Long-term tumour-treating fields for glioblastoma and beyond disease progression: a case report

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Long-term tumour-treating fields for glioblastoma and beyond disease progression: a case report
Peter YM Woo, MB, BS, FRCS1; TC Lam, MB, BS, FRCR2; Aya El Helali, MB, BCh, PhD2
1 Department of Neurosurgery, Kwong Wah Hospital, Hong Kong
2 Department of Clinical Oncology, The University of Hong Kong, Hong Kong
 
Corresponding author: Dr Peter YM Woo (wym307@ha.org.hk)
 
 Full paper in PDF
 
Case report
In May 2018, a 55-year-old Chinese man experienced sudden headache, vomiting and generalised seizures. On hospitalisation, he had a Glasgow Coma Score of 13/15 and global aphasia. Gadolinium contrast-enhanced magnetic resonance imaging revealed a left middle temporal gyrus heterogeneously enhancing intra-axial brain tumour with intratumoural haemorrhage (Fig 1a). A craniotomy for gross total tumour resection was performed under general anaesthesia 1 day after admission (Fig 1b). The patient fully recovered his language ability and was discharged from the hospital 3 days after surgery with no focal neurological deficit. At discharge, he had a Karnofsky Performance Score of 90 and an Eastern Cooperative Oncology Group (ECOG) performance status of 1. The histopathological diagnosis was glioblastoma (IDH-1 wildtype, promoter MGMT unmethylated). Targeted nextgeneration gene sequencing revealed the presence of CDKN2A homozygous deletion and EGFR amplification, molecular biomarkers associated with a poorer prognosis.1
 

Figure 1. (a) Preoperative axial magnetic resonance imaging: left temporal glioblastoma with intratumoural haemorrhage. (b) After concomitant temozolomide chemoradiotherapy and 5 months of tumour-treating fields (TTF). (c) First disease progression after 12 months of TTF. (d, e) TTF current density (Amp/cm2) and electric field intensity (V/cm) maps revealing increased electromotive force delivery to the peritumoural region after gross total resection of the patient’s first tumour recurrence. (f) No evidence of residual tumour 3 years after initial diagnosis and 30 months of TTF
 
The patient received concomitant temozolomide (TMZ) chemoradiotherapy with a total of 60 Gy of radiation given over 30 fractions. After three adjuvant cycles of TMZ, 6 months after diagnosis, alternating electric field therapy also known as tumour-treating fields (TTF) was started in December 2018. After initiation, the patient was able to return to work as a bartender with a Karnofsky Performance Score of 100 and ECOG status of 0. His mean monthly TTF compliance was 75% and although he experienced grade I scalp skin toxicity (mild dermatitis), this was resolved with topical hydrocortisone cream (Fig 2). The patient received a total of six cycles of TMZ and declined further chemotherapy, relying on TTF alone for tumour control for the next 12 months. His EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer global quality of life) score was 67/100 before TTF, which improved to 84/100 after 6 months. The caregiver stress index, a self-reported measure of primary caregiver burden, was 2 (a threshold of >7 indicates high stress).
 

Figure 2. Clinical photographs revealing grade I skin toxicity and its resolution after topical hydrocortisone cream treatment. Lateral views of the craniotomy wound after (a) 1 week, (b) 2 weeks, and (c) 8 weeks of tumour-treating fields; scalp vertex after (d) 1 week, (e) 2 weeks, and (f) 8 weeks of tumour-treating fields
 
There was focal tumour recurrence 18 months after diagnosis and a second craniotomy with supratotal resection was performed in December 2019 (Fig 1c). The patient received six cycles of second-line lomustine chemotherapy and TTF was restarted 6 weeks after the operation. The treatment field plan was adjusted after the second resection to enhance the current density (CD, Amp/cm2) and electric field intensity (EF, V/cm) to the peritumoural regions (Fig 1d and e). The patient’s monthly TTF compliance increased to 85% and his ECOG status was 1. After 14 months, in February 2021, there was a second glioblastoma recurrence at the inferior temporal gyrus located beyond the treatment EF50% and CD50% isodose regions. An awake craniotomy for language mapping and 5-aminolevulinic acid fluorescent-guided gross total resection was performed. Since the patient’s recurrent glioblastoma now had acquired TMZ and lomustine resistance, without effective third-line systemic therapy options, he was promptly restarted on TTF 2 weeks after surgery achieving a mean compliance of 90%. The patient received a further 10 months of TTF monotherapy after his second recurrence, experiencing minimal adverse effects with an ECOG performance status of 1, good quality of life (EORTC 89/100) and no recurrence (Fig 1f). In December 2021, multifocal disease progression with leptomeningeal spread was detected and the patient passed away in February 2022, 45 months (3.8 years) after diagnosis.
 
Discussion
Glioblastoma is the most common primary malignant brain tumour in adults with a prevalence of 3 to 5 per 100 000 population. In Hong Kong, 80 to 100 patients are diagnosed annually. Multimodality standard-of-care treatment has remained unchanged over the last 15 years comprising of maximal safe resection followed by concomitant TMZ chemoradiotherapy.2 Prognosis nonetheless remains poor and patients have a median overall survival (OS) of only 15 months and for those with an unmethylated pMGMT tumour molecular profile, 12 months.2 Tumour-treating fields is a novel therapy approved by the United States Food and Drug Administration and has been incorporated in several national guidelines as a first-line treatment option for patients with newly diagnosed glioblastoma. The therapy consists of the non-invasive local administration of alternating electric fields of low intensity (1-3 V/cm) and intermediate frequency (200 kHz) to the post-resection region. The mechanism of action involves the exertion of an electromotive force on intracellular proteins critical for mitosis, namely the microtubule substrates tubulin and septin. The antimitotic effect is most pronounced during the tumour cell cycle metaphase when microtubule assembly is disrupted, resulting in aneuploidy, post-mitotic stress, and ultimately apoptosis.3
 
The efficacy of TTF in glioblastoma is well supported by several randomised controlled trials. The landmark EF-14 phase III trial that recruited 695 patients with newly diagnosed glioblastoma revealed a significant increase in median OS among those who received TTF and standard TMZ chemoradiotherapy compared with their control group counterparts that received standard treatment alone (21 vs 17 months; hazard ratio=0.63; 95% confidence interval=0.53-0.76).3 The 2-year OS rate for patients receiving TTF with standard care was 43% compared with 29% for those that received standard care alone.3 These findings were independent of conventional predictors of OS such as pMGMT methylation status or extent of resection and were validated by subsequent studies. Our patient’s glioblastoma carried a relatively poor prognostic molecular profile and to observe his longer-than-expected OS demonstrates how TTF-generated antimitotic electromotive forces remain unaffected by tumour chemoresistance mechanisms. Studies have also documented a dose-response relationship whereby mean monthly treatment compliance, above a threshold of 60%, was associated with improved median OS.3 4 5 This phenomenon was also noted in our patient where his first progression-free survival was 12 months with 75% TTF compliance but subsequently increased to 14 months when his compliance was improved to 85%. In general, the median OS of patients with recurrent glioblastoma is 6.5 months and it is encouraging that our experience documented an additional survival benefit from TTF beyond first and second disease progression regardless of the systemic therapy prescribed.6 7
 
The only modifiable predictor for OS is the extent of glioblastoma resection8 and we believe this played an important role in our patient’s response to TTF. There is robust evidence that maximal safe resection, even beyond radiologically defined tumour boundaries (ie, supratotal resection), confers a significant advantage.9 To this end, awake craniotomy with intra-operative brain mapping and 5-aminolevulinic acid fluorescent guided resection have been proven to be useful surgical adjuncts.10 11 In contrast, standards of care for systemic treatment at recurrence are much less well-defined.7 12 Despite limited evidence to support its use, lomustine, a nitrosourea alkylating agent, is the most frequently administered second-line treatment.12 Randomised controlled clinical trials revealed lomustine treatment response rates to only be in the range of 10%, conferring a median progression-free survival of <2 months.12 13 Furthermore, lomustine activity is largely restricted to pMGMT methylated tumours, which our patient did not have.12
 
Starting in December 2018, Hong Kong was the first Asian region outside of Japan to provide patients with access to TTF. Treatment is generally started as early as 2 weeks after radiotherapy and patients are required to have their hair clipped during the entire period. The electric fields are delivered through disposable adhesive scalp transducer arrays connected to a portable generator with interchangeable batteries, each lasting for 4 hours. Dosimetry in terms of field intensity (V/cm) and current density (Amp/cm2) can significantly influence OS therefore array positioning requires an analysis of magnetic resonance imaging scans to achieve the greatest therapeutic effect (Fig 1).4
 
Scalp arrays are typically changed every 3 days when hair regrowth interrupts their apposition. Patients are required to be constantly connected to the 1.2-kg field generator for at least 15 hours per day. Despite this treatment commitment, reviews of the quality of life of TTF patients report outcomes comparable to those without such therapy.14 The most common adverse effect, occurring in up to 45% of patients, is scalp dermatitis, which is often mild to moderate in nature and sufficiently managed by temporary array repositioning or topical hydrocortisone.3 There is no evidence to suggest that patients receiving TTF are at higher risk of developing seizures. The only absolute contra-indications to TTF are the presence of a large skull defect, an active implantable medical device, uncontrolled scalp wound infection, or allergies to adhesive tape or hydrogels.
 
