Enhancing Patient-Reported Outcome Measures for Drug Hypersensitivity: A Validated 6-Item Quality-of-Life Questionnaire for Patients With Drug Hypersensitivity.

BACKGROUND: Drug hypersensitivity reactions (DHRs) can significantly impair patients' health-related quality of life (HRQoL). However, tools for HRQoL assessment for patients with DHR are time-consuming and remain underutilized. OBJECTIVE: To develop and validate an optimized version of the Drug Hypersensitivity Quality-of-Life Questionnaire (DrHy-Q) designed for everyday clinical use. METHODS: Item response theory (IRT), a statistical framework for psychometric measurement, was used to evaluate the 15 questions from the original DrHy-Q for their respective item difficulty, discrimination, and information using prospective data from 243 patients with histories of suspected/confirmed DHR before allergy workup. Accordingly, the best-performing items were identified to develop a 6-item optimized version (DrHy-Q6), which was subsequently validated with another prospective cohort of 156 patients. RESULTS: All 15 items of the original DrHy-Q demonstrated satisfactory parameters in IRT analysis, including very high discrimination (>1.7), appropriate difficulty (in between -1.5 and 1.5), and good information (a high and broad peak in the information curve). Six items with top-ranked IRT parameters were identified to construct an optimized version, which we named the DrHy-Q6. The DrHy-Q6 demonstrated a 1-factor structure with an improved fit compared with the original DrHy-Q (comparative fit index = 0.985, Tucker-Lewis index = 0.974), excellent convergent validity (unadjusted Pearson correlation with the full version = 0.955; adjusted = 0.894, P < .001), reliability (Cronbach's α and McDonald's ω = 0.93), divergent validity (Pearson correlation with all Short Form 12-item Health Survey Version 2 subscales <0.60, P < .001), and discriminant validity (significantly higher scores with multiple DHR labels [42.45 ± 27.26 vs 32.93 ± 26.66], P = .013). CONCLUSIONS: From an IRT perspective, the DrHy-Q and all its constituent items are psychometrically valid for HRQoL assessment. We propose an optimized 6-item version (DrHy-Q6) as an abbreviated alternative for assessing HRQoL in patients with DHR, especially for routine use in clinical practice. Patients and physicians may benefit from its streamlined length and simpler scoring algorithm.

Clinical utility of and correlation between Sniffin' Sticks and TIB smell identification test (TIBSIT) among Hong Kong Chinese with or without chronic rhinosinusitis.

Introduction: Olfactory dysfunction (OD) is common among patients with chronic rhinosinusitis (CRS). Validated and culturally specific tests, such as the "Sniffin' Sticks" test (SST) and the TIB Smell Identification Test (TIBSIT), are crucial for the diagnosis and monitoring of OD. However, they have not been utilised in Hong Kong Chinese and their correlations are unknown. Methods: Twelve CRS patients and twenty healthy volunteers were prospectively recruited from a joint allergy-otorhinolaryngology clinic in Hong Kong and performed both SST and TIBSIT. Demographics, baseline characteristics and all test results were compared and analysed. Results: Patients with CRS demonstrated significantly lower test scores than healthy controls (all p < 0.001). Significant and strong correlations were observed between all composite and subtest scores, particularly between the composite SST and TIBSIT scores (ρ = 0.789, p < 0.001). Multivariate analysis demonstrated that the presence of CRS and increasing age were significantly associated with OD. Conclusion: Both SST and TIBSIT are useful olfactory tests and are strongly correlated among Hong Kong Chinese. We advocate that either test can be used for measuring OD among CRS patients.

Hong Kong-Macau Severe Hives and Angioedema Referral Pathway.

