failures including intolerance [
However, no clinical trial has investigated the effect of infliximab after loss of response to adalimumab. In a large cohort study, the remission rate did not significantly differ between patients who received adalimumab followed by infliximab and those who received infliximab followed by adalimumab (48% vs. 42%,
We suggest the use of TNF-α receptor antagonists to prevent postoperative recurrence in high-risk patients with CD. (Weak recommendation with a low level of evidence)
Symptomatic recurrence is observed in approximately 40% of patients with CD within 5 years after bowel surgery. In addition, endoscopic recurrence in a postoperative setting is frequently detected in up to 97% of patients with CD within 1 year [
Several RCTs have reported the efficacy of TNF-α receptor antagonists to reduce postoperative recurrence in patients with CD. The recurrence rate was lower among patients treated with infliximab (1/11 patients, 9.1%) than among those treated with the placebo (11/13 patients, 84.6%) (
The effect of adalimumab on recurrence after surgery was evaluated in a randomized, 3-arm study. Adalimumab effectively reduced endoscopic (adalimumab, 6.3%; azathioprine, 65.7%; 5-ASA, 83.3%) and clinical (adalimumab, 12.5%; azathioprine, 64.7%; 5-ASA, 50%) recurrence within 2 years [
In a meta-analysis comprising 2,006 participants that compared 7 treatment strategies, mesalamine (RR, 0.60; 95% credible interval [CrI], 0.37–0.88), antibiotics (RR, 0.26; 95% CrI, 0.08–0.61), immunomodulator monotherapy (RR, 0.36; 95% CrI, 0.17–0.63), immunomodulator with antibiotics (RR, 0.11; 95% CrI, 0.02–0.51), and TNF-α receptor antagonist monotherapy (RR, 0.04; 95% CrI, 0.00–0.14), but not budesonide (RR, 0.93; 95% CrI, 0.40–1.84), reduced the risk of clinical relapse, compared with the placebo. Likewise, antibiotics (RR, 0.41; 95% CrI, 0.15–0.92), immunomodulator monotherapy (RR, 0.33; 95% CrI, 0.13–0.68), immunomodulator with antibiotics (RR, 0.16; 95% CrI, 0.04–0.48), and TNF-α receptor antagonist monotherapy (RR, 0.01; 95% CrI, 0.00–0.05), but not mesalamine (RR, 0.67; 95% CrI, 0.39–1.08) and budesonide (RR, 0.86; 95% CrI, 0.61–1.22), reduced the risk of endoscopic relapse [
We suggest therapeutic drug monitoring (TDM) to optimize treatment in patients with CD who lose their response to TNF-α receptor antagonists. (Conditional recommendation with a low level of evidence)
One RCT reported that TDM in patients who lose their response to anti-TNF therapy was associated with reduced treatment costs. However, there was no significant difference in clinical response rates, compared with routine dose intensification [
a. We recommend the use of infliximab for induction and maintenance of fistula remission in CD patients with active perianal fistulas. (Strong recommendation with a moderate level of evidence)
b. We suggest the use of adalimumab for induction and maintenance of fistula remission in CD patients with active perianal fistulas. (Conditional recommendation with a low level of evidence)
Infliximab is the only TNF-α receptor antagonist whose efficacy in patients with fistulizing CD has been evaluated in 2 RCTs. Among 94 CD patients who had symptomatic draining fistulas, fistulas were completely closed more frequently within 18 weeks among those administered infliximab than among those administered the placebo (RR, 0.52; 95% CI, 0.34–0.78) [
No RCT has investigated the use of adalimumab for induction or maintenance of remission using fistula remission as the primary outcome. Adalimumab did not effectively induce complete fistula closure (RR, 1.08; 95% CI, 0.93–1.27) in subgroup analyses of 2 clinical trials of 77 patients with symptomatic fistulas [
Non-TNF-α receptor antagonists such as vedolizumab and ustekinumab can also be suggested over no treatment for fistulizing CD. However, evidence to support this is limited [
We recommend that currently approved anti-TNF biosimilars can be used for induction and maintenance of remission in patients with moderate-to-severe CD. (Strong recommendation with a moderate level of evidence)
A biosimilar is defined as a biotherapeutic product that is similar to a licensed reference biotherapeutic product in terms of quality, safety, and efficacy [
In a study using the French nationwide health administrative database, 5,050 infliximab-naïve patients with CD had started treatment with infliximab (n = 2,551) or CT-P13 (n = 2,499), and a composite endpoint of death, CD-related surgery, all-cause hospitalization, and reimbursement of another biologic therapy was compared between the 2 groups as the primary outcome [
The subcutaneous formulation of CT-P13 (CT-P13 SC) was recently developed and was compared with intravenous (IV) CT-P13 in a phase 1, randomized, double-blind, multinational, multicenter trial [
Another biosimilar of infliximab, SB2, was compared with infliximab in patients with moderate-to-severe RA despite methotrexate therapy in a phase 3, randomized, double-blind, multinational, multicenter parallel group trial [