The TTF therapy is the first breakthrough treatment for glioblastoma in >15 years. As exhibited by our patient, long-term TTF therapy was well-tolerated and conferred a significant benefit in terms of OS.
 
Author contributions
Concept or design: PYM Woo, TC Lam.
Acquisition of data: PYM Woo, TC Lam.
Analysis or interpretation of data: PYM Woo, TC Lam.
Drafting of the manuscript: All authors.
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.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
Institutional Review Board of The University of Hong Kong/Hospital Authority Hong Kong West Cluster (Ref No. UW 19-626). Patient consent available upon request.
 
References
1. Mirchia K, Richardson TE. Beyond IDH-mutation: emerging molecular diagnostic and prognostic features in adult diffuse gliomas. Cancers (Basel) 2020;12:1817. Crossref
2. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96. Crossref
3. Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 2017;318:2306-16. Crossref
4. Ballo MT, Urman N, Lavy-Shahaf G, Grewal J, Bomzon Z, Toms S. Correlation of tumor treating fields dosimetry to survival outcomes in newly diagnosed glioblastoma: a large-scale numerical simulation-based analysis of data from the phase 3 EF-14 randomized trial. Int J Radiat Oncol Biol Phys 2019;104:1106-13. Crossref
5. Toms SA, Kim CY, Nicholas G, Ram Z. Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial. J Neurooncol 2019;141:467-73. Crossref
6. Kesari S, Ram Z, EF-14 Trial Investigators. Tumor-treating fields plus chemotherapy versus chemotherapy alone for glioblastoma at first recurrence: a post hoc analysis of the EF-14 trial. CNS Oncol 2017;6:185-93. Crossref
7. van Linde ME, Brahm CG, de Witt Hamer PC, et al. Treatment outcome of patients with recurrent glioblastoma multiforme: a retrospective multicenter analysis. J Neurooncol 2017;135:183-92. Crossref
8. Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS. An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg 2011;115:3-8. Crossref
9. Jackson C, Choi J, Khalafallah AM, et al. A systematic review and meta-analysis of supratotal versus gross total resection for glioblastoma. J Neurooncol 2020;148:419-31. Crossref
10. Zhang JJ, Lee KS, Voisin MR, Hervey-Jumper SL, Berger MS, Zadeh G. Awake craniotomy for resection of supratentorial glioblastoma: a systematic review and meta-analysis. Neurooncol Adv 2020;2:vdaa111. Crossref
11. Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 2006;7:392-401. Crossref
12. Weller M, Le Rhun E. How did lomustine become standard of care in recurrent glioblastoma? Cancer Treat Rev 2020;87:102029. Crossref
13. Brada M, Stenning S, Gabe R, et al. Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. J Clin Oncol 2010;28:4601-8. Crossref
14. Taphoorn MJ, Dirven L, Kanner AA, et al. Influence of treatment with tumor-treating fields on health-related quality of life of patients with newly diagnosed glioblastoma: a secondary analysis of a randomized clinical trial. JAMA Oncol 2018;4:495-504. Crossref

Luxatio erecta of the hip in a 64-year-old man: a case report

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Luxatio erecta of the hip in a 64-year-old man: a case report
Kemal Gokkus, MD; Mehmet S Sahin, MD
Department of Orthopedics and Trauma, Baskent University Medical Faculty–Alanya Research and Practice Center, Turkey
 
Corresponding author: Dr Kemal Gokkus (kemalg@baskent.edu.tr)
 
 Full paper in PDF
 
Case report
In March 2021, a 64-year-old man who was injured in a fall was brought to our emergency department. He had lost his balance and fallen while harvesting avocados from a tree. He reported severe right hip and right lateral chest pain and was unable to move his right hip. His vital signs were unremarkable. He held his right hip in flexion and abduction (Fig 1a). The limb was neurologically intact and good distal arterial pulses were present. Plain anteroposterior radiograph of the pelvis revealed an inferior dislocation of the femoral head (Fig 1b).
 

Figure 1. (a) Clinical photograph showing the patient with right hip in flexion and abduction. This position of the lower limb is typical luxatio erecta of the hip (inferior dislocation of the hip). (b) Plain anteroposterior radiograph of the pelvis taken before reduction showing the femoral head dislocated inferiorly
 
Computed tomography (CT) scan of the chest (not shown) revealed an ipsilateral nondisplaced rib (8-10) and scapular spine fractures. A CT scan of the pelvis (Fig 2) demonstrated an empty acetabulum with no associated fractures. Later, the patient was brought to the operating theatre and 0.5 mg/kg propofol and 0.5 μg/kg remifentanil administered intravenously for the first 90 s. Thereafter, further doses of both propofol 0.25 mg/kg and remifentanil 0.25 μg/kg were administered. After 3 to 4 minutes the patient was adequately sedated and pain-free.
 

Figure 2. (a) Coronal and (b) axial computed tomography scans showing the empty acetabulum without associated fracture. Because the patient could not bring his hip into adduction, it was not possible to obtain an image at the level of the dislocation
 
The dislocation was reduced under sedation and fluoroscopy by manual traction in the line of deformity, initially followed by adduction of the femur, resulting in an uneventful reduction (Video 1). Fluoroscopy confirmed that the hip range of motion was safe after reduction; the hip was safe at 90° of flexion, 20° of adduction, 30° of abduction, and 30° of internal or external rotation.
 
After clinic follow-up the next day, the patient was discharged home and advised to remain on bed rest for 3 weeks, and to use a walker (with toe-touch weight-bearing) solely for going to the toilet.
 
To prevent heterotopic bone formation and thromboprophylaxis, 25-mg indomethacin orally 3 times daily and 0.4-mL enoxaparin sodium daily were prescribed for the first 2 weeks after surgery. The use of indomethacin for prophylaxis is well documented in the literature and its use to prevent heterotopic ossification following treatment for posterior hip dislocation with acetabular fractures has been reported by Mitsionis et al.1 Deep venous thrombosis has rarely been reported after an isolated hip dislocation.1 Nevertheless, indomethacin for prophylaxis was prescribed to our patient in view of the need for prolonged bed rest and his relatively advanced age.
 
At follow-up examination 3 weeks after reduction, the patient was able to bear weight with a mildly antalgic gait (Video 2). The observed antalgic gait prompted us to be more conservative so the patient was advised to avoid strenuous activity and to use crutches with partial weight-bearing. At the same visit, a post-reduction radiograph and CT scan was performed to rule out chip or flake fractures of the femoral head or acetabulum during reduction; if hip pain persists, a magnetic resonance imaging scan can be performed to look for evidence of a labral tear. No associated acetabular or femoral head fracture was observed (Fig 3). The patient will continue to be monitored for a year for possible aseptic necrosis and myositis ossificans.
 

Figure 3. Follow-up examination at 3 weeks after reduction of the hip dislocation. (a, b) Plain anteroposterior radiographs of the pelvis showing concentric reduction without concomitant acetabular or femoral head fracture. (c) Coronal and (d) axial computed tomography scans showing no associated acetabular or femoral head fracture
 
Discussion
There are two types of inferior hip dislocation: obturator and ischial. Parvaresh et al2 analysed acetabular development and concluded that between the ages of 12 and 16, the three ossification centres and triradiate cartilage are ossified in both sexes. It is realistic then to consider it an adult hip if the patient is >16 years.2 Few cases of inferior (ischial type) hip dislocation have been reported. We reviewed the English-language literature search and found only five reported cases of inferior hip dislocation in adult patients (age >16 years).3 4 5 6 7 Among them, our patient is the oldest case reported with uneventful reduction.
 
Traumatic hip dislocation can cause complications that include avascular necrosis (6%-27% for early closed reduction), post-traumatic osteoarthritis (17%-48%), heterotopic ossification (up to 32%),1 8 and sciatic nerve injury (approximately 10%).9 To avoid complications, early and uneventful reduction is critical. In our patient, reduction was achieved within 2 hours of initial presentation. Our patient may be the only case documented with radiographic imaging performed before and after the reduction (including CT) and video of the reduction manoeuvre and a clinical video of the patient (demonstrating the patient walking in the third week after the reduction).
 
