The patient was diagnosed in 1989, at age 27 years, with human immunodeficiency virus-1 (HIV-1) infection. He later presented with hypertension and left loin discomfort. Workup revealed proteinuria of 0.51 g over 24 hours and impaired renal function, with serum creatinine of 230 μmol/L (normal range, 59-104 μmol/L). An ultrasound scan showed bilateral shrunken kidneys with loss of corticomedullary differentiation. Renal biopsy was not performed in view of the bilateral shrunken kidneys. His renal function progressively deteriorated, and he commenced automated peritoneal dialysis in June 2017 at age 55 years. His elder brother volunteered to donate a kidney. The patient’s HIV infection was well controlled with lamivudine, abacavir, lopinavir, and ritonavir. Lopinavir/ritonavir was switched to raltegravir in view of a potential drug-drug interaction between ritonavir and calcineurin inhibitors. Pre-transplantation CD4+ count was 717 cells/μL and HIV viral load was undetectable. Human leukocyte antigen matching revealed one mismatch between donor and recipient. Both donor and recipient tested cytomegalovirus antibody positive. The recipient was started on cyclosporine, mycophenolate mofetil, and prednisolone for immunosuppression according to our centre’s protocol.

Living donor renal transplantation was successfully performed in September 2018 when the patient was 56 years old. Postoperative ultrasound of the graft kidney and radioisotope scan showed good graft perfusion and function. Valganciclovir and pentamidine inhalation were given as prophylaxis against cytomegalovirus and Pneumocystis jirovecii, respectively, in view of his underlying glucose-6-phosphatase deficiency. The lowest creatinine level since hospital discharge was 112 μmol/L. At 6 months post-transplantation, he was found to have a low level of donor-specific anti-DQ7 antibody (DSA), which persisted at repeat testing 9 months post-transplantation. Cyclosporine was therefore switched to tacrolimus to optimise immunosuppression. The tacrolimus trough level has been maintained at 5 to 8 μg/L since commencement (Fig a). Despite the presence of DSA, the patient has enjoyed stable renal function with no proteinuria; thus, renal biopsy was not performed (Fig b). In his latest follow-up, at 51 months post-transplantation, his renal function remained stable with a creatinine level of 141 μmol/L. He also has excellent HIV control with abacavir, dolutegravir, and lamivudine. CD4+ cell count has been maintained in the range of 600 to 800 cells/μL since transplantation (Fig c). He did not experience any infections after transplantation.

To the best of our knowledge, this is the first reported case of living donor renal transplantation in a patient with HIV in Hong Kong. The global prevalence of HIV is increasing, and its association with chronic kidney disease is notable. In a local cohort, 16.8% of Chinese HIV-infected patients developed chronic kidney disease.1 With the advancement of highly active antiretroviral therapy (HAART), life expectancy among people living with HIV (PLHIV) approaches that of the general population, leading to more cases of end-stage renal failure requiring management. The combination of intense immunosuppression and intrinsic immunodeficiency can expose HIV-infected transplant recipients to life-threatening opportunistic infections. It is crucial to achieve excellent HIV control before proceeding with transplantation. The American Society of Transplantation recommends that PLHIV achieve a CD4+ cell count of more than 200 cells/μL during the 3 months prior to transplantation and an undetectable HIV viral load while receiving HAART.2 Our patient met these criteria prior to transplantation.

Kidney transplantation in PLHIV has been explored in many Western countries over the past decades. In a systematic review, the 1- and 3-year patient survival rates after transplantation were reported at 97% and 94%, respectively, with graft survival at 91% and 81%.3 In another cohort study that compared 510 HIV-infected kidney transplant recipients with HIV-negative controls, comparable 5- and 10-year survival rates were reported; 5-year patient and graft survival were 88.7% and 75%, respectively. Co-infection of HIV and hepatitis C virus was an important prognostic marker for poor graft and patient survival.4 These excellent survival data encouraged us to perform the first kidney transplant in an HIV-infected patient. Despite these promising results, the rejection rate in HIV-infected recipients is significantly higher, up to 2- to 3-fold, potentially due to drug-drug interactions between HAART and immunosuppressants or immune dysregulation.5 6 The pathophysiology behind this increased rejection rate is unclear, but strategies such as induction therapy with anti-interleukin-2 receptor antibody or antithymocyte globulin and optimised immunosuppressive therapy are utilised to mitigate risks. Nonetheless, the use of antithymocyte globulin is controversial due to its association with marked CD4+ cell suppression (ie, <200 cells/μL), prolonged recovery, and subsequent infection risk.7 Therefore, antithymocyte globulin induction should be reserved for HIV-infected recipients with very high immunological risk.

The optimal immunosuppression regimen for HIV-infected recipients is yet to be determined. Tacrolimus is favoured over cyclosporine for reducing acute rejection risks.8 Observational studies and the landmark ELITE-Symphony trial suggest lower rejection rates with tacrolimus, up to 2-fold.6 8 Our centre initially chose cyclosporine due to the patient’s low immunological risk profile with only one human leukocyte antigen mismatch but switched to tacrolimus after the development of DSA 6 months post-transplantation. This case highlights the challenges of balancing overimmunosuppression and rejection risks in HIV-infected recipients. Ongoing evidence supports the use of tacrolimus as the first-line immunosuppressive agent, irrespective of immunological risk, with future randomised controlled trials needed to establish the best regimen.

