In vitro testen bij patiënten met hypersensitiviteitsreacties na CM
Uitgangsvraag
Wat is de diagnostische waarde van serum en/of urinetesten voor contrastmiddel-geïnduceerde hypersensitiviteitsreacties?
Aanbeveling
Meet serum tryptase, het liefst binnen 1-2 uur (tussen 15 minuten en 4 uur) vanaf de start van alle matige tot ernstige acute hypersensitiviteitsreacties na contrastmiddeltoediening. Deze meting dient als baseline voor verder allergologisch onderzoek.
*Zie ook flow charts
Basofiele activatietesten zijn gereserveerd voor selecte patiënten met matige tot ernstige acute hypersensitiviteitsreacties, en zijn alleen beschikbaar in gespecialiseerde allergologiecentra.
Voor niet-acute hypersensitiviteitsreacties zijn geen noemenswaardige in-vitro testen beschikbaar in Nederland.
Overwegingen
- Immediate/acute hypersensitivity reactions (IHR)
Tryptase
Histamine and tryptase can be both measured to confirm IHR to CM. However, histamine is degraded quickly, being less specific and more complicated to measure by commercially available assays. Thus, tryptase is regarded as the preferred mediator. The approach is to compare acute (within 4 hours of the event) and baseline total tryptase levels (at least 24 hours after all signs and symptoms of the event have subsided) to distinguish between an increased mast cell burden (e.g., mastocytosis, in which baseline tryptase levels remain elevated) and mast cell degranulation (with only acute tryptase levels elevated). The minimal elevation of acute over baseline tryptase levels suggested to be clinically significant is calculated as at least 2 ng/mL + [1.2 x baseline tryptase level] (Sprung, 2015) or at least 20% above baseline plus 2 ng/mL during or within 4 hours after a symptomatic period (Valent, 2012). An increase from baseline level during allergic symptoms is suggestive of an IHR to CM. It has been reported that higher tryptase elevations are indicative of IgE- mediated mast cell activation and correlate with the clinical severity of the reaction (Clement, 2018; Laroche, 2005; Schwarz, 2006).
Therefore, the ESUR guidelines suggests serum tryptase measurements following a suspected immediate hypersensitivity reaction. The minimum recommendation is one sample 1 to 2 hours after the reaction point. Ideally, three samples should be obtained, the first one once this histamine release is underway, the second at 1 to 2 hours after the reaction, and the third at 24 hours or during convalescence (ESUR, 2018). The recently published practice guideline by the European Academy of Allergy and Clinical Immunology (EAACI) considers tryptase determination in the acute phase useful for confirming IHR to CM, if a transient increase is detectable (strong/moderate) (Torres, 2021). It is advised to measure tryptase within 4 hours of the acute event.
Basophil Activation Test (BAT)
The BAT technique is based on detection of activation of basophils with flow cytometry. CD63 expression serves as a unique marker for identifying activated cells. The technique requires a small amount of fresh blood, less than 0.1 mL. The CD63 marker is located to the same secretory granule that contains histamine; in principle, histamine production could also be used as a marker of basophil activation, but determination of histamine is more cumbersome than detecting CD63 upregulation (Hoffmann, 2015).
BAT has shown its usefulness in diagnosing immediate hypersensitivity reactions to contrast media. The use of BAT in acute reactions to GBCA demonstrated an excellent specificity (93%) in the diagnosis of allergic immediate hypersensitivity to GBCA and a quite good sensitivity (69%). It was concluded that BAT remains especially useful for patients with uncertain diagnosis and to confirm a positive ST result (Kolenda, 2018).
Three studies published on the diagnostic value of BAT regarding CM. The sensitivity ranged from 46 to 63%, while specificity varied between 89 and 100% (Pinnobphun, 2011; Salas, 2013; Trcka, 2008). Pinnobphun et al. also reported an area under the ROC curve of 0.79 by using the stimulation index as the diagnostic criteria with 1:100 dilution of radiocontrast media (Pinnobphun, 2011).