Brogdon and Woolridge10 described the mechanism of ischial and obturator injury. In the ischial type, the person falls on the trunk with the hip flexed and lands on the flexed knee. The accumulated force from further flexion of the upper trunk and body weight may create the momentum to push the femoral head inferiorly through the shallow and relatively rimless inferior margin of the acetabulum. Treatment consists of closed reduction under sedation or general anaesthesia with axial traction, together with gradual extension of the femur with additional internal rotation manoeuvres.9
 
The common obturator type of dislocation occurs when the femur is physically abducted and twisted outwards when the patient slips or when another force is applied. If the forcible abduction and external rotation continue with flexion against the pelvis, the femur is levered anteriorly out of the acetabulum. Treatment comprises closed reduction under sedation/general anaesthesia with longitudinal traction in the direction of the femoral axis and gentle adduction and flexion of the hip with additional internal rotation manoeuvres.10
 
There is a strong consensus in the literature that CT examination be performed prior to reduction to assess a probable acetabular wall fracture or head split fracture of the femoral head.8 In the present case, we could not complete all markings on the CT scan because the abducted hip automatically blocked the CT platform. Fortunately, we evaluated the anterior and posterior acetabular walls and confirmed no remnants in the acetabular fossa nor any fractures on the acetabular walls. Based on the reduction and stability confirmed by physical examination after the reduction, radiographic examination after reduction and CT was postponed until 3 weeks after reduction, when the patient was allowed to fully weight bear for the first time.
 
Inferior hip dislocation is rare and can be successfully treated with closed reduction. Orthopaedic surgeons must be able to diagnose and optimally treat this type of dislocation. This report and videos serve as a teaching tool for this reduction manoeuvre.
 
Author contributions
Concept or design: Both authors.
Acquisition of data: Both authors.
Analysis or interpretation of data: Both Gokkus.
Drafting of the manuscript: K Gokkus.
Critical revision of the manuscript for important intellectual content: All authors.
 
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.
 
Conflicts of interest
Both authors have no conflicts of interest to disclose.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated according to the principles of the Declaration of Helsinki. The patient provided informed consent for all treatments, procedures, and consent for publication.
 
References
1. Mitsionis GI, Lykissas MG, Motsis E, et al. Surgical management of posterior hip dislocations associated with posterior wall acetabular fracture: a study with a minimum follow-up of 15 years. J Orthop Trauma 2012;26:460-5. Crossref
2. Parvaresh KC, Pennock AT, Bomar JD, Wenger DR, Upasani VV. Analysis of acetabular ossification from the triradiate cartilage and secondary centers. J Pediatr Orthop 2018;38:e145-50. Crossref
3. Kolar MK, Joseph S, McLaren A. Luxatio erecta of the hip. J Bone Joint Surg Br 2011;93:273. Crossref
4. Singh R, Sharma SC, Goel T. Traumatic inferior hip dislocation in an adult with ipsilateral trochanteric fracture. J Orthop Trauma 2006;20:220-2. Crossref
5. Walther MM, McCoin NS. Luxatio erecta of the hip. J Emerg Med 2013;44:985-6. Crossref
6. Tekin AÇ, Çabuk H, Büyükkurt CD, Dedeoğlu SS, İmren Y, Gürbüz H. Inferior hip dislocation after falling from height: a case report. Int J Surg Case Rep 2016;22:62-5. Crossref
7. Zeytin AT, Kaya S, Kaya FB, Ozcelik H. Traumatic inferior hip dislocation. J Med Cases 2015;6:238-9. Crossref
8. Yang RS, Tsuang YH, Hang YS, Liu TK. Traumatic dislocation of the hip. Clin Orthop Relat Res 1991;(265):218-27. Crossref
9. Cornwall R, Radomisli TE. Nerve injury in traumatic dislocation of the hip. Clin Orthop Relat Res 2000;(377):84-91.Crossref
10. Brogdon BG, Woolridge DA. Luxatio erecta of the hip: a critical retrospective. Skeletal Radiol 1997;26:548-52. Crossref

Clinical and molecular features of pleuropulmonary blastoma in children in Hong Kong: case reports

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Clinical and molecular features of pleuropulmonary blastoma in children in Hong Kong: case reports
Anthony PY Liu, MB, BS1; Marcus KL Fung, PhD1; Mianne Lee, MSc1; Jasmine LF Fung, BSc1; Mandy HY Tsang, MMedSc1; CW Luk, MB, BS2; Brian HY Chung, MB, BS, MD1; Godfrey CF Chan, MD1
1 Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
2 Department of Paediatrics and Adolescent Medicine, Hong Kong Children’s Hospital, Hong Kong
 
Corresponding author: Prof Godfrey CF Chan (gcfchan@hku.hk)
 
 Full paper in PDF
 
Case report
Patient 1
In January 1998, a 14-month-old girl presented with fever and dyspnoea. Plain chest radiograph showed opacification of the right hemithorax that corresponded to a multicystic mass on computed tomography. Thoracotomy was performed and a 11-cm × 9.5-cm × 5-cm mixed cystic-solid mass excised. Together with histological findings, type II pleuropulmonary blastoma (PPB) was diagnosed. The patient was treated with adjuvant chemotherapy according to the Intergroup Rhabdomyosarcoma Study-IV regimen but developed ifosfamide-induced renal tubulopathy. At the time of writing, the patient remains in remission (age 23 years). Sanger sequencing revealed no DICER1 mutation in the patient’s peripheral blood DNA.
 
Patient 2
In November 2008, a 9-month-old girl presented with progressive dyspnoea. Plain chest radiograph revealed left-sided pneumothorax. Computed tomography scan of the thorax after thoracocentesis revealed a 3-cm cystic lesion in the lingula, suspicious of congenital cystic adenomatoid malformation. In view of the risk of recurrent pneumothorax, left upper lobectomy was performed. Microscopically, features of the excised lesion were compatible with type I PPB. No adjuvant treatment was required and the patient remained in remission for 10 years. Multinodular goitre (MNG) was also diagnosed at age 7 years. Sanger sequencing of the patient’s peripheral blood DNA revealed a heterozygous frameshift mutation in DICER1 (NM_177438.2:c.4022del(p.(Gly1341Alafs*6)); Fig 1), inherited from her father (Fig 2), who also had a history of MNG with thyroidectomy done. Familial counselling was offered with discussion about the role of further cascade testing and recommendations for surveillance.
 

Figure 1. Sanger sequencing indicating germline DICER1 mutation in the proband of Case 2
 

Figure 2. Sanger sequencing indicating germline DICER1 mutation in the father of Case 2
 
Patient 3
In December 1999, a 2-year-old girl presented with presumed right-sided pneumonia unresolved for 2 months. Computed tomography scan of the thorax showed collapse-consolidation with pleural effusion. Exploratory thoracotomy revealed a huge mass in the right middle lobe and debulking was performed. Histology confirmed type II PPB. A new computed tomography scan of the thorax demonstrated a residual multiloculated cystic mass with intermixed solid components. Adjuvant chemotherapy based on the Intergroup Rhabdomyosarcoma Study-IV regimen was adopted. Right middle lobectomy was performed after week 8 of chemotherapy. The patient subsequently developed cerebral relapses at age 7 years and again at age 17 years for which she was treated with excision and chemoradiotherapy (ifosfamide/carboplatin/etoposide + 40-Gy focal radiotherapy and irinotecan/temozolomide + 40-Gy focal radiotherapy, respectively). At the time of writing, the patient (age 21 years) has been in remission for 4 years. Multinodular goitre was also diagnosed at age 13 years. A heterozygous frameshift mutation in DICER1 was detected in the patient’s peripheral blood using Sanger sequencing (NM_17 7438.2:c.1651_1654delGGAA(p(Gly551Glufs*10)); Fig 3).
 

Figure 3. Sanger sequencing indicating germline DICER1 mutation in proband of Case 3
 
Patient 4
In January 2016, a 2-year-old girl presented with fever, cough and progressive dyspnoea. Computed tomography of the thorax revealed a large space-occupying lesion in the right thoracic cavity, with pleural effusion, mediastinal shift and superior vena cava compression. Biopsy confirmed type III PPB. Considering the risk of upfront surgery, neoadjuvant chemotherapy with ifosfamide, vincristine, actinomycin and doxorubicin was started. Unfortunately her response was suboptimal and she developed respiratory embarrassment and required emergency surgery during which she went into cardiopulmonary arrest. Despite successful resuscitation and debulking surgery, the patient demonstrated signs of severe hypoxic ischaemic encephalopathy. In view of the poor neurodevelopmental prognosis, the family elected to continue only palliative care. The patient eventually succumbed to progression 6 months after diagnosis. Sanger sequencing of peripheral blood DNA showed a nonsense mutation on exon 7 of DICER1 (NM_177438.2:c.1174C>T, p.R392*; Fig 4); her father tested negative for the same germline mutation and her mother was not available for evaluation.
 