Background: Urticaria (defined as the presence of hives, angioedema, or both) can be caused by a variety of etiologies ranging from more common conditions such as chronic spontaneous urticaria (CSU) to rarer conditions such as hereditary angioedema (HAE). Specialist referral may be necessary in cases of severe urticaria or HAE, but access to specialist services remains limited in certain regions, such as the Greater Bay Area (GBA) of China. To address this, the Hong Kong-Macau Severe Hives and Angioedema Referral Pathway (SHARP) was initiated by the Hong Kong Institute of Allergy and Macau Society of Dermatology to promote multidisciplinary collaboration and regional exchange of expertise in the diagnosis and management of severe urticaria. Methods: A nominated task force of dermatologists and immunologists who manage patients with severe urticaria formulated the consensus statements (CS) using the Delphi method. The consensus was defined a priori as an agreement of ≥80%. Results: A total of 24 CS were formulated, including four statements on classifications and definitions, seven statements on diagnosis, and 13 statements on management and referral. The definitions for acute/chronic urticaria and severe CSU were stated. Unnecessary investigations and inappropriate medications were discouraged. The characteristics and recommended approach to suspected bradykinergic angioedema were specified. Stepwise treatment options using second-generation antihistamines, omalizumab, or cyclosporin for patients with CSU were addressed, and the importance of access to HAE-specific medications was emphasized. Furthermore, an integrated referral pathway for patients with severe hives and angioedema was constructed. Conclusion: The SHARP provides guidance for the management and specialist referral of patients with severe hives and angioedema in Hong Kong and Macau.

Long-term prophylaxis for hereditary angioedema: Initial experiences with garadacimab and lanadelumab.

Background: With no approved long-term prophylaxis (LTP) for the prevention of hereditary angioedema (HAE) attacks in Hong Kong, patients rely on compassionate use programs and drug trials. Moreover, studies regarding the use and efficacy of LTP in Asia are lacking. Objectives: Our aim was to assess 2 LTP medications for HAE in Hong Kong: lanadelumab and garadacimab. Methods: A prospective study was performed. Adult patients with a diagnosis of type I or type II HAE with 1 or more expert-confirmed attacks per month were consecutively recruited. The patients had been receiving treatment for at least 6 months. Clinical data were obtained, and questionnaires were administered before treatment periodically for at least 6 months following initiation of LTP. Results: Almost one-third of the patients with HAE experienced frequent attacks and began receiving LTP (8 of the 11 received garadacimab and 3 of the 11 received lanadelumab). At baseline, the time-normalized number of HAE attacks was 2.5 plus or minus 1.3 per month. At month 6, there was an overall reduction of time-normalized number of attacks per month of -2.4 attacks per month (95% CI = -3.3 to -1.5. [P < .01]). The time-normalized number of HAE attacks at month 6 was 0.1 plus or minus 0.1 per month. More than 70% of the patients (8 of 11) were completely attack-free during the 6-month period while receiving LTP, and no patients required hospitalization. LTP improved patients' scores of the Angioedema Quality-of-Life Questionnaire (P < .001) and reduced activity impairment due to health (P = .008). Patients experienced significant improvement across all dimensions of the Treatment Satisfaction for Medication Questionnaire (54.5%-76.8% [P = .002]), and no adverse events were reported. Conclusion: The patients receiving LTP with garadacimab and lanadelumab experienced a significant reduction in number of HAE attacks and improvement in quality of life, and they were satisfied with treatment.

Prospective Assessment of Penicillin Allergy (PAPA): Evaluating the performance of penicillin allergy testing and post-delabelling outcomes among Hong Kong Chinese.

BACKGROUND: Incorrect penicillin 'allergy' labels predispose patients to adverse outcomes but are under-recognised in many Asian countries. Studies on performance and post-delabelling outcomes of penicillin allergy evaluation among Chinese remain scarce. OBJECTIVE: To evaluate the diagnostic performance of allergy testing and post-delabelling outcomes among Chinese patients in a prospective penicillin allergy cohort - Prospective Assessment of Penicillin Allergy (PAPA). METHODS: All adult patients (age ≥ 18 years) who underwent penicillin allergy evaluation between January 2020 to December 2021 were recruited and prospectively reviewed by both medical records and individual interviews at least 6 months after delabelling or allergy confirmation. RESULTS: Out of 372 patients who completed penicillin allergy evaluation, 335 (90%) patients were delabelled. The overall negative predictive value of penicillin skin testing was 95%, but lower for patients with non-immediate type reactions (88%). History of non-immediate symptom onset (OR = 4.501 [95%CI = 2.085-9.716], p < 0.001) and duration since index reaction (OR = 0.942 [95%CI = 0.899-0.987], p = 0.012) were associated with positive skin testing. After at least 6 months, 60 (18%) of de-labelled patients had received penicillins again without any adverse reactions. Fluoroquinolone-use was significantly lower among delabelled patients compared to those with penicillin allergy (38[11%] vs 11[30%], p = 0.004). CONCLUSIONS: After at least 6 months, one in six delabelled patients already received penicillins again safely, with significantly lower fluoroquinolone usage. None experienced adverse reactions. History of non-immediate onset and shorter duration since index reaction were associated with genuine allergy. In patients with severe non-immediate reactions, skin tests should be supplemented with thorough clinical history and adjunct diagnostic evaluations.