Thus, BAT can be a complementary tool to diagnose IHR to CM (Brockow, 2020), showing good correlation with ST and DPT results (Salas, 2013). Since it is an in vitro test, it may be especially useful in cases with severe reaction and contraindications for ST or DPT (Brockow, 2020). However, there are several limitations to consider. The NPV has not been clearly determined (Decuyper, 2017) and that certain factors may affect BAT result, such as the time between the reaction and the test or the severity and type of reaction (Salas, 2013). In addition, it has to be considered that more than 10% of patients have non-reacting basophils
(i.e., the positive control remains negative), rendering this test unsuitable for these patients at that time. Lastly, BAT is currently only available in specialized drug allergy centres in the Netherlands. The EAACI practical guidelines (Torres, 2021) consider BAT an additional tool for diagnosing patients with IHR with severe reactions or those with high risk (weak/low).
- Nonimmediate/late hypersensitivity reactions (NIHR)
Lymphocyte Transformation Test (LTT)
LTT is not recommended at the acute stage, but after 4-8 weeks after remission (Hari, 2011) and within 2 -3 years after the reaction (Pichler, 2004). Corticosteroids in doses higher than
0.2 mg/kg prednisone equivalent and other immunosuppressive or immunomodulatory agents may interfere with the test. A NPV for LTT in NIHR to CM is not available. As radioactive materials have been banned in many laboratories, the use of "modified non- radioactive LTT" will be a better choice.
The LTT is recommended as an additional diagnostic tool in selected cases with contraindications for STs (weak/low). It should only be performed by experienced physicians (weak/low) (Torres, 2021). Unfortunately, LTT is currently not available in any allergology centre in the Netherlands. Alternative in vitro tests such as the OX40 test are still under development.
|
Measure serum tryptase, preferably between 1-2 hours (range 15 minutes to 4 hours) from the start of all moderate to severe immediate hypersensitivity reactions to contrast media. This measurement serves as a baseline for further allergologic examinations.
*See also flow charts |
|
Basophil activation tests are reserved for selected patients with moderate to severe acute hypersensitivity reactions and are only available in specialized drug allergy centres. |
|
For nonimmediate hypersensitivity reactions there are no meaningful in vitro tests available in the Netherlands. |
Onderbouwing
Achtergrond
In vitro tests using blood or urine can be employed in the analysis of possible hypersensitivity reactions, immediately following the event or in an outpatient setting. Which diagnostics should be performed depends on the timing and the type of reaction.
Hypersensitivity reactions to contrast media are described as immediate (acute) or nonimmediate (delayed, late). Reactions occurring within one hour after application of the agents are coined as immediate, reactions occurring later are called nonimmediate. For more information see the Introduction of this chapter.
Nonimmediate hypersensitivity reactions (NIHM) are mediated by CM specific T- lymphocytes (Christiansen, 2000; Kanny, 2005; Lerch, 2007; Romano, 2002). In the (semi)acute setting, there are no in vitro diagnostic methods available to confirm the diagnosis. To date, only a skin biopsy can be useful in this setting, but specific pathognomonic features are lacking. Routine laboratory diagnosis (leukocyte count + differential, liver enzymes, urea, creatinine) is useful to screen for extracutaneous organ involvement. Eosinophilia may support the diagnosis of NIHM but lacks both sensitivity and specificity.
Additional diagnostic methods in the outpatient setting are also mostly performed in vivo by means of patch testing and/or skin prick or intradermal testing with late (>24 hours) readings. Lymphocyte transformation tests (LTT) are currently not available in the Netherlands.
Immediate hypersensitivity reactions (IHR) are nowadays considered to be mediated by both allergic (IgE-mediated) and nonallergic (non-IgE-mediated, i.e., direct nonspecific mast cell degranulation or complement activation) mechanisms (Torres, 2021).
In the acute event of an IHR, mast cell degranulation (via IgE or non-IgE mediated mechanisms) can be studied by measuring serum beta-tryptase (tryptase) or histamine. Serum histamine determination is unpractical because of its short half-life in circulation. An alternative is detection of histamine metabolites in urine. (N-τ-Methylhistamine). Although this is a reliable parameter (Keyzer, 1984), very few laboratories have this test in their routine repertoire, and there are not enough data available with respect to contrast media. So, this parameter is not further discussed.