Figure 4. Germline DICER1 mutation spectrum on genomic DNA of patients with pleuropulmonary blastoma with reference data from the Human Gene Mutation Database (https://www.hgmd.cf.ac.uk/), a recent report on Chinese patients with pleuropulmonary blastoma4 (underlined text) and our results of Cases 2, 3, and 4 (bold text). NM_177438.2 was used as the reference sequence for DNA bases. The amino acid numbering used begins with the Kozak consensus sequence. *: stop codon
 
Discussion
Pleuropulmonary blastoma is a rare thoracic tumour that arises during infancy or young childhood.1 Its aggressiveness and presenting features vary according to the histological subtype, ranging from the self-limiting cystic form (type I) with potential to undergo spontaneous regression (type Ir) or the mixed cystic/solid form (type II) that would benefit from adjuvant cytotoxic treatment, to a solid form (type III) that carries a considerable risk of disease relapse despite multimodal therapy. As an entity originally designated in 1988, familial clustering of PPB was first reported in 1996. This led to the recognition of underlying germline DICER1 alterations, and subsequently the definition of DICER1 syndrome—an autosomal dominant condition with variable penetrance and associated with almost 30 neoplastic conditions, including MNG, cystic nephroma, and ovarian stromal tumours.2 The oncogenic mechanism consequent to DICER1 mutations is hypothesised to be related to the resulting imbalance of mature miRNAs derived from the 5′ and 3′ ends of the precursor pre-miRNA. Because of its rarity, data on the presentation and molecular features of patients with PPB in Chinese are limited and that in Hong Kong have never been reported.
 
We reviewed a territory-wide paediatric oncology database and report the various presenting features and clinical course of four patients with PPB treated between 1998 and 2020. Type I/type Ir PPB should be considered in cases of cystic lung lesions; while many represent as incidental findings, the risk of pneumothorax remains a concern for peripherally located lesions. Among those where resection has been performed, 90% will remain progression-free without the use of adjuvant chemotherapy.1 Type II and III PPB are differential diagnoses for young children (age <6 years) who present with a space-occupying thoracic mass or apparent, persistent chest infection. The surgical and perioperative management of massive lung lesions with mediastinal compression carries a high-risk of cardiovascular compromise and necessitates care at a tertiary referral centre with available expertise including extracorporeal membrane oxygenation support. For adjuvant therapy, the addition of doxorubicin to ifosfamide, vincristine and actinomycin has been shown to be efficacious in Types II/III PPB.3 However, half of these patients still develop progression by age 5 years, 60% with a central nervous system component.
 
The prevalence of germline pathogenic DICER1 mutations in the general population is estimated to be 1:10 600 in the ExAC-nonTCGA (The Cancer Genome Atlas) database, although mutations have been identified in two-thirds of patients with PPB with thus far a lack of genotype-phenotype correlation. In our series, novel heterozygous germline DICER1 frameshift mutations were found in cases 2 and 3; while a heterozygous germline nonsense mutation, reported recently in another Chinese patient, was detected in Case 4 (Fig 4).4 The findings of our case series add to the spectrum of known DICER1 mutations, especially to the very limited data from Asia.4 Diagnosing DICER1 syndrome facilitates surveillance of associated morbidities, familial testing and reproductive counselling for both probands and symptomatic carriers.5 Further studies and consideration of a prospective patient registry to define the prevalence of DICER1-associated conditions in both paediatric and adult populations in Hong Kong are warranted.
 
Author contributions
Concept or design: APY Liu, MKL Fung, BHY Chung, GCF Chan.
Acquisition of data: All authors.
Analysis or interpretation of data: APY Liu, MKL Fung, M Lee, JLF Fung.
Drafting of the manuscript: APY Liu, MKL Fung.
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.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Acknowledgement
We would like to thank the patients and family for their consent to this study.
 
Funding/support
This study was supported by The Society for the Relief of Disabled Children. The funder had no role in study design, data collection/analysis/interpretation or manuscript preparation.
 
Ethics approval
This study was approved by the Institutional Review Board of the University of Hong Kong (Ref No. UW12-211) with informed consent obtained from patient guardians.
 
References
1. Messinger YH, Stewart DR, Priest JR, et al. Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry. Cancer 2015;121:276-85. Crossref
2. de Kock L, Wu MK, Foulkes WD. Ten years of DICER1 mutations: provenance, distribution, and associated phenotypes. Hum Mutat 2019;40:1939-53. Crossref
3. Doros LA, Schultz KA, Harris A, et al. IVADo treatment of type II and type III pleuropulmonary blastoma (PPB): a report from the International PPB Registry. J Clin Oncol 2014;32(15 Suppl):10060. Crossref
4. Cai S, Wang X, Zhao W, Fu L, Ma X, Peng X. DICER1 mutations in twelve Chinese patients with pleuropulmonary blastoma. Sci China Life Sci 2017;60:714-20. Crossref
5. Schultz KA, Williams GM, Kamihara J, et al. DICER1 and associated conditions: identification of at-risk individuals and recommended surveillance strategies. Clin Cancer Res 2018;24:2251-61. Crossref

Candida glabrata fungal ball cystitis is a rare complication of conservative treatment of placenta accreta: a case report

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Candida glabrata fungal ball cystitis is a rare complication of conservative treatment of placenta accreta: a case report
CK Wong, MB, ChB1; LY Cho, MB, BS, FHKAM (Obstetrics and Gynaecology)1; WL Lau, MB, BS, FHKAM (Obstetrics and Gynaecology)1; Ingrid YY Cheung, MB, ChB, FHKAM (Pathology)2; Chloe HT Yu, MB, BS3; IC Law, MB, BS, FHKAM (Surgery)3; WC Leung, MD, FHKAM (Obstetrics and Gynaecology)1
1 Department of Obstetrics and Gynaecology, Kwong Wah Hospital, Hong Kong
2 Department of Pathology, Kwong Wah Hospital, Hong Kong
3 Department of Surgery, Kwong Wah Hospital, Hong Kong
 
Corresponding author: Dr CK Wong (wongchunkitjack@hotmail.com)
 
 Full paper in PDF
 
Case report
In October 2019, a 42-year-old pregnant woman was admitted to hospital at 35+2 weeks of gestation for an elective caesarean section because of anterior placenta praevia type I and suspected placenta accreta. She was gravida 6 and parity 3+2. Her first pregnancy in 1996 resulted in a normal vaginal delivery. The second and third pregnancies were surgically terminated in the first trimester. Fourth and fifth pregnancies resulted in a lower segment caesarean section in China due to oligohydramnios and previous caesarean section.
 
The patient had an uneventful antenatal course in the current pregnancy. Nonetheless ultrasound examination at 35+2 weeks of gestation revealed an anterior placenta praevia type I with the placenta’s leading-edge 2.7 cm from the os. A diagnosis of placenta accreta was made due to vascularities over the subserosal surface of the lower segment.
 
A classical caesarean section was performed after completing a course of antenatal corticosteroid at 36+4 weeks of gestation. Around four-fifths of the placenta separated spontaneously after 30 minutes. The placenta was trimmed away and 3 × 3 cm of anterior adherent placenta around the internal os was left in place. Active bleeding from the lower segment of the uterus and anterior placental bed was controlled with Sengstaken–Blakemore balloon tamponade (Rüsch Teleflex, Germany). Uterine artery embolisation was performed at the same operation by interventional radiologists. Total blood loss for the operation was 500 mL.
 
After surgery, the patient was transferred to the intensive care unit. Balloon tamponade was removed on day 1 (Fig 1). Prophylactic amoxicillin and clavulanate was administered intravenously after the operation. She complained of dysuria and developed a persistent swinging fever from day 2. Amoxicillin and clavulanate was switched to piperacillin/tazobactam on day 4 after blood and urine tests for sepsis. Culture of midstream urine showed Morganella morganii sensitive to piperacillin/tazobactam and a gram-negative bacillus. Microbiologists advised continuation of piperacillin/tazobactam for 7 to 10 days.
 

Figure 1. Timeline of patient treatment
 
Examination under anaesthesia and ultrasound-guided suction evacuation were performed on day 14 due to increased per-vaginal bleeding. Intra-operatively, yellowish pus was seen leaking from the cervical os and retained product of gestation weighing 48 g was retrieved. Culture of the pus grew Escherichia coli sensitive to piperacillin/tazobactam. The patient again presented with fever postoperatively and blood culture revealed E coli septicaemia. Piperacillin/tazobactam was switched to meropenem on day 17. Blood culture sensitivity testing revealed E coli sensitive to meropenem and cefuroxime. Hence, meropenem was switched to cefuroxime. Ultrasound examination on day 24 revealed no evidence of retained product of gestation. Cefuroxime was continued for 14 days.
 
At 5-week follow-up examination, the patient reported a 1-week history of whitish debris in her urine, dysuria, and urinary frequency. Ultrasonography revealed incomplete emptying of the bladder with a lot of frothy shadows (Fig 2a). Urinary tract infection was suspected so amoxicillin and clavulanate and phenazopyridine were prescribed for 1 week. Culture of the midstream urine showed Candida glabrata (Fig 2b). A microbiologist was consulted and fluconazole 400 mg prescribed for 10 days.
 