Ten-year outcomes of Perioperative Anaphylaxis Workup Study in Hong Kong (PAWS-HK): Performance of diagnostic modalities.

BACKGROUND: Studies on perioperative anaphylaxis (PA) in Asia are lacking. Furthermore, allergy workup for PA has largely been limited to the "silver standard" of skin tests (ST). Using in vitro tests as an adjunct to ST may improve and overcome these diagnostic challenges. OBJECTIVE: To evaluate the clinical characteristics and diagnostic tests of patients with suspected PA through the Perioperative Anaphylaxis Workup Study in Hong Kong cohort. METHODS: Patients with a diagnosis of PA over a 10-year period were recruited into the Perioperative Anaphylaxis Workup Study in Hong Kong. We reviewed the medical records, tryptase elevation, and diagnostic tests including ST, specific immunoglobulin E, and basophil activation tests (BAT). RESULTS: In 151 patients with PA, diagnosis was reached in three-fourths of the cases (113/151, 74.8%). The most common culprits identified were neuromuscular blocking agents (25.8%), ß lactams (17.2%) and chlorhexidine (13.9%). Severe anaphylaxis was associated with female sex, older age, elevated acute tryptase levels, and more cardiovascular manifestations during induction. Skin tests remained the most sensitive diagnostic modality overall (66.2%). BAT showed better performance for chlorhexidine and gelofusine anaphylaxis, with sensitivity of 80.0% and 79.6%, respectively. Specific Immunoglobulin E indicated even higher sensitivity (95.2%) than did ST (85.0%) and BAT (80.0%) for chlorhexidine anaphylaxis but performed poorly for other drugs. CONCLUSION: Neuromuscular blocking agents remain the most common culprit in PA. There was a higher prevalence of gelofusine anaphylaxis in our cohort than was seen in the literature. Skin tests remain the most sensitive testing modality. In vitro tests for chlorhexidine and gelofusine showed promising results, but more studies to further elucidate its use are warranted.

Comparative Effectiveness, Safety, and Real-World Outcomes of a Nurse-Led, Protocol-Driven Penicillin Allergy Evaluation From the Hong Kong Drug Allergy Delabelling Initiative (HK-DADI).

BACKGROUND: There is a high prevalence of unconfirmed penicillin allergy, which is associated with a multitude of adverse clinical outcomes. With the overwhelming burden of currently incorrect labels and the lack of allergy specialist services, new delabeling strategies are urgently needed. OBJECTIVE: To assess the effectiveness, safety, and real-world outcomes of a nurse-led, protocol-driven evaluation of penicillin allergy, the Hong Kong Drug Allergy Delabelling Initiative (HK-DADI). METHODS: Adult patients with suspected penicillin allergy were recruited into HK-DADI. Allergy and postdelabeling outcomes were retrospectively compared between patients evaluated via HK-DADI or traditional allergist evaluation. RESULTS: A total of 312 completed penicillin allergy evaluation: 84 (27%) and 228 (73%) via HK-DADI and traditional pathways, respectively. Overall, 280 penicillin allergies were delabeled (90%). The delabeling rate between HK-DADI and traditional pathways was similar (90% vs 89%; P = .796). Among patients of the HK-DADI pathway, the delabeling rate was significantly higher among low-risk (LR) compared with non-LR patients (97% vs 77%; P = .010). Skin tests did not add diagnostic value among LR patients. No patients developed severe or systemic reactions during the evaluation. Upon 6- to 12-month follow-up (median, 10 months), 123 patients experienced infective episodes (44%) and 63 used penicillins again after delabeling (23%). This proportion was significantly higher in patients who were delabeled via HK-DADI compared with the traditional pathway (32% vs 19%; P = .026). CONCLUSIONS: The Hong Kong Drug Allergy Delabelling Initiative, a nurse-led, protocol-driven evaluation, was safe and effective in penicillin allergy delabeling. It led to an even higher rate of future penicillin use after delabeling and mitigated the need for unnecessary skin testing among LR patients.