In the outpatient setting, analysis of IHR mostly depends on in vivo diagnostic methods using skin prick and intradermal testing. In the recent years, additional drug provocation tests (DPT) have gradually been implemented in specialized centres. In vitro diagnosis is limited to detection of specific IgE antibodies and basophil activation tests (BAT). Specific antibodies against certain ionic contrast media have been detected in patients with IHR (Laroche 1998;
Mita 1998); however, to date there are no specific IgE antibodies commercially available. Application of BAT to heparin stabilized blood samples of patients shows interesting results but its availability is limited to specialized laboratories.
Samenvatting literatuur
No studies were included in the analysis of the literature; therefore, no systematic literature analysis was performed.
Zoeken en selecteren
A systematic review of the literature was performed to answer the following question: What is the diagnostic value of serum and/or blood testing compared to clinical diagnosis of hypersensitivity reaction after contrast administration / no in vitro tests for contrast media induced hypersensitivity reactions?
P (Patients) Patients with hypersensitivity reactions after undergoing radiological examinations with contrast media.
I (Intervention) Serum tests: tryptase, blood test, basophil activation test.
C (Comparison) Clinical diagnosis of hypersensitivity reaction after contrast administration / no serum tests.
R (Reference test) Drug provocation test.
O (Outcomes) Correctly confirmed diagnosis of hypersensitivity reaction to contrast media (sensitivity, specificity, area under the curve, positive predictive value PPV, negative predictive value NPV).
Relevant outcome measures
The working group considered sensitivity and specificity critical outcome measures for the decision-making process; and considered the area under the curve and the positive and negative predictive values important outcome measures.
Search and select (Methods)
The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until April 22nd, 2021. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 368 hits. Studies were selected based on the following criteria:
- Adult patients with hypersensitivity reaction to radio contrast media.
- Evaluation of diagnostic properties of serum tests to contrast media.
- Application of a provocation test to confirm results of cutaneous testing.
- Reports predefined outcome measures: sensitivity, specificity, area under the curve, positive predictive value, negative predictive value.
- Serum tests tryptase and urine-metabolites should be performed within 24 hours after hypersensitivity reaction.
- No reports of case series or exploratory findings (n≥10).
Seven studies were initially selected based on title and abstract screening. After reading the full text, all seven studies were excluded (see Table of excluded studies in ‘Appendices to modules’).
Referenties
- Brockow K. Medical algorithm: Diagnosis and treatment of radiocontrast media hypersensitivity. Allergy. 2020;75(5):1278-1280.
- Christiansen C, Pichler WJ, Skotland T. Delayed allergy-like reactions to X-ray contrast media: mechanistic considerations. Eur Radiol 2000; 10: 1965-1975.
- Clement O, Dewachter P, Mouton-Faivre C, et al. Immediate hypersensitivity to contrast agents: the French 5-year CIRTACI study. EClinicalMedicine. 2018; 1: 51-61.
- Decuyper II, Mangodt EA, Van Gasse AL, et al. In Vitro Diagnosis of Immediate Drug Hypersensitivity Anno 2017: Potentials and Limitations. Drugs R D. 2017; 17(2): 265-
278. - European Society of Urogenital Radiology Contrast Media Safety Committee. ESUR Guidelines on contrast safety, v10. Available at: [URL]. Accessed: 22. May 2022.
- Hari Y, Frutig-Schnyder K, Hurni M, et al. T cell involvement in cutaneous drug eruptions. Clin Exp Allergy. 2001; 31(9): 1398-1408.
- Kanny G, Pichler W, Morisset M, Franck P, Marie B, Kohler C, Renaudin JM, Beaudouin E, Laudy JS, Moneret-Vautrin DA. T cell-mediated reactions to iodinated contrast media: evaluation by skin and lymphocyte activation tests. J Allergy Clin Immunol. 2005; 115(1): 179-185.
- Keyzer JJ, Kauffman HF, de Monchy JG, Keyzer-Udding JJ, de Vries K. Urinary N tau- methylhistamine during early and late allergen-induced bronchial-obstructive reactions. J Allergy Clin Immunol. 1984; 74(3 Pt 1): 240-245.