Managing drug-drug interactions in HIV-infected transplant recipients is complex. Non-nucleoside reverse transcriptase inhibitors induce cytochrome P450 enzymes, while protease inhibitors significantly inhibit these enzymes, notably raising calcineurin inhibitor levels in the plasma. Ritonavir, a strong CYP3A4 inhibitor commonly used in HAART, requires a substantial increase in tacrolimus dosage up to 70-fold upon its discontinuation to maintain effective immunosuppression.9 To avoid drug-drug interactions, our patient was switched to an integrase strand transfer inhibitor-based HAART regimen prior to transplantation. Nonetheless, there was a risk of serum creatinine elevation. Dolutegravir has been shown to inhibit organic cation transporter 2, which inhibits active creatinine secretion into renal tubules, leading to a slight elevation in serum creatinine level without affecting the glomerular filtration rate. After administering dolutegravir, serum creatinine clearance in healthy subjects has been reported to decrease by 10% to 14%.10

In conclusion, renal transplantation in PLHIV can offer improved quality of life and survival compared with continued dialysis, provided there is excellent HIV control and careful management of immunosuppression and drug-drug interactions. Challenges remain in preventing and treating acute rejection to improve long-term graft survival. We observed an early appearance of DSA 6 months post-transplantation in our patient. Although the DSA was transiently suppressed after switching to tacrolimus, it reappeared later. The appearance of DSA and its potential long-term impact on graft survival require further investigation. Our experience, alongside data from Western cohorts, supports expanding renal transplantation among HIV-infected patients, with a focus on tailored immunosuppressive strategies and management of complications.

All authors contributed to the concept or design of the study, acquisition of the data, analysis or interpretation of the data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This case has been presented during oral presentation at the 18th Congress of The Asian Society of Transplantation (CAST) in Hong Kong SAR, China, 25-28 July 2023.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patient was treated in accordance with the Declaration of Helsinki and provided informed consent for all procedures.

1. Cheung CY, Wong KM, Lee MP et al. Prevalence of chronic kidney disease in Chinese HIV-infected patients. Nephrol Dial Transplant 2007;22:3186-90. Crossref

2. Blumberg EA, Rogers CC; American Society of Transplantation Infectious Diseases Community of Practice. Solid organ transplantation in the HIV-infected patients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Cli Transplant 2019;33:e13499. Crossref

3. Zheng X, Gong L, Xue W, et al. Kidney transplant outcomes in HIV-positive patients: a systematic review and meta-analysis. AIDS Res Ther 2019;16:37. Crossref

4. Locke JE, Mehta S, Reed RD, et al. A national study of outcomes among HIV-infected kidney transplant recipients. J Am Soc Nephrol 2015;26:2222-9. Crossref

5. Stock PG, Barin B, Murphy B, et al. Outcomes of kidney transplantation in HIV-infected recipients. N Engl J Med 2010;363:2004-14. Crossref

6. Gathogo E, Harber M, Bhagani S, et al. Impact of tacrolimus compared with cyclosporin on the incidence of acute allograft rejection in Human Immunodeficiency virus-positive kidney transplant recipients. Transplantation 2016;100:871-8. Crossref

7. Carter JT, Melcher ML, Carlson LL, Roland ME, Stock PG. Thymoglobulin-associated Cd4+ T-cell depletion and infection risk in HIV-infected renal transplant recipients. Am J Transplant 2006;6:753-60. Crossref

8. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007;357:2562-75. Crossref

9. Jimenez HR, Natali KM, Zahran AA. Drug interaction after ritonavir discontinuation: considerations for antiretroviral therapy changes in renal transplant recipients. Int J STD AIDS 2019;30:710-4. Crossref

10. Koteff J, Borland J, Chen S, et al. A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para-aminohippurate clearance in healthy subjects. Br J Cli Pharmacol 2013;75:990-6. Crossref

A 37-year-old male attended for evaluation of an interventricular septal (IVS) mass incidentally discovered during a routine physical examination. On admission he was hypertensive at 153/85 mm Hg) with heart rate 93 bpm. Electrocardiogram findings revealed occasional premature ventricular contractions with horizontal ST-segment depression and T-wave inversion, suggestive of myocardial ischaemia. Laboratory results were normal. Transthoracic echocardiography (TTE) identified a well-defined, ovoid mass within the inferior segment of the IVS, appearing as a complex solid-cystic mass lesion. The mass measured approximately 35 × 31 × 40 mm³ (anteroposterior × transverse × longitudinal) [Fig 1a]. The left ventricular apical cavity was compressed by the mass. Colour Doppler imaging showed blood flow within the lesion, with diastole filling and systole outflow (Fig 1b). Notably, the cystic cavity exhibited minimal changes during the cardiac cycle. Continuous-wave Doppler at the lesion (Fig 1c) revealed bidirectional blood flow across systole and diastole. Tracking revealed a 4.3-mm dilated coronary artery branch at the heart’s apex as the flow’s source, with no proximal stenosis or dilation in the coronary arteries. Contrast TTE (cTTE) detected a small (1-2 mm) left anterior descending (LAD) artery fistula within the IVS, with delayed cystic enhancement relative to the left ventricle but simultaneous with the IVS myocardium post-contrast, and no infiltration of the solid component (Fig 1d-e, SV1). These findings indicated the presence of a coronary artery fistula originating from the LAD artery that drains into an IVS forming a dissecting aneurysm.