Sensitisation profile of Chinese allergic rhinitis patients and effectiveness of a joint allergy-ENT clinic.

Purpose: House dust mite (HDM) is the predominant cause of allergic rhinitis (AR) in Hong Kong but remains under-diagnosed and -treated. The association between patient-reported outcome measures (PROMs) and nasoendoscopy findings for AR have also not been investigated. This study investigated the demographics, sensitisation patterns, quality of life, use of sublingual immunotherapy and the association of PROMs and nasoendoscopy findings in AR patients through the first allergist-otorhinolaryngologists AR joint (ARJ) clinic in Hong Kong. Methods: This single-centred, retrospective observational study was conducted between January 2021 and December 2021. Clinical data from AR patients attending the ARJ clinic were analysed to identify the prevalence of HDM allergens, change in PROMs and the association of PROMs with nasoendoscopy scores. Results: The three most common sensitising HDM allergens were Dermatophagoides pterynosinus (94.4%), Dermatophagoides farinae (88.9%) and Euroglyphus maynei (88.9%). At the 13- to 32-week follow-up (median 28 weeks), patients who attended the ARJ clinic had significant improvement in Total Nasal Symptom Score (TNSS; p = 0.038). The visual analogue scale (VAS) was associated with nasoendoscopy score (p = 0.018). Patients using SLIT (sublingual immunotherapy) showed overall improvements in PROMs. Conclusion: The ARJ clinic significantly improved AR symptoms. SLIT was effective and safe for patients who failed conventional treatments. VAS positively correlated with nasoendoscopy findings. Testing for Dermatophagoides pterynosinus as a single agent during skin testing was sufficient for the diagnosis of HDM AR and should be prioritized when resources are restricted. Further studies should be done to investigate the treatment outcome of AR patients and the effectiveness of SLIT in the Chinese population. Supplementary Information: The online version of this article (10.1007/s40629-022-00218-5) contains supplementary material, which is available to authorized users.

Differences in beta-lactam and penicillin allergy: Beyond the West and focusing on Asia-Pacific.

Beta-lactam (BL) antibiotic "allergy" labels are common, but often overdiagnosed. Although much research has been focused on the BL allergy and the delabelling process in the West, studies from other parts of the world remain sparse. This review outlines the contrasting global epidemiology, shifting clinical practices and disparities of BL allergy in the Asia-Pacific region compared with the West. Innovative strategies to overcome barriers in BL allergy workup are discussed and potential directions for future research and service development are also proposed.

Hong Kong Drug Allergy Delabelling Initiative (HK-DADI) consensus statements for penicillin allergy testing by nonallergists.

Introduction: Penicillin allergy testing has been traditionally performed by allergists, but there remains a huge deficit of specialists. A multidisciplinary effort with nonallergists would be invaluable to overcome the magnitude of penicillin allergy labels via the Hong Kong Drug Allergy Delabelling Initiative (HK-DADI). These consensus statements (CSs) offer recommendations and guidance to enable nonallergists to screen for low-risk (LR) patients and perform penicillin allergy testing. Methods: CSs were formulated by the HK-DADI Group using the Delphi method. An agreement was defined as greater than or equal to 80% consensus. Results: A total of 26 CSs reached consensus after multiple rounds of Delphi. CSs were categorized into risk assessment, skin testing, drug provocation testing (DPT), and post-testing management. For risk assessment, the essentials of allergy history and exclusion criteria were detailed. Patients with only LR features can proceed with testing by nonallergists. Skin tests should be performed prior to DPT. Details regarding the timing, preparation, and interpretation of skin tests were elaborated. DPT remains the gold standard to diagnose genuine allergy or tolerance and should be performed when there is a low pretest probability following negative skin testing. Details of DPT preparations, dosing protocols, and interpretation were elaborated. For post-testing management, inaccurate allergy labels should be delabeled following negative DPT with proper patient counseling. Conclusion: CSs support penicillin allergy testing by nonallergists in Hong Kong. LR cases can be managed by nonallergists at Spoke Clinics, with training and support of an allergist-led Hub.

Prospective Study on the Efficacy and Impact of Cascade Screening and Evaluation of Hereditary Angioedema (CaSE-HAE).