- Laroche D, Aimone-Gastin I, Dubois F, et al. Mechanisms of severe, immediate reactions to iodinated contrast material. Radiology 1998; 209(1): 183-190.
- Laroche D. Immediate reactions to contrast media: mediator release and value of diagnostic testing. Toxicology. 2005; 209(2): 193-194.
- Lerch M, Keller M, Britschgi M, Kanny G, Tache V, Schmid DA, Beeler A, Gerber BO, Luethi M, Bircher AJ, Christiansen C, Pichler WJ. Cross-reactivity patterns of T cells specific for iodinated contrast media. J Allergy Clin Immunol. 2007; 119(6): 1529-1536.
- Mita H, Tadokoro K, Akiyama K. Detection of IgE antibody to a radiocontrast medium. Allergy 1998; 53(12): 1133-1140.
- Pichler WJ, Tilch J. The lymphocyte transformation test in the diagnosis of drug hypersensitivity. Allergy. 2004; 59(8): 809-820.
- Pinnobphun P, Buranapraditkun S, Kampitak T, Hirankarn N, Klaewsongkram J. The diagnostic value of basophil activation test in patients with an immediate hypersensitivity reaction to radiocontrast media. Ann Allergy Asthma Immunol 2011; 106(5): 387-393.
- Romano A, Artesani MC, Andriolo M, Viola M, Pettinato R, Vecchioli-Scaldazza A. Effective prophylactic protocol in delayed hypersensitivity to contrast media: report of a case involving lymphocyte transformation studies with different compounds. Radiology. 2002; 225(2): 466-470.
- Salas M, Gomez F, Fernandez TD, et al. Diagnosis of immediate hypersensitivity reactions to radiocontrast media. Allergy. 2013; 68(9): 1203-1206.
- Schrijvers R, Breynaert C, Ahmedali Y, Bourrain JL, Demoly P, Chiriac AM. Skin testing for suspected iodinated contrast media hypersensitivity. J Allergy Clin Immunol Pract 2018; 6: 1246-1254.
- Schwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol Allergy Clin North Am. 2006; 26(3): 451-463.
- Sprung J, Weingarten TN, Schwartz LB. Presence or absence of elevated acute total serum tryptase by itself is not a definitive marker for an allergic reaction. Anesthesiology. 2015; 122(3): 713-714.
- Torres MJ, Trautmann A, Böhm I, Scherer K, Barbaud A, Bavbek S, et al. Practice parameters for diagnosing and managing iodinated contrast media hypersensitivity. Allergy 2021; 76(5): 1325-1339.
- Trcka J, Schmidt C, Seitz CS, Brocker EB, Gross GE, Trautmann A. Anaphylaxis to iodinated contrast material: nonallergic hypersensitivity or IgE-mediated allergy? AJR Am J Roentgenol 2008; 190(3): 666-670.
- Valent P, Akin C, Arock M, et al. Definitions, criteria, and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol. 2012; 157(3): 215-225.
Verantwoording
Autorisatiedatum en geldigheid
Laatst beoordeeld : 28-11-2022
Laatst geautoriseerd : 28-11-2022
Geplande herbeoordeling :
Validity
The Radiological Society of the Netherlands (NVvR) will determine around 2027 if this guideline (per module) is still valid and applicable. If necessary, the scientific societies will form a new guideline group to revise the guideline. The validity of a guideline can be shorter than 5 years, if new scientific or healthcare structure developments arise, that could be a reason to commence revisions. The Radiological Society of the Netherlands is the owner of this guideline and thus primarily responsible for the actuality of the guideline. Other scientific societies that have participated in the guideline development share the responsibility to inform the primarily responsible scientific society about relevant developments in their field.
Algemene gegevens
General Information
The Kennisinstituut van de Federatie Medisch Specialisten (www.kennisinstituut.nl) assisted the guideline development group. The guideline was financed by Stichting Kwaliteitsgelden Medisch Specialisten (SKMS) which is a quality fund for medical specialists in The Netherlands.