Coronary computed tomography angiography showed no proximal left coronary artery dilation but mild distal dilation. The aneurysm showed significant enhancement and slight calcification, with no enhancement observed in the surrounding myocardium (Fig 1f). Cardiac magnetic resonance confirmed the findings, showing the mass with slightly high T1-weighted and predominantly high T2-weighted signal intensities, encircled by a low-signal intensity ring, with no significant myocardial enhancement post-contrast (Fig 1).

The patient underwent surgical correction of the coronary artery fistula and reduction of the dissecting aneurysm of the interventricular septum (DAIS). Intraoperatively, the LAD was observed penetrating the myocardium, forming a sac-like cavity due to the convergence of the coronary fistula into the myocardial layer of the IVS. Histopathology from a myocardial biopsy showed fibrosis (Fig 2a-d). At 3-month postoperative follow-up, TTE showed a reduced IVS cystic cavity (Fig 2e), and cTTE confirmed fistula closure with no contrast entering the cavity (Fig 2f).

Cardiac space-occupying lesions include tumours and non-neoplastic conditions, occurring anywhere in the heart.1 Dissecting aneurysm of the interventricular septum often results from a ruptured Valsalva aneurysm, myocardial infarction, or trauma.2 Aneurysms within the IVS caused by congenital coronary artery fistulas are rare, with only a few reported cases.3 4 5 These cases often present with marked dilation of the involved coronary artery trunk and dynamic fluctuations in the cystic cavity dimensions throughout the cardiac cycle. The cavity typically expands during diastole and contracts during systole.

In this case, the absence of dilation in the main trunk of the coronary artery could be attributed to the fistula’s origin from a small branch of the LAD artery, with a narrow internal diameter and minimal shunting volume. As the patient was young, the coronary arteries exhibited greater elasticity, leading to a reduced propensity for dilation in the main trunk.

In this case, the cystic cavity in the IVS showed minimal size change throughout the cardiac cycle due to a blind-ending coronary artery fistula that prevented left ventricular communication. Chronic shunting from the coronary artery fistula led to the gradual enlargement of a dissecting aneurysm within the interventricular septum, compressing adjacent myocardium and branches of the coronary arteries. This compression resulted in localised myocardial ischaemia and subsequent myocardial fibrosis, as demonstrated by both the patient’s electrocardiogram and pathological findings. The fibrosis and high-velocity flow at the fistula site contributed to myocardial thickening and reduced elasticity, impairing the cavity’s expansion and contraction, and resulting in minimal size variation.

Transthoracic echocardiography is often the initial imaging choice for coronary artery fistulas into the IVS, providing critical haemodynamic and anatomical data, but its limitations may result in misdiagnosis. Coronary computed tomography angiography and cardiac magnetic resonance provide detailed assessments of coronary anatomy and myocardial fibrosis, complementing TTE. Coronary computed tomography angiography provides diagnostic clarity with the caveat of radiation exposure, especially for repeated scans. Cardiac magnetic resonance, while valuable for its soft tissue characterisation, presents cost considerations for patients. Contrast TTE, valued for its safety, cost-effectiveness, and timeliness, excels in visualising myocardial perfusion and detecting congenital cardiac defects, enhancing diagnostic precision when TTE results are indeterminate. In our case, cTTE, with its high sensitivity to blood flow signals, rapidly delineated the shunt and accurately mapped the fistula. The contrast agent, perfusing the myocardium via the coronary arteries, resulted in delayed opacification of the interventricular septum compared with the left ventricle, thereby disclosing DAIS. This comprehensive diagnostic profiling was pivotal for tailored treatment strategies and prognostic enhancement. This marks the first instance, to our knowledge, where cTTE has been utilised to diagnose DAIS.

Concept or design: D Xie, G Yang, C Li.
Acquisition of data: D Xie, C Li, H Li, X Hao, Y Zhang.
Analysis or interpretation of data: D Xie, H Li, X Hao, Y Zhang, M Xie, Y Xu.
Drafting of the manuscript: D Xie, G Yang, Y Xu.
Critical revision of the manuscript for important intellectual content: D Xie, G Yang, C Li, Y Xu.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

The authors declared no conflicts of interest.

The authors thank Prof Yunhua Gao who provided guidance and assistance in the diagnosis.

This study was supported by the Individualized Training Program for Key Supported Talents, part of the Excellent Talents Database at the Army Medical University (Grant No.: 2019R038).

The patient was treated in accordance with the Declaration of Helsinki. The patient provided written consent for publication of this case report.