BACKGROUND: Recommendations regarding family screening for hereditary angioedema (HAE) remain variable and mostly based on expert opinion. Studies evaluating its implementation and efficacy are lacking. OBJECTIVES: A novel HAE screening program was established to evaluate the efficacy and impact of cascade family screening (CFS) for at-risk relatives. METHODS: Potential HAE relatives were screened through the CFS approach. Prospective data on clinical, psychological, and HAE-related outcomes were collected at baseline and 1-year follow-up. Longitudinal outcomes were analyzed and compared between index patients and those given a diagnosis through CFS. RESULTS: Of 179 relatives, 53% were contactable, 67% of whom consented to screening. Twenty-nine patients (46%) were newly given the diagnosis of HAE; half were symptomatic at baseline (52%). There was a stronger trend toward higher diagnostic yield among first-degree families, although this did not meet statistical significance (57.6% vs 33.3%; P = .077). Among symptomatic patients, there was a higher proportion with complete annual HAE remission (15% vs 46%; P = .021) and a reduction in annual HAE-related hospital admissions (1 vs 0; P = .016) and length of stay (3 vs 2 days; P = .001) after 1 year. Among all patients, there were reduced Hospital Anxiety and Depression Scale-anxiety (14.35 ± 6.32 vs 6.47 ± 4.14; P = .001) and improved Angioedema Quality of Life scores (55% vs 35%; P < .001). By extrapolation, CFS led to a reduction of at least HK $1,200 (US $153) in HAE-related costs per patient per year. Screening using a greater than suggested C4 cutoff of 22.9 mg/dL yielded superior sensitivity (100%) and specificity (77%). CONCLUSION: Cascade family screening is an effective approach to family screening in HAE, improving clinical and psychological outcomes, and reducing disease-related costs.

Seasonal Growth of the Purple Sea Urchin Heliocidaris crassispina Revealed by Sequential Fluorochrome Tagging.

Many studies have applied fluorochrome tagging to examine the growth of animals with calcified skeletons, but most of them have used only a single tag to determine the annual growth rate. We used sequential fluorochrome tagging to study the seasonal growth of the purple sea urchin Heliocidaris crassispina in Hong Kong waters from February 2012 to February 2013. Sea urchins ranging from 18.9 to 42.7 mm in test diameter had a yearly growth from 0.6 to 13.0 mm. During that year, the sea urchins grew from 0.6 to 5.0 mm in test diameter during the first six months, and from 0.4 to 10.2 mm in test diameter in the second six months. The seasonal differences in growth were confirmed using the von Bertalanffy model. The growth was clear for young sea urchins, especially for individuals less than 5 years old, but was not evident for sea urchins older than 7 years. The seasonal differences in growth were probably related to the reproductive cycle and the seasonal differences in environmental conditions. Our empirical results provide the first evidence of seasonal changes in growth for H. crassispina, demonstrating the usefulness of sequential fluorochrome tagging in studying the growth of sea urchins in the field. We also identify the problem of low recovery of tagged individuals and provide recommendations to improve the tagging procedure.

Holobiont nitrogen control and its potential for eutrophication resistance in an obligate photosymbiotic jellyfish.

BACKGROUND: Marine holobionts depend on microbial members for health and nutrient cycling. This is particularly evident in cnidarian-algae symbioses that facilitate energy and nutrient acquisition. However, this partnership is highly sensitive to environmental change-including eutrophication-that causes dysbiosis and contributes to global coral reef decline. Yet, some holobionts exhibit resistance to dysbiosis in eutrophic environments, including the obligate photosymbiotic scyphomedusa Cassiopea xamachana. METHODS: Our aim was to assess the mechanisms in C. xamachana that stabilize symbiotic relationships. We combined labelled bicarbonate (13C) and nitrate (15N) with metabarcoding approaches to evaluate nutrient cycling and microbial community composition in symbiotic and aposymbiotic medusae. RESULTS: C-fixation and cycling by algal Symbiodiniaceae was essential for C. xamachana as even at high heterotrophic feeding rates aposymbiotic medusae continuously lost weight. Heterotrophically acquired C and N were readily shared among host and algae. This was in sharp contrast to nitrate assimilation by Symbiodiniaceae, which appeared to be strongly restricted. Instead, the bacterial microbiome seemed to play a major role in the holobiont's DIN assimilation as uptake rates showed a significant positive relationship with phylogenetic diversity of medusa-associated bacteria. This is corroborated by inferred functional capacity that links the dominant bacterial taxa (~90 %) to nitrogen cycling. Observed bacterial community structure differed between apo- and symbiotic C. xamachana putatively highlighting enrichment of ammonium oxidizers and nitrite reducers and depletion of nitrogen-fixers in symbiotic medusae. CONCLUSION: Host, algal symbionts, and bacterial associates contribute to regulated nutrient assimilation and cycling in C. xamachana. We found that the bacterial microbiome of symbiotic medusae was seemingly structured to increase DIN removal and enforce algal N-limitation-a mechanism that would help to stabilize the host-algae relationship even under eutrophic conditions. Video abstract.