Figure 2. (a) Ultrasonograph showing “fungal debris” inside the bladder. (b) Photograph of Candida glabrata colony on CHROMagar Candida agar
 
Susceptibility testing of the C glabrata isolated from urine collected after admission was performed by using Sensititre YeastOne (TREK Diagnostic Systems, United Kingdom) and revealed a required fluconazole minimal inhibitory concentration of 16 μg/mL, confirming that it was in the susceptible-dose dependent category. However, the patient’s symptoms persisted after completing 24 days of fluconazole and ultrasound showed persistent “fungal debris” inside the bladder. She was readmitted 13 weeks after the operation for further management. Amphotericin B deoxycholate was administered intravenously for 7 days. A drug-related fever developed during the first dose but resolved after premedication with oral acetaminophen and intravenous diphenhydramine.
 
Flexible cystoscopy revealed necrotic tissue approximately 3 × 4 cm over the left posterior bladder wall, away from the left ureteric orifice, with an underlying ulcer (Fig 3a and b). It was removed with forceps and a basket. A fistula was suspected, and second flexible cystoscopy scheduled 2 months later. A computed tomography urogram with contrast was arranged to exclude fistula.
 

Figure 3. Cystoscopy images showing (a) necrotic tissue (b) and an ulcer over the bladder wall. (c) Second cystoscopy image taken 2 months later showing the healed ulcer
 
The second flexible cystoscopy revealed a normal bladder and a healed ulcer over the left posterior wall (Fig 3c). Computed tomography urogram showed no evidence of fistula. During postnatal follow-up, there were no urinary symptoms.
 
Discussion
This is the first case of C glabrata cystitis as a complication in our case series of planned conservative management of placenta accreta.1 Candida species are a part of the normal flora of the gastrointestinal and vaginal tracts. The incidence of candiduria has been increasing in recent decades and the presence of C glabrata has become clinically significant due to its high resistance to routine antifungal agents. Risk factors for candiduria in our case included urinary catheterisation, intensive care unit stay, use of broad-spectrum antibiotics, female sex, and prior surgery.2
 
The placental remnants in our case induced infection and septicaemia. Subsequent prolonged use of broad-spectrum antibiotics predisposed our patient to fungal cystitis. There was no clinical or pathological evidence of placenta percreta. Chandraharan et al3 introduced the use of the Triple-P procedure to manage patients with morbidly adherent placenta. As the Triple-P procedure removes all intrauterine placental remnants, it may reduce the risk of intrauterine infection and sepsis. Nevertheless, there is limited surgical expertise in this procedure in our unit.
 
Compared with other Candida species, many C glabrata isolates are resistant to azoles due to efflux pump–mediated resistance, genetic alterations under stress and biofilm protection.4 A study in the United States revealed that 14% of C glabrata isolates were resistant to fluconazole.5
 
The presence of fungus ball/fungal bezoars in urinary tract infection is extremely rare in adults. According to treatment guidelines of the Infectious Diseases Society of America, removal of the obstructing mycelial mass by surgical or endoscopic means is strongly recommended.6 Although culture results revealed that the C glabrata was susceptible-dose-dependent to fluconazole, use of fluconazole alone was likely to be insufficient due to the fungal ball in the bladder. A multidisciplinary approach including microbiologists and urologists is essential.
 
In symptomatic Candida cystitis, first-line treatment is oral fluconazole 200 mg daily for 2 weeks. For fluconazole-resistant C glabrata, amphotericin B deoxycholate or oral flucytosine are the drugs of choice. Around 50% of patients prescribed an amphotericin B infusion experience infusion-related adverse events, such as fever, chills, rigors, hypotension, and rarely, hypokalaemia resulting in ventricular fibrillation. In addition, renal toxicity is a well-known adverse effect.5 Close monitoring of renal function and electrolytes is essential.
 
Placenta accreta spectrum treated conservatively by leaving the placenta in situ is a recognised and successful management option, but is associated with risks of infection or postpartum haemorrhage. Our case demonstrates that fungal infection can develop during the period of conservative management and requires multidisciplinary consultation.
 
Author contributions
Concept or design: CK Wong, WC Leung.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: CK Wong, WC Leung.
Critical revision of the manuscript for important intellectual content: All authors.
 
Conflicts of interest
The authors have no conflicts of interest to disclose.
 
Acknowledgement
The authors thank interventional radiologists Dr KH Lee and Dr CW Tang for their contributions to this report.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki, provided informed consent for all treatments and procedures, and provided consent for publication.
 
References
1. Lo TK, Yung WK, Lau WL, Law B, Lau S, Leung WC. Planned conservative management of placenta accreta—experience of a regional general hospital. J Maternal Fetal Neonatal Med 2013;27:291-6. Crossref
2. Gajdács M, Dóczi I, Ábrók M, Lázár A, Burián K. Epidemiology of candiduria and Candida urinary tract infections in inpatients and outpatients: results from a 10-year retrospective survey. Cent European J Urol 2019;72:209-14.
3. Chandraharan E, Rao S, Belli A, Arulkumaran S. The Triple-P procedure as a conservative surgical alternative to peripartum hysterectomy for placenta percreta. Int J Gynecol Obstet 2012;117:191-4. Crossref
4. Rodrigues CF, Silva S, Henriques M. Candida glabrata: a review of its features and resistance. Eur J Clin Microbiol Infect Dis 2013;33:673-88. Crossref
5. Pfaller MA, Messer SA, Hollis RJ, et al. Variation in susceptibility of bloodstream isolates of Candida glabrata to fluconazole according to patient age and geographic location in the United States in 2001 to 2007. J Clin Microbiol 2009;47:3185-90. Crossref
6. Pappas PG, Kauffman CA, Andes DR, et al. Executive Summary: Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016;62:409-17. Crossref

Managing limitations of the LMA Classic laryngeal mask as a conduit for tracheal intubation in impending paediatric airway obstruction: a case report

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Managing limitations of the LMA Classic laryngeal mask as a conduit for tracheal intubation in impending paediatric airway obstruction: a case report
Gareth CH Cheng, MB, ChB; Jaclyn WM Wong, FHKCA, FHKAM (Anaesthesiology)
Department of Anaesthesia and Operating Theatre Services, Kwong Wah Hospital, Hong Kong
 
Corresponding author: Dr Gareth CH Cheng (gareth@fellow.hkam.hk)
 
 Full paper in PDF
 
Case report
Peritonsillar abscess (quinsy) is the most common deep neck infection in children and adolescents, although it is less frequently seen in young children.1 Airway compromise is a feared complication. We describe the successful management of a patient with impending paediatric airway obstruction. The LMA Classic™ laryngeal mask (Teleflex Medical Ltd., Co. Westmeath, Ireland) was the only paediatric-sized supraglottic device available in our operating theatre and was modified to work around its limitations as a conduit for tracheal intubation.
 
In March 2020, an 18-month-old girl with good past health weighing 9.5 kg was admitted to our district general hospital 8 days after onset of fever up to 38.9°C, with worsening left facial swelling, inspiratory stridor during sleep, drooling and poor feeding.
 
On examination, she was pink and calm when carried upright. Her throat was swollen with bilateral grade 3 tonsils and the left cheek and submandibular region were grossly swollen (~10 cm × 6 cm). Contrast computed tomography of the neck revealed a 3.3-cm × 4.8-cm × 3.8-cm peritonsillar abscess with rightward deviation of the upper airway and significant narrowing at the larynx, with the narrowest cross-section measuring 3.5 mm (Fig 1).
 

Figure 1. Computed tomography films showing critical airway narrowing at the larynx (arrowhead) due to obstruction by peritonsillar abscess (arrow)
 
In view of the critical airway diameter and the impending progression to complete airway obstruction, and after discussion with the on-call head and neck surgeons and the patient’s mother, the decision was made to proceed with emergency incision and drainage under general anaesthesia.
 
The sizing of all our airway equipment was checked in advance. The distal aperture bars of a #1.5 LMA Classic laryngeal mask were cut to facilitate use as an intubation conduit.
 
The patient had a 24G intravenous cannula in situ on arrival in theatre. Surgeons were ready at the bedside with front-of-neck access equipment on standby. Hong Kong College of Anaesthesiologists standard monitoring was applied. Gaseous induction with spontaneous ventilation was performed using an Ayres’ T-piece and 4% sevoflurane in 100% oxygen. After an adequate depth of anaesthesia was achieved as assessed by vital parameters, intubation using video laryngoscopy was attempted. Two initial attempts were unsuccessful, with very rapid desaturation down to an SpO2 of 50% to 60%. Subsequent attempts at rescue bag mask ventilation failed despite optimisation by positioning and oropharyngeal airway. Fortunately, a final attempt to insert the laryngeal mask was successful and ventilation was maintained.
 