1. Maleszewski JJ, Anavekar NS, Moynihan TJ, Klarich KW. Pathology, imaging, and treatment of cardiac tumours. Nat Rev Cardiol 2017;14:536-49. Crossref

2. Zhang JP, Meng H, Wang H. Dissecting aneurysm of the interatrial and interventricular septum with concomitant ventricular septal defect-multimodality cardiac imaging and surgical repair. Echocardiography 2016;33:932-5. Crossref

3. Zhi Ku L, Xia J, Lv H, Song LC, Ma XJ. Giant interventricular septal dissecting aneurysm resulting from congenital coronary fistula. Circ Cardiovasc Imaging 2022;15:e013861. Crossref

4. Wu Q, Jin Y, Zhou L, Liu Y, Wu D. A dissecting aneurysm of interventricular septum resulting from congenital coronary artery fistula. J Clin Ultrasound 2019;47:55-8. Crossref

5. Tekinhatun M, Cihan F, Demir M. Interventricular septal dissecting aneurysm resulting from congenital coronary fistula: a case report. Echocardiography 2023;40:1140-3. Crossref

A 56-year-old man was presented to the emergency department of our institution in June 2023 and has had been followed up in our medical clinic for 1 year prior to his current hospital admission. He had been diagnosed with frequent symptomatic premature ventricular complexes with an ectopic burden of 8.2% on extended ambulatory rhythm monitoring. There were also multiple recorded episodes of non-sustained ventricular tachycardia. Beta-blocker was initiated and uptitrated according to clinical symptoms. His family history was remarkable for the sudden cardiac death of his father at the age of 64 years. Subsequent transthoracic echocardiogram of the patient revealed a global hypokinetic left ventricle with a biplane-measured left ventricular ejection fraction (LVEF) of 45%. There was mild left atrial enlargement with a two-dimensional area of 25.7 cm² but no other structural abnormalities. Computed tomography coronary angiogram showed mild to moderate coronary artery disease in three vessels and guideline-directed medical treatment was initiated. Cardiac magnetic resonance imaging (CMR) was scheduled to assess cardiac structures and function, as well as tissue characterisation for features of non-ischaemic cardiomyopathy. He had been scheduled to undergo catheter ablation for frequent symptomatic premature ventricular complexes.

The patient presented to our emergency department with out-of-hospital cardiac arrest. He had been found collapsed adjacent to a swimming pool and a bystander had initiated cardiopulmonary resuscitation. Spontaneous circulation was restored shortly after a single defibrillation delivered by an automated external defibrillator and he was transferred to our hospital immediately. On arrival at the emergency department, he was hemodynamically stable with a Glasgow Coma Scale score of 15. High-sensitive troponin I level was elevated at 44.9 ng/L. Electrocardiogram showed sinus rhythm of 71 beats/min with occasional premature ventricular complexes. There was no ST-segment elevation or significant conduction abnormalities. Bedside echocardiogram showed a similar biplane-measured LVEF of 43% with global hypokinesia. Urgent coronary angiogram showed non-occlusive moderate to severe coronary artery disease in three vessels. Given his current presentation, together with angiographic progression in coronary artery disease, complete revascularisation was performed uneventfully. He was then transferred to our cardiac care unit postoperatively for close monitoring. Inpatient CMR revealed a non-dilated left ventricle with mildly reduced LVEF of 43% with global hypokinesia. There was multifocal patchy mid-wall and subepicardial late gadolinium enhancement (LGE) at the mid-ventricular anterior, anteroseptal and anterolateral walls, as well as basal to mid-ventricular inferior and inferolateral walls (Fig 1). There was no evidence of myocardial infarct. Parametric mapping showed a mild increase in myocardial T1 with values up to 1067 ms to 1080 ms (native T1 values in healthy subjects obtained in our Aera 1.5T magnetic resonance imaging scanner [Siemens, Munich, Germany] is 996±26 ms for males), suggestive of mild diffuse interstitial fibrosis (Fig 2). Prior to hospital discharge, a transvenous implantable cardioverter defibrillator (ICD) was implanted for secondary prevention. Subsequent genetic testing identified a heterozygous pathogenic truncating variant NM_001458.5(FLNC):c.3279del p.(Gly1094Alafs^*4) in the filamin-C gene. The final clinical diagnosis was sudden cardiac arrest secondary to filamin-C variant–associated cardiomyopathy in a patient with non-dilated left ventricular cardiomyopathy (NDLVC) and mid-range ejection fraction.

The filamin-C gene encodes the filamin-C protein that plays essential roles in the sarcomere stability in cardiac muscles. Filamin-C variants have been increasingly recognised as an important cause of cardiomyopathy. It has been identified in approximately 3% to 4% of patients with dilated cardiomyopathy and commonly presents in early-to-mid adulthood with high arrhythmic risks.1

According to the 2021 European Society of Cardiology (ESC) Guidelines for the diagnosis and treatment of acute and chronic heart failure,2 primary prevention ICD is indicated in patients with symptomatic heart failure with an LVEF ≤35% despite optimal medical treatment and a reasonable quality of life. Such recommendation is supported by numerous landmark trials including MADIT (Multicenter Automatic Defibrillator Implantation Trial),3 DEFINITE (DEFibrillators In Non-Ischemic Cardiomyopathy Treatment Evaluation),4 and SCD-HeFT (the Sudden Cardiac Death in Heart Failure Trial).5 In addition, several additional clinical risk factors should also be considered in sudden cardiac death risk assessment, especially in patients with non-ischaemic cardiomyopathy.2 These risk factors include significant LGE on CMR, younger age, and specific genotypes. Nonetheless these recommendations are ambiguous, and the guideline has not defined, for example, the burden of LGE and variant mechanisms in several high-risk genes that would warrant ICD implantation. Moreover, there are limited recommendations for primary prevention ICD in patients with heart failure with mid-range or preserved ejection fraction.