Samenstelling werkgroep
Guideline development group (GDG)
A multidisciplinary guideline development group (GDG) was formed for the development of the guideline in 2020. The GDG consisted of representatives from all relevant medical specialization fields which were using intravascular contrast administration in their field.
All GDG members have been officially delegated for participation in the GDG by their scientific societies. The GDG has developed a guideline in the period from June 2020 until November 2022. The GDG is responsible for the complete text of this guideline.
Guideline development group
- Dekkers I.A. (Ilona), clinical epidemiologist and radiologist, Leiden University Medical Center, Leiden
- Geenen R.W.F. (Remy), radiologist, Noordwest Ziekenhuisgroep, Alkmaar
- Kerstens M.N. (Michiel), internist-endocrinologist, University Medical Centre Groningen
- Krabbe J.G. (Hans), clinical chemist-endocrinologist, Medisch Spectrum Twente, Enschede
- Rossius M.J.P. (Mariska), radiologist, Erasmus Medical Centre, Rotterdam
- Uyttenboogaart M. (Maarten), neurologist and neuro-interventionalist, University Medical Centre Groningen
- van de Luijtgaarden K.M. (Koen), vascular surgeon, Maasstad Ziekenhuis, Rotterdam
- van der Molen A.J. (Aart), chair guideline development group, radiologist, Leiden University Medical Center, Leiden
- van der Wolk S.L. (Sabine), gynaecologist-obstetrician, Haga Ziekenhuis, Den Haag
- van de Ven A.A.J.M. (Annick), internist-allergologist-immunologist, University Medical Centre Groningen (until 1.7.2022)
- van der Houwen, T.B. (Tim), internist-allergologist-immunologist, Amsterdam University Medical Center (from 1.7.2022)
Invited experts
- van Maaren M.S. (Maurits), internist-allergologist-immunologist, Erasmus MC, Rotterdam
Methodological support
- Abdollahi M. (Mohammadreza), advisor, Knowledge Institute of the Federation Medical Specialists
- Labeur Y.J. (Yvonne), junior advisor, Knowledge Institute of the Federation Medical Specialists
- Mostovaya I.M. (Irina), senior advisor, Knowledge Institute of the Federation Medical Specialists
Belangenverklaringen
Conflicts of interest
The GDG members have provided written statements about (financially supported) relations with commercial companies, organisations or institutions that were related to the subject matter of the guideline. Furthermore, inquiries have been made regarding personal financial interests, interests due to personal relationships, interests related to reputation management, interest related to externally financed research and interests related to knowledge valorisation. The statements on conflict of interest can be requested from the administrative office of Kennisinstituut van de Federatie Medisch Specialisten (secretariaat@kennisinstituut.nl) and were summarised below.
|
Last name |
Function |
Other positions |
Personal financial interests |
Personal relations |
Reputation management |
Externally financed research |
Knowledge valorisation |
Other interests |
Signed |
Actions |
|
Dekkers IA |
Radiologist, LUMC |
Clinical Epidemiologist
Member of contrast media safety committee, European Society of Urogenital Radiology (no payment)
Member, Gadolinium Research and Education Committee, European Society of Magnetic Resonance in Medicine, and Biology (no payment) |
No |
No |
No |
No |
No |
Received consultancy fees from Guerbet, 2019- 2022 |
July 24th, 2020, Reaffirmed October 12th, 2022 |
No restrictions: received in part 3 of the guideline speaker fees, but this guideline does not mention specific medication, not of working mechanism, nor of side effects. |
|
Geenen RWF |
Radiologist, Noordwest ziekenhuisgroep /Medisch specialisten Noordwest |
Member of contrast media safety committee, European Society of Urogenital Radiology (no payment) |
No |
No |
No |
No |
No |
No |
April 11th, 2020, Reaffirmed October 12th, 2022 |
No restrictions |
|
Houwen T, van der |
Internist - Immunologist - Allergologist, Amsterdam UMC, also seconded allergologist in Huid Medisch Centrum |
None |
None |
None |
None |
None |
None |
None |
July 11th, 2022 Reaffirmed October 12th, 2022 |
No restrictions |
|
Kerstens MN |
Internist- endocrinologist, UMCG |
Chairman Bijniernet (no payment) |