As a definitive airway was still necessary, a 2.2-mm fibreoptic bronchoscope was passed through the laryngeal mask and a 3.5-mm Microcuff endotracheal tube (ETT) carefully railroaded over the bronchoscope into the trachea. Correct positioning was confirmed by bilateral chest auscultation and capnography. We deemed it unsafe to leave the laryngeal mask in place as traction could risk ETT dislodgement postoperatively. The video laryngoscope was used to visualise the distal end of the ETT near the vocal cords and it was secured with Magill forceps. The laryngeal mask was slowly pulled out over the ETT, but the 15-mm connector of the laryngeal mask could not be passed over the ETT pilot balloon even when deflated. Hence, we carefully cut down the laryngeal mask with scissors, leaving only the end with the 15-mm connector still attached (Fig 2).
 

Figure 2. Endotracheal tube cuff ‘stuck’ on 15-mm connector (arrow); remnants of cut down LMA Classic laryngeal mask with scissor incision line seen (arrowhead)
 
The operation proceeded uneventfully. Subsequently the patient was transferred to the paediatric intensive care unit and kept intubated and sedated. She was discharged after a short hospital stay, with good recovery on clinic follow-up examination.
 
Discussion
Paediatric airway emergencies are rare and among the most challenging crises faced by anaesthetists. Unique paediatric considerations such as inability to cooperate during preoxygenation, intolerance to awake techniques and difficult front-of-neck access, in addition to inherent differences in paediatric physiology, significantly reduce the safe apnoeic time and greatly increase the risk of hypoxia.
 
Ideally, this case would have been managed in a specialist tertiary centre with a wider selection of equipment and expertise; unfortunately, our requests for night-time case transfer were denied. The availability and use of an intubating laryngeal mask with a larger-sized inner channel such as an air-Q™ (Salter Labs, Lake Forest [IL], United States) would have been preferable to an LMA Classic. This would have made it easier for us to remove the laryngeal mask over the ETT after intubation without having to improvise with our limited equipment in an already stressful situation. Although the Association of Paediatric Anaesthetists guidelines2 recommend leaving the laryngeal mask in place after intubation, we deemed it necessary to remove it since continued postoperative ventilation was anticipated.
 
Often, manufacturer-recommended ETT/laryngeal mask combinations take account only of the ability to pass the ETT through the laryngeal mask. They may not consider the ability to remove the laryngeal mask over the ETT when the diameter of the ETT pilot balloon cuff exceeds that of the outer diameter of the ETT. This problem was illustrated in an article by Kleine-Brueggeney et al3 who found that only the air-Q models of supraglottic airways were able to be removed over the ETT with all manufacturer-recommended size combinations, as the air-Q had the largest inner channel diameter among other equivalently sized supraglottic airways.
 
Alternatively, we could have chosen to cut off the pilot balloon and repair the cuff with an angiocatheter.4 Another option might have been to use an uncuffed tube, although it would not have been ideal in our case due to the possibility of postoperative blood or secretions tracking down and contaminating the lower airway. Furthermore, exchange of a poorly fitting uncuffed tube would have been difficult and potentially dangerous in our situation, as the airway could easily have been lost.
 
In conclusion, in addition to meticulous airway planning, testing combinations of ETT and laryngeal mask for both insertion and subsequent removal is important to avoid complications during airway management. Availability of an intubating laryngeal mask such as an air-Q may be particularly advantageous in such cases.
 
Author contributions
Concept or design: GCH Cheng.
Acquisition of data: GCH Cheng.
Analysis or interpretation of data: GCH Cheng.
Drafting of the manuscript: Both authors.
Critical revision of the manuscript for important intellectual content: GCH Cheng.
 
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.
 
Conflicts of interest
Both authors have disclosed no conflicts of interest.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
This case report was published with the written consent of the patient’s mother.
 
References
1. Ungkanont K, Yellon RF, Weissman JL, Casselbrant ML, González-Valdepeña H, Bluestone CD. Head and neck space infections in infants and children. Otolarngol Head Neck Sur 1995;112:375-82. Crossref
2. Association of Paediatric Anaesthetists. Unanticipated difficult tracheal intubation during routine induction of anaesthesia in a child aged 1 to 8 years. Available from: https://www.das.uk.com/files/APA2-UnantDiffTracInt-FINAL.pdf. Accessed 21 Jan 2021.
3. Kleine-Brueggeney M, Kotarlic M, Theiler L, Greif R. Limitations of pediatric supraglottic airway devices as conduits for intubation—an in vitro study. Can J Anaesth 2018;65:14-22. Crossref
4. Kovatsis PG, Fiadjoe JE, Stricker PA. Simple, reliable replacement of pilot balloons for a variety of clinical situations. Paediatric Anaesth 2010;20:490-4. Crossref

Intravenous iron isomaltoside (Monofer)–induced hypophosphataemia: a case report

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Intravenous iron isomaltoside (Monofer)–induced hypophosphataemia: a case report
KY Wong, MRCP, FHKAM (Medicine); KY Yu, MRCP, FHKAM (Medicine); Maria WH Mak, MRCP, FHKAM (Medicine); KM Lee, MRCP, FHKAM (Medicine); KF Lee, FRCP, FHKAM (Medicine)
Department of Medicine and Geriatrics, Kwong Wah Hospital, Hong Kong
 
Corresponding author: Dr KY Wong (wky697@ha.org.hk)
 
 Full paper in PDF
 
Case report
In January 2019, an 85-year-old woman with a history of osteoporosis and collapsed L1 had gastric antral vascular ectasia with multiple failed attempts of argon photo-coagulation, resulting in severe iron deficiency anaemia (haemoglobin 4 g/dL). The patient had been repeatedly admitted for congestive heart failure precipitated by anaemia that required blood transfusion. In view of her severe and ongoing blood loss, intravenous iron isomaltoside (Monofer) 800 mg monthly was started in February 2019. Before commencement of iron isomaltoside, iron saturation was 5% (normal 15%-50%). She was optimally nourished with normal serum calcium (2.27 mmol/L; normal 2.15-2.55 mmol/L), phosphate (1.4 mmol/L; normal 0.8-1.5 mmol/L), alkaline phosphatase (108 IU/L; normal 53-141 IU/L) and vitamin D level (79 nmol/L; normal 50-220 nmol/L). Hypophosphataemia (0.5 mmol/L) was first noted in June 2019 (Fig). Owing to the patient’s history of collapsed vertebra, she was given a first dose of denosumab in October 2019 by a private orthopaedic surgeon but serum phosphate further worsened to 0.1 mmol/L despite aggressive oral phosphate replacement. She refused hospital admission at this time. In December 2019, the patient was hospitalised for anaemia and hypophosphataemia (0.4 mmol/L) with concomitant serum calcium 2.07 mmol/L and alkaline phosphatase 199 IU/L. Her estimated glomerular filtration rate was >90 mL/min/1.73 m2. Fractional excretion of phosphate confirmed renal phosphate wasting (FePO4 14%; normal <5%) and bicarbonate was 30 mmol/L (normal 22-26 mmol/L). Urinary protein and glucose were negative. Iron saturation was 24% and parathyroid hormone 22.6 nmol/L (normal 1.6-7.2 nmol/L). Fibroblast growth factor 23 (FGF23), measured 3 weeks after the last dose of iron isomaltoside, was 155 IU/mL (normal <188 IU/mL). Intravenous iron-induced hypophosphataemia was suspected. Iron isomaltoside was stopped and rocaltrol was commenced in January 2020 with prompt improvement in phosphate level. Another intravenous iron preparation, iron sucrose (Venofer), was started due to her severe anaemia. Attempted re-challenge with iron isomaltoside resulted in recurrent hypophosphataemia. Rocaltrol and phosphate sandoz were gradually tapered down over 6 months. Serum phosphate remained normal while on iron sucrose and denosumab.
 

Figure. Changes in serum calcium (Ca), phosphate (PO4) and alkaline phosphatase (ALP) levels before and after administration of intravenous iron and denosumab
 
Discussion
Iron deficiency anaemia is a commonly encountered problem in daily practice. Although oral iron remains the recommended route of replacement due to its low cost and availability, intravenous iron is considered superior in several respects. First, the gastrointestinal side-effects of oral iron are avoided. Second, bioavailability is improved where that of oral iron is reduced in conditions such as achlorhydria (eg, proton pump inhibitors, gastric bypass), small bowel malabsorption (eg, inflammatory bowel disease, prior small bowel resection, celiac disease) and chronic inflammation (via upregulation of hepcidin). Third, intravenous iron allows rapid repletion of iron, making it a more suitable choice when there is severe and/or ongoing blood loss.
 