In the updated 2023 ESC Guidelines for the management of cardiomyopathies,6 a new entity of NDLVC is introduced. An algorithm for consideration of primary prevention ICD similar to that for patients with dilated cardiomyopathy is recommended in this patient population. Patient genotype and imaging features on CMR have been proposed in the early sudden cardiac death risk assessment for patients with NDLVC. A previous study has demonstrated a higher rate of malignant arrhythmic events in patients who are genotype-positive, compared with their genotype-negative counterparts.7 Such association has been observed irrespective of LVEF. Variants in certain genes including lamin A/C, phospholamban, filamin-C, RNA-binding motif protein 20, desmoplakin and plakophilin-2 are associated with a high risk of malignant ventricular arrhythmias and sudden cardiac death. Apart from genotype information, the presence and distribution of LGE on CMR, such as a ring-like pattern of LGE, has also been shown to be a strong risk marker for ventricular arrhythmias.8 Hence, based on the current ESC Guidelines,6 primary prevention ICD should be considered in patients with NDLVC and high-risk genotype and in the presence of additional risk factors such as syncope and LGE on CMR, irrespective of LVEF.

Our case highlights the need to incorporate a patient’s genotype and imaging features on CMR into the personalised risk assessment for sudden cardiac death in patients with NDLVC. This will facilitate a more comprehensive and informative discussion about the indication for primary prevention ICD and improve the clinical outcome for patients with cardiomyopathy.

Concept or design: KWC Lun, DPH Lee.
Acquisition of data: All authors.
Analysis or interpretation of data: KWC Lun, DPH Lee.
Drafting of the manuscript: KWC Lun, DPH Lee.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patient was treated in accordance with the Declaration of Helsinki. The patient provided consent for all treatments and procedures, and consent for publication of the case report.

1. Agarwal R, Paulo JA, Toepfer CN, et al. Filamin C cardiomyopathy variants cause protein and lysosome accumulation. Circ Res 2021;129:751-66. Crossref

2. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599-726. Crossref

3. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877-83. Crossref

4. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004;350:2151-8. Crossref

5. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225-37. Crossref

6. Arbelo E, Protonotarios A, Gimeno JR, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J 2023;44:3503-626. Crossref

7. Escobar-Lopez L, Ochoa JP, Mirelis JG, et al. Association of genetic variants with outcomes in patients with nonischemic dilated cardiomyopathy. J Am Coll Cardiol 2021;78:1682-99. Crossref

8. Meier C, Eisenblätter M, Gielen S. Myocardial late gadolinium enhancement (LGE) in cardiac magnetic resonance imaging (CMR)—an important risk marker for cardiac disease. J Cardiovasc Dev Dis 2024;11:40. Crossref

Twenty-four–hour pH monitoring is indicated for evaluation of gastroesophageal reflux symptoms in children, as well as part of a preoperative work-up for those who require long-term nasogastric tube feeding or a gastrostomy. Its use is nonetheless restricted by the need to keep a nasal catheter in place for at least 24 hours. This can cause great discomfort and may be poorly tolerated by children, especially those with behavioural issues. Wireless pH monitoring can improve patient satisfaction and the overall sensitivity of diagnosing gastroesophageal reflux (Fig 1). Despite its rising popularity among adults, its use has been limited in children. This report documents the first experience in Hong Kong of a wireless oesophageal pH monitoring system in children with gastrointestinal symptoms and feeding problems.

A 9-year-old girl with good previous health and normal development presented to a surgical clinic in March 2023 with recurrent epigastric pain and heartburn. She was prescribed a proton pump inhibitor without symptom improvement. As her parents were keen to determine the cause of her symptoms, upper endoscopy and a pH study were offered. With consideration of patient comfort and the sensitivity of the test, wireless oesophageal pH monitoring was arranged. Endoscopy under general anaesthetic revealed mild antral gastritis but was otherwise unremarkable. An antral biopsy confirmed mild gastritis without Helicobacter pylori. The oesophagogastric junction (OGJ) was measured as 34 cm from the incisor, and a wireless pH monitoring capsule (Bravo; Medtronic Inc, Minneapolis [MN], United States) was inserted at 30 cm under direct endoscopic visualisation (Fig 2a). Post-insertion endoscopy confirmed secure placement at a satisfactory position (Fig 2b). An X-ray after the procedure further confirmed the good position of the capsule (Fig 2c). pH monitoring lasted 96 hours, with a DeMeester score of 6.8. The girl initially complained of mild chest discomfort and a globus sensation during swallowing on the first 2 days post procedure but this resolved spontaneously after 4 days. The capsule passed spontaneously within 3 weeks of the procedure. The diagnosis of gastritis was made after excluding gastroesophageal reflux by pH monitoring; the patient was prescribed a short course of a proton pump inhibitor that resolved the symptoms.

A 6-year-old girl with known glucose phosphate isomerase deficiency, cerebral ataxia and mild intellectual impairment presented to the same surgical clinic in January 2023. She had feeding problems with failure to thrive and needed supplemental milk feeding via a nasogastric tube. Given her medical background and neurodevelopment, she could not tolerate nasogastric tube insertion during her regular revision and required frequent sedation during the procedure. Owing to the anticipated requirement for long-term tube feeding, her parents were advised of the need for gastrostomy tube insertion and a preoperative pH study. As both the patient and parents could not accept a conventional 24-hour pH study, a wireless oesophageal pH monitoring system was inserted under monitored anaesthetic care. The upper endoscopy was unremarkable with no sign of oesophagitis or gastritis. Bravo was inserted at 25 cm from the incisor (ie, 5 cm from the OGJ). Monitoring continued for 96 hours, with a DeMeester score of 0.7. The capsule passed without any complications within 3 weeks of the procedure. The patient was well and there were no adverse events during the study period. In view of the negative pH study, an anti-reflux procedure was deemed unnecessary and subsequently only a laparoscopic gastrostomy was performed.