BI 695501, a biosimilar drug of innovator adalimumab has shown equivalent efficacy, highly similar safety and immunogenicity compared with the innovator in patients with RA (VOLTAIRE-RA) and in those with chronic plaque psoriasis (VOLTAIRE-PSO) through phase 3 randomized clinical trials [
Although no RCT has compared SB2, CT-P17, and SB5 with the innovator drugs in patients with CD, they will be equally efficacious and safe for patients with moderate-to-severe CD, based on extrapolation of indications [
We recommend patients with CD receiving anti-TNF agents can be switched to biosimilars if they are stable. (Strong recommendation with a moderate level of evidence)
The NOR-SWITCH trial was a 52-week, randomized, double-blind, phase 4 non-inferiority study that compared continuing treatment with infliximab and switching from infliximab to CT-P13 among stable patients with immune-mediated inflammatory diseases in terms of efficacy, safety, and immunogenicity [
At week 54 of a phase 3, randomized, double-blind trial comparing SB2 and infliximab in patients with RA [
In the phase 3 VOLTAIRE-CD trial, the innovator adalimumab group was switched to BI 695501 at week 24 and efficacy up to week 48 and safety up to week 56 were comparable with the BI 695501 maintenance group [
At week 24 of a phase 3, randomized, double-blind trial comparing SB5 and adalimumab in patients with RA [
Based on the NOR-SWITCH study, its extension, and transition studies of RA patients, and considering the indication extrapolation, stable patients with CD can be switched to biosimilars without issues such as loss of efficacy, increased occurrence of adverse events, or increased immunogenicity [
We recommend vedolizumab for induction and maintenance of remission in patients with moderate-to-severe CD who have an inadequate response to TNF-α receptor antagonists. (Strong recommendation with a low level of evidence)
In the GEMINI 3 trial, vedolizumab induction treatment was not effective compared with the placebo in patients with moderately-to-severely active CD with an inadequate response to TNF-α receptor antagonists (clinical remission at week 6, 15.2% vs. 12.1%,
Combination therapy with vedolizumab and a thiopurine was not effective compared with vedolizumab monotherapy in patients with CD. A recent meta-analysis reported that combination treatment with vedolizumab and an immunomodulator was not more effective than treatment with vedolizumab alone for 54 weeks [
We recommend ustekinumab for induction and maintenance of remission in patients with CD who have an inadequate response to TNF-α receptor antagonists. (Strong recommendation with a moderate level of evidence)
Ustekinumab has been approved for clinical use and is efficacious to induce and maintain remission in patients with moderately-to-severely active CD (UNITI-1 and 2). UNITI-1 registered patients with CD and primary or secondary TNF-α receptor antagonist failure. Among CD patients who received 6 mg/kg or 130 mg ustekinumab, the clinical response was 37.8% and 33.5% at week 8, respectively. These rates were significantly higher than those in patients who received the placebo (20.2%) [
No clinical trial has addressed the efficacy of combination therapy with azathioprine and ustekinumab compared with ustekinumab monotherapy. Among patients enrolled in the UNITI trials, concomitant immunosuppressant use resulted in a numerically higher symptomatic response in CD patients. However, statistical assessment was not performed [
Some studies have shown that dose intensification of ustekinumab is effective in patients with CD who fail to respond to the standard dose. However, these results should be carefully interpreted because of the relatively small sample size and short follow-up periods [
We suggest that discontinuation of TNF-α receptor antagonists is not mandatory prior to surgery in patients with CD. (Conditional recommendation with a low level of evidence)
No RCT has assessed whether use of TNF-α receptor antagonists cause development of postoperative complications, which has been debated. Earlier meta-analyses of preoperative treatment with TNF-α receptor antagonists showed slight increases in postoperative complications including infectious adverse events (OR, 1.52; 95%; CI, 1.14-2.03; 8 studies) [
CD is progressive and refractory, resulting in diverse complications. Recently developed biological agents are expected to provide better outcomes for patients with CD. Clinical decisions and the choice of biologics should be individualized based on inflammatory burden, convenience, cost, side effects, and compliance. The third Korean guidelines for the management of CD have been developed based on recently published highquality clinical data. They provide evidence-based recommendations for IBD physicians when using biological agents. We hope that these guidelines will help physicians accurately make decisions regarding the management of patients with CD, including those with perianal fistulas.