The new-generation intravenous iron preparations are all stable iron-carbohydrate complexes. The three commonly used intravenous iron preparations locally are iron carboxymaltose (Ferinject), iron isomaltoside (Monofer) and iron sucrose (Venofer). They differ in the attaching carbohydrate ligands that affect the capacity, stability and immunogenicity of the complex. Hypophosphataemia is a well-described complication of iron carboxymaltose but is far less common in the other two preparations: the incidence1 of hypophosphataemia is 58%, 4% and 1% for patients with preserved renal function given iron carboxymaltose, iron isomaltoside and iron sucrose, respectively. In addition, iron carboxymaltose–induced hypophosphataemia can be severe and protracted resulting in osteomalacia and multiple fractures. Although the pathogenesis2 is not fully understood, it is believed to be mediated through iron carboxymaltose–induced production of biologically active intact FGF23. The FGF23 is a phosphaturic hormone produced by osteocytes and osteoblasts. It reduces phosphate reabsorption by downregulation of sodium-phosphate co-transporter in the proximal renal tubule. The FGF23 also inhibits 1,25-dihydroxyvitamin D synthesis, leading to vitamin D deficiency and secondary hyperparathyroidism that contribute to reduced intestinal phosphate uptake and further increased renal phosphate wasting, respectively. Iron isomaltoside also increases intact FGF23 secretion, but to a much lesser extent than iron carboxymaltose.3 Again, such difference is speculated to be due to the carbohydrate ligand, since iron carboxymaltose and iron isomaltoside are equally effective in replenishing iron store. Although other indicators of proximal renal tubular dysfunction such as fractional excretion of urate and urine amino acid were not measured in this patient, the absence of glycosuria and non-suppressed FGF23 level were not typical of a diagnosis of renal Fanconi syndrome. In addition, improved serum phosphate level after stopping iron isomaltoside supported the diagnosis of iron-induced phosphaturia in this patient.
 
In the meta-analysis by Schaefer et al,4 low baseline iron saturation and normal renal function were identified as positive predictors of iron-induced hypophosphataemia; both were present in this patient. Severe iron deficiency may cause a higher increase in FGF23 transcription and renal impairment is protective due to intrinsic kidney resistance to FGF23. Furthermore, denosumab may have worsened the pre-existing hypophosphataemia induced by iron isomaltoside in this patient since serum phosphate level fell abruptly in October 2019, 1 week after denosumab injection. Denosumab is an anti-RANKL (receptor activator of nuclear factor-κB ligand) antibody that inhibits osteoclastic activity and hence bone resorption. Severe hypophosphataemia caused by denosumab has been described in a patient with tenofovir-induced osteomalacia5 and is possibly mediated through the following two mechanisms: first, decreased bone resorption directly reduces phosphate release; second, fall in bone-derived calcium worsens secondary hyperparathyroidism that in turn enhances phosphaturia. These may explain the profound hypophosphataemia in this patient after denosumab injection.
 
There are several reasons for the normal FGF23 level in this patient. First, the commercial FGF23 assay detects both intact and cleaved FGF23; an increased intact FGF23 together with a reduced cleaved FGF23 may result in a “normal” FGF23 level. Second, FGF23 may have dropped significantly 3 weeks after the last dose of iron isomaltoside. Third, FGF23 transcription was reduced with correction of iron deficiency as reflected by the normal iron saturation.
 
In addition to phosphate replacement and switching to a less phosphaturic intravenous iron preparation, activated vitamin D is needed to increase phosphate reabsorption during the initial phase, even in a patient with preserved renal function. This is because FGF23 inhibits renal activation of 25-dihydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D.
 
In conclusion, although hypophosphataemia is much less common in patients on iron isomaltoside than iron carboxymaltose, it is advisable to monitor phosphate level 1 to 2 weeks after iron isomaltoside injection in high-risk patients, such as those with severe anaemia who require repeat dosing, and patients with pre-existing vitamin D deficiency and/or hyperparathyroidism.
 
Author contributions
All authors contributed to the concept, acquisition of data, interpretation of data, drafting of the manuscript, and critical revision 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.
 
Conflicts of interest
The authors have no conflicts of interest to disclose.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki. The patient provided informed consent for the treatment/procedures and publication.
 
References
1. Zoller H, Schaefer B, Glodny B. Iron-induced hypophosphatemia: an emerging complication. Curr Opin Nephrol Hypertens 2017;26:266-75. Crossref
2. Edmonston D, Wolf M. FGF23 at the crossroads of phosphate, iron economy and erythropoiesis. Nat Rev Nephrol 2020;16:7-19. Crossref
3. Wolf M, Rubin J, Achebe M, et al. Effects of iron isomaltoside vs ferric carboxymaltose on hypophosphatemia in iron-deficiency anemia: two randomized clinical trials. JAMA 2020;323:432-43. Crossref
4. Schaefer B, Tobiasch M, Viveiros A, et al. Hypophosphataemia after treatment of iron deficiency with intravenous ferric carboxymaltose or iron isomaltoside—a systematic review and meta-analysis. Br J Clin Pharmacol 2021;87:2256-73. Crossref
5. Chung TL, Chen NC, Chen CL. Severe hypophosphatemia induced by denosumab in a patient with osteomalacia and tenofovir disoproxil fumarate-related acquired Fanconi syndrome. Osteoporos Int 2019;30:519-23. Crossref

Primary pulmonary mucosa-associated lymphoid tissue lymphoma with radiological presentation of middle lobe syndrome diagnosed by bronchoscopy: a case report

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Primary pulmonary mucosa-associated lymphoid tissue lymphoma with radiological presentation of middle lobe syndrome diagnosed by bronchoscopy: a case report
H Zhou, MD1; Z Yang, MD2; S Wu, MD1
1 Cancer Center, Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), PR China
2 Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), PR China
 
Corresponding author: Dr S Wu (wushengchang@126.com)
 
 Full paper in PDF
 
Case report
In March 2018, a 49-year-old woman was admitted to our respiratory medicine ward with a 2-year history of recurrent productive cough. Symptoms first developed after the patient underwent laparoscopic myomectomy and subsequently developed a fever (around 38°C). Chest computed tomography (CT) revealed patchy opacity in the right middle lobe (Fig 1a and b). Based on these symptoms, she was diagnosed with “pneumonia” for which antibiotics were prescribed. Her fever resolved but cough persisted so she was prescribed cough suppressants and antibiotics intermittently. These therapies were likewise ineffective.
 

Figure 1. Chest computed tomography (CT) scan showing patchy opacity in the right middle lobe during onset. (a) Lung window. (b) Mediastinal window. Chest CT scan showing patchy opacity persisting in the same location 2 years later. (c) Lung window. (d) Mediastinal window
 
A series of tests and examinations conducted during hospitalisation revealed no definitive cause and symptoms again persisted. A new chest CT scan revealed no change to the right middle lobe opacity compared with previous CT scan and stenosis of the middle bronchus (Fig 1c and d).
 
In the absence of any treatment response, the patient was advised to undergo bronchoscopy that revealed a narrowed lumen and rough mucosa of the middle bronchus. Pathological examination of mucosal tissue biopsy from the lesion revealed infiltration of large numbers of lymphocytes (Fig 2a and b) suggestive of diagnosis of lymphoma. Further immunohistochemistry examination confirmed that the lesion was caused by mucosa-associated lymphoid tissue (MALT) lymphoma. These lymphoma cells tested positive for CD20, CD79a and CD43 (Fig 2c-f). Further examinations including positron emission tomography–computed tomography and gastroscopy revealed no evidence of lymphoma elsewhere.
 

Figure 2. Bronchoscopic and pathological presentation of lesion in right middle lobe. (a) Bronchoscopic examination showing stenosis of the middle bronchus and nodular hyperplasia in the submucosa. (b) Hyperaemia and swelling change to the mucosa of the middle lobar bronchus. (c) Pathological examination suggested large numbers of lymphoma cells infiltrating the lesion. Immunohistochemical examination showing lymphoma cells were positive for (d) CD20, (e) CD43 and (f) CD79a
 
The patient underwent radiotherapy about 6 months after final diagnosis, with a total dose of 3960 cGy. After the last radiotherapy treatment, chest CT confirmed that the lesion in the right middle lobe had nearly disappeared. In addition, symptoms of cough and expectoration had improved significantly. The patient was followed up once every 3 months. Chest CT scan at the most recent follow-up examination indicated no sign of relapse and her symptoms had resolved.
 
Discussion
Primary pulmonary lymphoma belongs to a group of lymphoproliferative diseases, and accounts for 0.5% to 1% of all pulmonary tumours.1 Mucosa-associated lymphoid tissue lymphoma is the most common pathological type of primary pulmonary lymphoma.2 However, the disease may not be diagnosed until pathological examinations are conducted due to a lack of clinical and radiological characteristics.
 
Previous study suggests that about half of patients with MALT lymphoma are asymptomatic and some are diagnosed by accident.3 In patients with symptoms, respiratory symptoms are more frequently observed than B symptoms, including fever, fatigue and weight loss.3 Our patient presented with a transient B symptom of fever, but a chronic respiratory symptom of cough.
 
The radiological presentation of this disease is diverse and includes nodules, masses, consolidation and group glass opacity. Multiple lesions, which are often bilaterally distributed, can be detected by CT scan in most cases, but a solitary lesion is less common in patients with MALT lymphoma.4 In addition, MALT lesions may occur in any lung lobe or large airway including the trachea and main bronchus.4 5 In our patient, the right middle lobe was affected, and middle lobe syndrome (MLS) was the major radiological feature.
 