Drug allergy management in the elderly.

PURPOSE OF REVIEW: Drug allergy management has previously not been emphasized in the elderly. However, the geriatric population poses several unique characteristics, challenges for drug allergy testing and considerations in the management. Especially in the era of COVID-19, the elderly population is a vulnerable cohort and reviewing the management during this unprecedented time is both timely and relevant. RECENT FINDINGS: In recent years, larger scale studies focusing on the epidemiology and prevalence trends of drug allergies among older adults has been summarized in this review. Emphasis on anaphylaxis in the older adults has been studied. SUMMARY: There are many implications of these findings. Epidemiological studies are useful in realizing the burden and spectrum of drug allergies on our healthcare system. It has allowed us to identify certain barriers in drug allergy management and develop ways to overcome these challenges through. Lastly, we have proposed an approach to drug allergy management based on previous studies as well as from our perspective and local experience.

Competitive traits of coral symbionts may alter the structure and function of the microbiome.

In the face of global warming and unprecedented coral bleaching, a new avenue of research is focused on relatively rare algal symbionts and their ability to confer thermal tolerance to their host by association. Yet, thermal tolerance is just one of many physiological attributes inherent to the diversity of symbiodinians, a result of millions of years of competition and niche partitioning. Here, we revealed that competition among cocultured symbiodinians alters nutrient assimilation and compound production with species-specific responses. For Cladocopium goreaui, a species ubiquitous within stable coral associations, temperature stress increased sensitivity to competition eliciting a shift toward investment in cell replication, i.e., putative niche exploitation. Meanwhile, competition led Durusdinium trenchii, a thermally tolerant "background" symbiodinian, to divert resources from immediate growth to storage. As such, competition may be driving the dominance of C. goreaui outside of temperature stress, the destabilization of symbioses under thermal stress, the repopulation of coral tissues by D. trenchii following bleaching, and ultimately undermine the efficacy of symbiont turnover as an adaptive mechanism.

Climate change promotes parasitism in a coral symbiosis.

Coastal oceans are increasingly eutrophic, warm and acidic through the addition of anthropogenic nitrogen and carbon, respectively. Among the most sensitive taxa to these changes are scleractinian corals, which engineer the most biodiverse ecosystems on Earth. Corals' sensitivity is a consequence of their evolutionary investment in symbiosis with the dinoflagellate alga, Symbiodinium. Together, the coral holobiont has dominated oligotrophic tropical marine habitats. However, warming destabilizes this association and reduces coral fitness. It has been theorized that, when reefs become warm and eutrophic, mutualistic Symbiodinium sequester more resources for their own growth, thus parasitizing their hosts of nutrition. Here, we tested the hypothesis that sub-bleaching temperature and excess nitrogen promotes symbiont parasitism by measuring respiration (costs) and the assimilation and translocation of both carbon (energy) and nitrogen (growth; both benefits) within Orbicella faveolata hosting one of two Symbiodinium phylotypes using a dual stable isotope tracer incubation at ambient (26 °C) and sub-bleaching (31 °C) temperatures under elevated nitrate. Warming to 31 °C reduced holobiont net primary productivity (NPP) by 60% due to increased respiration which decreased host %carbon by 15% with no apparent cost to the symbiont. Concurrently, Symbiodinium carbon and nitrogen assimilation increased by 14 and 32%, respectively while increasing their mitotic index by 15%, whereas hosts did not gain a proportional increase in translocated photosynthates. We conclude that the disparity in benefits and costs to both partners is evidence of symbiont parasitism in the coral symbiosis and has major implications for the resilience of coral reefs under threat of global change.