The authors received no financial support for the research, authorship, and/or publication of this article.
Koh SJ has received consulting fees from Daewoong Pharma. and Ferring Korea; speaking fees from AbbVie Korea, Ferring Korea, Daewoong Pharma., Janssen Korea, Pfizer Korea, Taejoon Pharma., Korea Pharma., Yuhan Pharma., and Takeda Korea. Hong SN has received a research grant from Celltrion; consulting fees from Celltrion, Takeda Korea, Janssen Korea, Eisai Korea, Ferring Korea; speaking fees and consulting fees from Celltrion, Takeda Korea, Janssen Korea, Eisai Korea, Daewoong Pharma., Ferring Korea, Pfizer Korea. Ye BD has served on advisory boards for AbbVie Korea, Celltrion, Daewoong Pharma, Ferring Korea, Janssen Korea, Pfizer Korea, Shire Korea, and Takeda Korea, has received research grants from Celltrion and Pfizer Korea, has received consulting fees from Chong Kun Dang Pharm., CJ Red BIO, Cornerstones Health, Daewoong Pharma, Kangstem Biotech, Korea United Pharm. Inc., Medtronic Korea, NanoEntek, and Takeda, and has received speaker fees from AbbVie Korea, Celltrion, Ferring Korea, IQVIA, Janssen Korea, Pfizer Korea, Shire Korea, Takeda, and Takeda Korea. Except for that, no potential conflict of interest relevant to this article was reported.
Not applicable.
Conceptualization: all authors. Data curation: Koh SN, Hong SN, Park SK, Ye BD, Kim KO, Shin JE, Yoon YS, Lee HS, Jung SH, Choi CH. Methodology: Choi M. Project administration: Kim JS. Resources: Hong SN. Supervision: Choi CH, Na SY, Kim JS. Writing - original draft: Koh SJ, Hong SN, Park SK, Ye BD, Kim KO, Shin JE, Yoon YS, Lee HS, Jung SH. Writing - review & editing: Koh SJ, Na SY. Approval of final manuscript: all authors.
Six Guidelines Selected through AGREE II
No | Title | Country | Journal | Year |
---|---|---|---|---|
1 | AGA clinical practice guidelines on the medical management of moderate to severe luminal and perianal fistulizing Crohn’s disease | USA | 2021 | |
2 | British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults | UK | 2019 | |
3 | ECCO guidelines on therapeutics in Crohn’s disease: medical treatment | EU | 2020 | |
4 | ACG clinical guideline: management of Crohn’s disease in adults | USA | 2018 | |
5 | Canadian Association of Gastroenterology clinical practice guideline for the management of luminal Crohn’s disease | Canada | 2019 | |
6 | Second Korean guidelines for the management of Crohn’s disease | Korea | 2017 |
AGREE II, Appraisal of Guidelines for Research & Evaluation II; AGA, American Gastroenterological Association; ECCO, European Crohn’s and Colitis Organisation; ACG, American College of Gastroenterology.
GRADE Definitions of Quality of Evidence Level
Quality of evidence | Definition/implication |
---|---|
High | We are very confident that the true effect lies close to that of the estimate of the effect. |
Moderate | We are moderately confident about the effect estimate: the true effect is most likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. |
Low | Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. |
Very low | We have very little confidence in the effect estimate: the true effect is most likely to be substantially different from the estimate of the effect. |
GRADE, Grading of Recommendations Assessment, Development and Evaluation.
GRADE Definition on Strength of Recommendation and its Interpretation
Strength of recommendation | Wording in the guideline | Interpretation for the clinician |
---|---|---|
Strong | Recommends | Most individuals should receive the recommended course of action. |
Conditional | Suggests | Different choices would be appropriate for different patients. |
GRADE, Grading of Recommendations Assessment, Development and Evaluation.