No |
No |
No |
No |
No |
No |
July 1st, 2020, reaffirmed October 25th, 2022 |
No restrictions |
|
Krabbe JG |
Clinical chemist, Medisch Spectrum Twente |
No |
No |
No |
No |
No |
No |
No |
September 1st, 2020, Reaffirmed October 13th, 2022 |
No restrictions |
|
Luijtgaarden KM, van de |
Vascular surgeon, Maasland Ziekenhuis |
No |
No |
No |
No |
No |
No |
No |
August 1st, 2020, reaffirmed October 26th, 2022 |
No restrictions |
|
Molen AJ, van der |
Radiologist LUMC |
Member of contrast media safety committee, European Society of Urogenital Radiology (no payment)
Member, Gadolinium Research and Education Committee, European Society of Magnetic Resonance in Medicine, and Biology (no payment) |
No |
No |
No |
No |
No |
Received consultancy fees from Guerbet, 2019- 2022 |
July, 24th, 2020 Reaffirmed October 12th, 2022 |
No restrictions: received in part 3 of the guideline speaker fees, but this guideline does not mention Specific medication, not of working mechanism, nor of side effects. |
|
Rossius MJP |
Radiologist Erasmus Medical Centre |
Medical coordinator (no payment) |
No |
No |
No |
No |
No |
No |
April 7th, 2020, Reaffirmed October 13th, 2022 |
No restrictions |
|
Uyttenboogaart M |
Neurologist and neuro- interventionalist UMCG |
Advisor International Federation of Orthopaedic Manipulative Physical Therapist / Nederlandse Vereniging Manuele Therapie |
No |
No |
Subsidy Hart Stichting for CONTRAST (Consortium of New Treatments in Acute Stroke): WP8 Stroke logistics and Epidemiology: financing of 2 PhD students by the Hart Stichting / PPS Allowance |
Work package leader CONTRAST (Consortium of New Treatments in Acute Stroke): WP8 Stroke logistics and Epidemiology |
No |
No |
June 30th, 2020, reaffirmed October 26th, 2022 |
No restrictions: the CONTRAST consortium wp8 is only about organisation and treatment of stroke. Stroke is not in this guideline. |
|
Ven AAJM, van de |
Internist- allergologist- immunologist, UMCG |
Education and research related to work as internist- allergist |
No |
No |
No |
No |
No |
No |
April 7th, 2020, Reaffirmed October 19th, 2022 |
No restrictions |
|
Wolk S, van der |
Gynaecologist- obstetrician, Haga Ziekenhuis |
No |
No |
No |
No |
No |
No |
No |
June 30th, 2021, reaffirmed October 25th, 2022 |
No restrictions |
Inbreng patiëntenperspectief
Input of patient’s perspective
The guideline does not address a specific adult patient group, but a diverse set of diagnoses. Therefore, it was decided to invite a broad spectrum of patient organisations for the stakeholder consultation. The stakeholder consultation was performed at the beginning of the process for feedbacking on the framework of subjects and clinical questions addressed in the guideline, and during the commentary phase to provide feedback on the concept guideline. The list of organisations which were invited for the stakeholder consultation can be requested from the Kennisinstituut van de Federatie Medisch Specialisten (secretariaat@kennisinstituut.nl). In addition, patient information on safe use of contrast media in pregnancy and lactation was developed for Thuisarts.nl, a platform to inform patients about health and disease.
Implementatie
Implementation
During different phases of guideline development, implementation and practical enforceability of the guideline were considered. The factors that could facilitate or hinder the introduction of the guideline in clinical practice have been explicitly considered. The implementation plan can be found in the ‘Appendices to modules’. Furthermore, quality indicators were developed to enhance the implementation of the guideline. The indicators can also be found in the ‘Appendices to modules’.
Werkwijze
Methodology
AGREE
This guideline has been developed conforming to the requirements of the report of Guidelines for Medical Specialists 2.0 by the advisory committee of the Quality Counsel (www.kwaliteitskoepel.nl). This report is based on the AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II) (www.agreetrust.org), a broadly accepted instrument in the international community and based on the national quality standards for guidelines: “Guidelines for guidelines” (www.zorginstituutnederland.nl).