A 16-year-old boy with recurrent postprandial heartburn and vomiting presented to the same surgical clinic in March 2024. Medical treatment with proton pump inhibitors elicited no improvement and he was referred for work-up for an anti-reflux procedure. At the time of referral, as capsule pH monitoring was not available locally, a catheter-based 24-hour pH-impedance probe was attempted. Nonetheless the patient could not tolerate the procedure with repeated vomiting and failure of catheter insertion. Given the parents’ wish to have a definitive diagnosis prior to initiating an anti-reflux procedure, pH study was rearranged with the wireless oesophageal pH monitoring system under monitored anaesthesia care. The procedure was well tolerated and the patient was able to complete a 96-hour pH study. The overall DeMeester score was 16.1. During the study period, Day 2 was the patient’s worst day, with acid exposure time at 5.9% and DeMeester score at 22.1. There was significant improvement following resumption of a proton pump inhibitor on Day 3 with acid exposure time at 1% and DeMeester score at 3.5. With the diagnosis of significant gastroesophageal reflux disease confirmed, the parents agreed to proceed with laparoscopic fundoplication.

According to the joint updated guidelines of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition in 2018,1 24-hour pH monitoring is indicated in children with persistent symptoms of gastroesophageal reflux disease despite proton pump inhibitor treatment. The aim is to correlate persistent troublesome symptoms with acid gastroesophageal reflux events, clarifying the role of acid reflux and determining the efficacy of acid suppression therapy.1 Twenty-four–hour pH monitoring is also recommended as pre-gastrostomy work-up in children to guide patient selection for a concomitant anti-reflux procedure.2 Nonetheless conventional transnasal catheter pH monitoring, although still widely used, is frequently criticised for causing great patient discomfort, limiting the patient’s mobility during the test and, more importantly, being neither tolerable nor inducing compliance by children with neurodevelopmental and behavioural issues,3 as illustrated by Case 2. Not only is the quality of life of patients jeopardised, the unpleasant experience may also restrict reflux-provoking activities, limiting the accuracy and sensitivity of the test and yielding false lower values, as illustrated by Case 3.

To overcome these difficulties, the wireless oesophageal pH monitoring system uses a capsule attached to the mucosal wall of the oesophagus for pH monitoring (Fig 1). It consists of a 6.0×6.3×26.0 mm³ capsule-based device, equipped with an internal battery and a pH electrode. The device is attached to the distal wall of the oesophagus, approximately 4 to 6 cm from the OGJ, under direct endoscopic visualisation.3 4 It transmits pH data to a mobile phone–sized recorder via radio telemetry, thus obviating the need for a transnasal pH probe. The capsule enables data to be recorded for at least 48 hours and up to 96 hours, with minimal patient discomfort. The capsule detaches from the oesophageal mucosa and is expelled in stools, with spontaneous sloughing of the oesophageal mucosa and uneventful healing, usually over 3 to 7 days. Its clinical use in children has been established in the United Kingdom and the United States, demonstrating a high success rate, with better tolerance than standard transnasal pH monitoring in children with behavioural issues and an improvement in the detection rate of gastroesophageal reflux disease by 16% through extended recording time.3 4 As illustrated by Case 3, not only is the procedure tolerated, the successful extension of study for a duration of 96 hours may result in a higher diagnostic yield and provision of more information, eg, effect of pump on and off (whether patient was on proton pump inhibitor).5 Currently, the wireless pH monitoring system is intended to be used in adults and children from 4 years of age but is contraindicated in those with bleeding diathesis, strictures, severe oesophagitis, varices, obstructions, pacemakers or implantable cardiac defibrillators. In situations where the wireless pH capsule needs to be removed, for instance in patients with severe discomfort or failure of spontaneous passage, cold snare and hot snare (when cold snare is not sufficient) can be applied to safely remove the capsule with only thin superficial oesophageal mucosal tissue.6

To the best of our knowledge, our centre is the first to introduce and report the use of the wireless oesophageal pH monitoring system in children in Hong Kong. The procedure was smooth, with no equipment or technical failure, and all patients could be discharged on the same day of the procedure. Since Case 1 was the first patient at our centre to receive the device, a chest X-ray was taken to double confirm its position. Nonetheless a post-procedure chest X-ray is not routine for the paediatric population since the device position can be confirmed with endoscopy, as in the adult population. All patients tolerated the pH study well except for the complaint of a self-limiting globus sensation in one patient (Case 1). All parents reported no difficulty in utilising the mobile pH recording system. All capsules were expelled from the patients within 3 weeks of the procedure without any complication.