Summary of Recommendations of the Korean Clinical Practice Guidelines on Biologics for Moderate to Severe CD
No. | Recommendations | Strength of recommendation | Quality of evidence |
---|---|---|---|
1 | We recommend infliximab, adalimumab, vedolizumab, or ustekinumab for induction of remission in patients with moderate-to-severe CD who are refractory or intolerant to conventional therapy. | Strong | Moderate |
2 | In patients with moderate-to-severe CD who achieve a clinical response or remission with infliximab, adalimumab, vedolizumab, or ustekinumab, we recommend maintenance therapy using the same biologic agents. | Strong | Moderate |
3 | a. We recommend infliximab in combination with thiopurines over infliximab monotherapy for induction of remission in patients with moderate-to-severe CD. | Strong | Moderate |
b. We suggest adalimumab in combination with thiopurines over adalimumab monotherapy for induction of remission in patients with moderate-to-severe CD. | Conditional | Very low | |
4 | We recommend the use of adalimumab in patients with moderate-to-severe CD who lose their response to infliximab maintenance therapy. | Strong | Moderate |
5 | We suggest the use of TNF-α receptor antagonists to prevent postoperative recurrence in high-risk patients with CD | Weak | Low |
6 | We suggest therapeutic drug monitoring (TDM) to optimize treatment in patients with CD who lose their response to TNF-α receptor antagonists. | Conditional | Low |
7 | a. We recommend the use of infliximab for induction and maintenance of fistula remission in CD patients with active perianal fistulas. | Strong | Moderate |
b. We suggest the use of adalimumab for induction and maintenance of fistula remission in CD patients with active perianal fistulas. | Conditional | Low | |
8 | We recommend that currently approved anti-TNF biosimilars can be used for induction and maintenance of remission in patients with moderate-to-severe CD. | Strong | Moderate |
9 | We recommend patients with CD receiving anti-TNF agents can be switched to biosimilars if they are stable. | Strong | Moderate |
10 | We recommend vedolizumab for induction and maintenance of remission in patients with moderate-to- severe CD who have an inadequate response to TNF-α receptor antagonists. | Strong | Low |
11 | We recommend ustekinumab for induction and maintenance of remission in patients with CD who have an inadequate response to TNF-α receptor antagonists. | Strong | Moderate |
12 | We suggest that discontinuation of TNF-α receptor antagonists is not mandatory prior to surgery in patients with CD. | Conditional | Low |
CD, Crohn’s disease; TNF, tumor necrosis factor.
Montreal Classification for Crohn’s Disease
Variable | Montreal classification |
---|---|
Age at diagnosis (yr) | A1, ≤ 16 |
A2, 17-40 | |
A3, > 40 | |
Location | L1, ileal |
L2, colonic | |
L3, ileocolonic | |
L4, isolated upper disease |
|
Behavior | B1, non-stricturing, non-penetrating |
B2, stricturing | |
B3, penetrating | |
p, perianal disease modifier |
L4 is a modifier that can be added to L1–L3 when concomitant upper gastrointestinal disease is present.
p is added to B1–B3 when concomitant perianal disease is present.
Crohn’s Disease Activity Index
No. | Item | Description | Multiplier | |
---|---|---|---|---|
1 | Number of liquid or very soft stools | Sum of 7 day | - | ×2 |
2 | Abdominal pain | Sum of 7 day | 0, none; 1, mild; 2, moderate; 3, severe | ×5 |
3 | General well-being | Sum of 7 day | 0, generally well; 1, slightly under par; 2, poor; 3, very poor; 4, terrible | × 20 |
4 | Number of 6 listed categories patient now has | Number of 6 listed categories | (1) Arthritis/arthralgia | |
(2) Iritis/uveitis | ||||
(3) Erythema nodosum/pyoderma gangrenosum/aphthous stomatitis | ||||
(4) Anal fissure, fistula, or abscess | ||||
(5) Other fistula | ||||
(6) Fever > 37.8°C (100°F) during the past week | ||||
5 | Antidiarrheal drug use | Use in the previous 7 day | 0, no; 1, yes | × 30 |
6 | Abdominal mass | 0, none; 2, questionable; 5, definite | × 10 | |
7 | Hematocrit | Expected-observed | Male, 47-hematocrit | ×6 |
Hematocrit | Female, 42-hematocrit | |||
8 | Body weight | Percent below standard weight (normogram) | ×1 |