Identification of subject matter
During the initial phase of the guideline development, the GDG identified the relevant subject matter for the guideline. The framework is consisted of both new matters, which were not yet addressed in part 1 and 2 of the guideline, and an update of matters that were subject to modification (for example in case of new published literature). Furthermore, a stakeholder consultation was performed, where input on the framework was requested.
Clinical questions and outcomes
The outcome of the stakeholder consultation was discussed with the GDG, after which definitive clinical questions were formulated. Subsequently, the GDG formulated relevant outcome measures (both beneficial and harmful effects). The GDG rated the outcome measures as critical, important and of limited importance (GRADE method). Furthermore, where applicable, the GDG defined relevant clinical differences.
Search and select
For clinical questions, specific search strategies were formulated, and scientific articles published in several electronic databases were searched. First, the studies that potentially had the highest quality of research were reviewed. The GDG selected literature in pairs (independently of each other) based on the title and abstract. A second selection was performed by the methodological advisor based on full text. The databases used, selection criteria and number of included articles can be found in the modules, the search strategy in the appendix.
Quality assessment of individual studies
Individual studies were systematically assessed, based on methodological quality criteria that were determined prior to the search. For systematic reviews, a combination of the AMSTAR checklist and PRISMA checklist was used. For RCTs the Cochrane risk of bias tool and suggestions by the CLARITY Group at McMaster University were used, and for cohort studies/observational studies the risk of bias tool by the CLARITY Group at McMaster University was used. The risk of bias tables can be found in the separate document Appendices to modules.
Summary of literature
The relevant research findings of all selected articles were shown in evidence tables. The evidence tables can be found in the separate document Appendices to modules. The most important findings in literature were described in literature summaries. When there were enough similarities between studies, the study data were pooled.
Grading quality of evidence and strength of recommendations
The strength of the conclusions of the included studies was determined using the GRADE- method. GRADE stands for Grading Recommendations Assessment, Development and Evaluation (see http://www.gradeworkinggroup.org) (Atkins, 2004). GRADE defines four levels for the quality of scientific evidence: high, moderate, low, or very low. These levels provide information about the certainty level of the literature conclusions (http://www.guidelinedevelopment.org/handbook).
The evidence was summarized in the literature analysis, followed by one or more conclusions, drawn from the body of evidence. The level of evidence for the conclusions can be found above the conclusions. Aspects such as expertise of GDG members, local expertise, patient preferences, costs, availability of facilities and organisation of healthcare aspects are important to consider when formulating a recommendation. These aspects are discussed in the paragraph justifications. The recommendations provide an answer to the clinical question or help to increase awareness and were based on the available scientific evidence and the most relevant justifications.
Appendices
Internal (meant for use by scientific society or its members) quality indicators were developed with the guideline and can be found in the separate document Appendices to modules. In most cases, indicators were not applicable. For most questions, additional scientific research on the subject is warranted. Therefore, the GDG formulated knowledge gaps to aid in future research, which can be found in the separate document Appendices to modules.
Commentary and authorisation phase
The concept guideline was subjected to commentaries by the involved scientific societies. The list of parties that participated in the commentary phase can be requested from the Kennisinstituut van de Federatie Medisch Specialisten (secretariaat@kennisinstituut.nl). The commentaries were collected and discussed with the GDG. The feedback was used to improve the guideline; afterwards the GDG made the guideline definitive. The final version of the guideline was offered to the involved scientific societies for authorization and was authorized.
Literature
Brouwers MC, Kho ME, Browman GP, et al. AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010; 182(18): E839-E842.
Medisch Specialistische Richtlijnen 2.0. Adviescommissie Richtlijnen van de Raad Kwaliteit, 2012. Available at: [URL].
Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available at: [URL].
Schünemann HJ, Oxman AD, Brozek J, et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008;336(7653):1106- 1110. Erratum published in: BMJ 2008;336(7654).
Ontwikkeling van Medisch Specialistische Richtlijnen: stappenplan. Kennisinstituut van Medisch Specialisten, 2020.