Wireless oesophageal pH monitoring cannot easily diagnose some conditions such as functional belching and rumination syndrome due to the lack of impedance monitoring. Nonetheless these cases highlight that it is well tolerated and feasible in evaluating gastroesophageal reflux symptoms in children and provides a sensible alternative to standard transnasal pH monitoring. In addition, it may result in a higher diagnostic yield and more comprehensive clinical information. As clinicians, we are obliged to keep track of technological advancements and strive to provide holistic and optimal care for children, improve patient satisfaction and shorten their hospital stay.

Both authors contributed to the concept or design, acquisition of data, analysis or interpretation of data, drafting of the manuscript and critical revision of the manuscript for important intellectual content. Both authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

As an editor of the journal, KKY Wong was not involved in the peer review process. The other author has disclosed no conflicts of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patients were treated in accordance with the Declaration of Helsinki. Verbal consent was obtained from the patients for the publication of the case reports.

1. Rosen R, Vandenplas Y, Singendonk M, et al. Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2018;66:516-54. Crossref

2. Fung AC, Ooi YN, Hui HM, Mok MK, Chung PH, Wong KK. Prophylactic anti-reflux procedure for children undergoing laparoscopic gastrostomy: rethinking of the routine practice. World J Surg 2024;48:739-45. Crossref

3. Rodriguez L, Morley-Fletcher A, Winter H, Timothy B. Evaluation of gastroesophageal reflux disease in children on the autism spectrum: a study evaluating the tolerance and utility of the BRAVO wireless pH monitoring. J Pediatr Gastroenterol Nutr 2022;75:450-4. Crossref

4. Rao NM, Campbell DI, Rao P. Two years’ experience of using the Bravo wireless oesophageal pH monitoring system at a single UK tertiary centre. Acta Paediatr 2017;106:312-5. Crossref

5. Zeki SS, Miah I, Visaggi P, et al. Extended wireless pH monitoring significantly increases gastroesophageal reflux disease diagnoses in patients with a normal pH impedance study. J Neurogastroenterol Motil 2023;29:335-42. Crossref

6. de Hoyos A, Esparza EA, Loredo ML. Cold and hot snare endoscopic techniques for removal of the Bravo pH monitoring capsule. Digestion 2009;79:14-6. Crossref

Two Chinese girls (22 months and 26 months of age [Case 1 and Case 2, respectively]) presented in August 2021 and November 2021 with progressive bowing of the lower limbs since infancy. Neither had any significant family history. Physical examination revealed rachitic deformity, waddling gait, and short stature. Further investigations showed hypophosphataemia, isolated hyperphosphaturia and a high serum alkaline phosphatase (ALP) level with normal serum calcium, 25(OH) vitamin D, and parathyroid hormone levels. Characteristic clinical and radiographical findings suggestive of hypophosphataemic rickets were also evident (Fig). Molecular testing confirmed a diagnosis of X-linked hypophosphataemia (XLH) with heterozygous pathogenic PHEX (phosphate-regulating endopeptidase homologue on the X chromosome) variants detected in both patients [Case 1: c.2104C>T, p.(Arg702); Case 2: (c.1699c>T) (Arg567)]. Neither set of parents was affected. Both girls were commenced on conventional treatment with phosphate solution and alfacalcidol for around 3 months with only fair improvement. They were then started on burosumab at a starting dose of 0.8 mg/kg every 2 weeks, titrated up to 2 mg/kg (20 mg) 4 months later based on fasting serum phosphate level. Despite maximum doses of burosumab, serum phosphate level remained slightly below the normal range for both patients. Nevertheless there was ongoing clinical improvement in ALP level, the ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate, growth velocity, and healing of rickets in both patients. After burosumab treatment for 24 months, both patients had significant clinical, biochemical, and radiological improvement (Table and Fig). They were followed up by the multidisciplinary team at the Hong Kong Children’s Hospital. No treatment-related adverse reactions or disease-related complications (including skull deformities, dental abscess, and hearing problem) were observed.

X-linked hypophosphataemia is the most common cause of genetic rickets, with a prevalence of 1:20 000 to 1:60 000.1 2 It is caused by mutations in the PHEX gene and results in an increased level of the fibroblast growth factor 23 (FGF-23) hormone. This leads to impaired renal reabsorption of phosphate, low serum 1,25-dihydroxyvitamin D concentration, and reduced intestinal phosphate absorption, and ultimately, chronic hypophosphataemia. Patients typically present in early childhood with signs and symptoms of rickets and osteomalacia, progressive bowing deformities of the lower limbs, bone pain and stunted growth, as in our patients.

X-linked hypophosphataemia is conventionally treated with oral phosphate and active vitamin D analogues but this does not address the underlying pathogenesis and may only partially correct the biochemical derangement and skeletal deformities. Patients often require repeated orthopaedic procedures, eg, hemiepiphysiodesis or even multiple corrective osteotomies to maintain the mechanical axis of the lower limbs. Surgical correction is fraught with technical difficulties due to osteomalacia and there are high rates of recurrence. Moreover, conventional treatment is associated with long-term side-effects such as hyperparathyroidism and nephrocalcinosis.

Burosumab, a monoclonal antibody to FGF-23 for XLH treatment, was approved by the United States Food and Drug Administration3 and the European Medicines Agency4 in 2018. Subsequently, a phase III trial to evaluate 61 children with XLH aged 1 to 12 years for 64 weeks5 and another trial evaluating children with XLH aged 5 to 12 years for 160 weeks6 further supported its safety and effectiveness in terms of improved total Rickets Severity Score and fasting serum phosphate level. These outcomes were also measured in our patients and similar improvements observed. With the approval of burosumab, there has been a paradigm shift in the treatment of XLH in Western countries. Nevertheless conventional treatment continues to be the norm in most parts of our region—partly attributed to the high cost of burosumab, and partly due to the lack of published regional experience with burosumab in the clinical setting.

In our patients, the dose of burosumab was titrated up slowly to the maximum dose based on age-specific fasting phosphate level, as per various clinical practice recommendations.7 8 With the maximum dose, fasting serum phosphate level improved but failed to reach that of the age-specific normal range. Other secondary causes including vitamin D deficiency and hyperparathyroidism were excluded. Nevertheless improvement in other clinical parameters including serum ALP level, the ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate, growth velocity, and clinical and radiological evidence of rickets healing were observed. We have maintained our two patients on the same dose with ongoing clinical improvements observed. This is consistent with the recently published opinion based on early experience in seven European countries, recommending that a serum phosphate concentration below the age- and sex-specific range may be acceptable and the same maintenance dose continued as improvements in other clinical parameters are maintained.9 This is based largely on expert opinion with no data on the proportion of patients who do not achieve a normalised phosphate level and no comparison of clinical outcomes.

X-linked hypophosphataemia is a rare, genetic multisystem disease. In addition to the skeletal manifestations, around two-thirds of affected individuals have associated dental and periodontal issues, such as spontaneous periapical abscesses, related to poor dentin mineralisation.10 Some patients also have other complications including craniosynostosis and impaired hearing. Consequently, most guidelines recommend a multidisciplinary approach for this group of patients.7 8 Despite treatment with burosumab, some complications cannot be mitigated. Dental abscess, a well-known complication in patients with XLH, has not been consistently shown to be ameliorated by burosumab treatment. In the phase 3 burosumab trial,5 dental abscess was observed at a higher rate in the treatment group than the control arm. This implies that the pathophysiology of dental abscess is not mediated only by the FGF-23 pathway. This highlights the importance of a multidisciplinary approach to the management of XLH, as recommended by recent international clinical practice guidelines7 and regional consensus statements.8 At the Hong Kong Children’s Hospital, this group of patients is seen in the multidisciplinary bone clinic with input from a paediatric endocrinologist, orthopaedic surgeon, geneticist, dental surgeon, radiologist, and case manager (nurse practitioner). This orchestrated, coordinated multidisciplinary care is particularly important to maximise the effect and overall clinical outcome of burosumab treatment that remains remarkably expensive.

To the best of our knowledge, this is the first report of real-world experience of XLH treated with burosumab outside clinical trials in Asia. The target of a normal phosphate level may not be achievable in practice, and treatment response should also be guided by other clinical parameters. Further research into factors that affect the biochemical outcome and the clinical response of groups with different biochemical outcome is needed. A multidisciplinary approach should be adopted in the care of children with XLH.

Concept or design: JYL Tung.
Acquisition of data: JYL Tung.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: JYL Tung.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

Preliminary results for these two cases were presented as a poster at the 12th Asia Pacific Paediatric Endocrine Society Biennial Scientific Meeting 2022 (South Korea, 5-8 October 2022).

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patients were treated in accordance with the Declaration of Helsinki. Consent for all treatments, procedures, and consent for publication was obtained from parents of the patients.

1. Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur J Endocrinol 2009;160:491-7. Crossref

2. Rafaelsen S, Johansson S, Ræder H, Bjerknes R. Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications. Eur J Endocrinol 2016;174:125-36. Crossref

3. United States Food and Drug Administration. FDA approves first therapy for rare inherited form of rickets, x-linked hypophosphatemia. 2018 Apr 17. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-rare-inherited-form-rickets-x-linked-hypophosphatemia. Accessed 28 Oct 2024.

4. European Medicines Agency. EU/3/14/1351—orphan designation for treatment of X-linked hypophosphataemia. Available from: https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-14-1351. Accessed 28 Oct 2024.

5. Imel EA, Glorieux FH, Whyte MP, et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet 2019;393:2416-27. Crossref

6. Linglart A, Imel EA, Whyte MP, et al. Sustained efficacy and safety of burosumab, a monoclonal antibody to FGF23, in children with X-linked hypophosphatemia. J Clin Endocrinol Metab 2022;107:813-24. Crossref

7. Sandy JL, Simm PJ, Biggin A, et al. Clinical practice guidelines for paediatric X-linked hypophosphataemia in the era of burosumab. J Paediatr Child Health 2022;58:762-8. Crossref

8. Munns CF, Yoo HW, Jalaludin MY, et al. Asia-Pacific consensus recommendations on X-linked hypophosphatemia: diagnosis, multidisciplinary management, and transition from pediatric to adult care. JBMR Plus 2023;7:e10744. Crossref

9. Mughal MZ, Baroncelli GI, de Lucas-Collantes C, et al. Burosumab for X-linked hypophosphatemia in children and adolescents: opinion based on early experience in seven European countries. Front Endocrinol (Lausanne)2023;13:1034580. Crossref

10. Baroncelli GI, Mora S. X-linked hypophosphatemic rickets: multisystemic disorder in children requiring multidisciplinary management. Front Endocrinol (Lausanne) 2021;12:688309. Crossref