Middle lobe syndrome was first mentioned several decades ago by Graham6 to describe atelectasis of the right middle lobe. The syndrome is usually caused by extrinsic compression or intrinsic stricture of the middle lobe bronchus.6 However, there is no uniform definition of this term. Broadly speaking, MLS is defined as damage to the right middle lobe due to any cause. The most common causes are bronchiectasis, non-specific inflammation, tuberculosis and tumours. Lung cancer is the most common type of tumour affecting the middle lobe. As a haematological disease, MALT lymphoma can affect any organ or tissue although in our patient, it affected only the right middle lobe with consequent misdiagnosis for more than 2 years. It is particularly rare for MALT lymphoma to present as MLS. Only one similar case has been reported: in 2004, Toishi et al7 reported a 70-year-old male patient with a radiological change of MLS who was diagnosed with MALT lymphoma by right middle lobectomy. In our case, the final diagnosis was obtained by biopsy during bronchoscopy, not surgery.
 
Given that the clinical and radiological features of MALT are non-specific, its definitive diagnosis relies on pathology. Diffuse infiltration of small lymphocytes into the bronchiolar mucosa is a major histological characteristic. Moreover, reactive lymphoid follicles and lymphoepithelial lesions are commonly observed by microscopy.4 The molecular markers of MALT are CD20, CD79a, CD43, as observed in our case. CD5, CD10 and cyclin D are always negative and may help to discriminate other types of lymphoma. It was difficult to distinguish this disease from infectious diseases and benign lymphoproliferative diseases in the absence of pathological examination.
 
Generally, MALT lymphoma is a tumour of low-grade malignancy and patients have a rather good prognosis. The 5-year survival rate for patients with MALT lymphoma is >80%.4 The main treatments for the disease are chemotherapy, radiotherapy, target therapy and immunotherapy. Radiotherapy is the first choice in patients with localised lesions. It has been estimated that >90% of patients can achieve a complete response after radiotherapy.8 Surgery may be indicated when the lesion is isolated in certain organs, such as lung, thyroid gland, and spleen. However, if MALT lymphoma progresses to an advanced stage, or patients have a high tumour burden, systemic therapy is recommended. Anti-CD20 combined with chemotherapy is considered first-line treatment.7 In the present case, the patient refused chemotherapy and agreed to radiotherapy that relieved her symptoms with no obvious adverse effects.
 
In summary, we first report MALT lymphoma as a rare cause of MLS that was confirmed using a minimally invasive approach. Mucosa-associated lymphoid tissue lymphoma should be considered a differential diagnosis when investigating the aetiology of MLS.
 
Author contributions
Concept or design: H Zhou, S Wu.
Acquisition of data: Z Yang, S Wu.
Analysis or interpretation of data: H Zhou, Z Yang.
Drafting of the manuscript: H Zhou, S Wu.
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.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki. The patient provided written informed consent for all treatment and procedures and for publication of this paper.
 
References
1. Cardenas-Garcia J, Talwar A, Shah R, Fein A. Update in primary pulmonary lymphomas. Curr Opin Pulm Med 2015;21:333-7. Crossref
2. Borie R, Wislez M, Antoine M, Copie-Bergman C, Thieblemont C, Cadranel J. Pulmonary mucosa-associated lymphoid tissue lymphoma revisited. Eur Respir J 2016;47:1244-60. Crossref
3. Zhang MC, Zhou M, Song Q, et al. Clinical features and outcomes of pulmonary lymphoma: a single center experience of 180 cases. Lung Cancer 2019;132:39-44. Crossref
4. Sirajuddin A, Raparia K, Lewis VA, et al. Primary pulmonary lymphoid lesions: radiologic and pathologic findings. Radiographics 2016;36:53-70. Crossref
5. Kawaguchi T, Himeji D, Kawano N, Shimao Y, Marutsuka K. Endobronchial mucosa-associated lymphoid tissue lymphoma: a report of two cases and a review of the literature. Intern Med 2018;57:2233-6. Crossref
6. Graham EA, Burford TH, Mayer JH. Middle lobe syndrome. Postgrad Med 1948;4:29-34. Crossref
7. Toishi M, Miyazawa M, Takahashi K, et al. Mucosa-associated lymphoid tissue lymphoma; report of two cases [in Japanese]. Kyobu Geka 2004;57:75-9.
8. Lumish M, Falchi L, Imber BS, Scordo M, von Keudell G, Joffe E. How we treat mature B-cell neoplasms (indolent B-cell lymphomas). J Hematol Oncol 2021;14:5. Crossref

Primary omental pregnancy after intrauterine insemination: a case report

© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Primary omental pregnancy after intrauterine insemination: a case report
Tony PL Yuen, MB, BS1; Winnie Hui, MRCOG, FHKAM (Obstetrics and Gynaecology)1; MK Ho, MB, BS1; Richard WC Wong, FRCPA, FHKAM (Pathology)2
1 Department of Obstetrics and Gynaecology, Pamela Youde Nethersole Eastern Hospital, Hong Kong
2 Department of Clinical Pathology, Pamela Youde Nethersole Eastern Hospital, Hong Kong
 
Corresponding author: Dr Tony PL Yuen (ypl634@ha.org.hk)
 
 Full paper in PDF
 
Introduction
Ectopic pregnancy (EP), a condition in which a fertilised ovum does not implant in the endometrial cavity, occurs in 1% to 2% of all pregnancies.1 Up to 97% of EPs occur within the fallopian tube, but implantation can also occur at locations such as the cervix, ovary, uterine cornua and abdomen. Abdominal EPs are extremely rare, making up less than 1% of EPs.1 Their presentation can be non-specific and they are classified as primary or secondary abdominal pregnancies. We present a case of primary omental pregnancy with laparoscopy and omentectomy performed.
 
Case summary
In January 2020, a 33-year-old gravida 1 para 0 woman was admitted to our gynaecology unit with right-sided abdominal pain. The patient’s past health was good and she had no history of gynaecological surgery, sexually transmitted disease or pelvic inflammatory disease. She had been treated in the private sector 3 weeks before to admission with ovulation induction and subsequent intrauterine insemination (IUI) for coital problems. Serum beta-human chorionic gonadotropin (HCG) was 48 mIU/L on day 18 and 768 mIU/L on day 22 after IUI. Ultrasound of the pelvis at 5 weeks of gestation showed no intrauterine sac. She also complained of mild per-vaginal bleeding on admission. Abdominal examination revealed tenderness over the right abdomen, next to the umbilicus. Transvaginal ultrasound of the pelvis on admission showed a linear endometrial lining, with no adnexal masses or pelvic free fluid identified. Blood tests showed a haemoglobin level of 12 g/dL and beta-HCG level of 1366 mIU/mL. Diagnostic laparoscopy was offered to the patient in view of her abdominal pain but she opted for beta-HCG monitoring as she was worried about a negative laparoscopy. She subsequently complained of severe right abdominal pain about 6 hours after admission. Repeat transvaginal ultrasound revealed no adnexal masses but a moderate amount of free fluid in the pouch of Douglas. Due to the increased abdominal pain and suspicion of a ruptured EP, the patient agreed to undergo laparoscopy.
 
Laparoscopy showed haemoperitoneum of 200 mL and a normal uterus, bilateral fallopian tubes and ovaries. Survey of the peritoneal cavity revealed a 5 × 5 cm haematoma attached to the omentum at the right hepatic flexure, with mild oozing from the site of attachment (Fig 1). The rest of the abdomen was unremarkable. General surgeons were consulted and omentectomy (including the site of bleeding) was performed.
 

Figure 1. Laparoscopic view of the omental ectopic pregnancy at the omentum, inferior to the liver
 
The patient made an uneventful postoperative recovery and haemoglobin was stable. She was discharged on day 4 after surgery. Pathological examination revealed products of gestation mixed with inflammatory and reactive mesothelial cells (Fig 2). Beta-HCG monitoring after surgery showed a satisfactory drop to a non-pregnant level: 366 mIU/mL, 144 mIU/mL, and 1.7 mIU/mL on days 2, 4, and 18 after surgery.
 

Figure 2. Histological findings in the omental resection specimen. (a) Syncytiotrophoblasts (arrows) are present in fibrin exudate over inflamed omental adipose tissue. (b) Intermediate trophoblasts (arrowheads) infiltrate the fibrofatty stroma of the omentum, consistent with omental pregnancy
 
Discussion
Among EPs, abdominal pregnancy is most rare. They have been classified as either primary or secondary. Our case meets the criteria established by Studdiford2 for a primary abdominal pregnancy: normal, bilateral fallopian tubes and ovaries with no recent or remote injury; absence of any uteroperitoneal fistula; and presence of a pregnancy related exclusively to the peritoneal surface and diagnosed early enough to exclude the possibility of secondary implantation after primary nidation elsewhere.
 
Early preoperative diagnosis of an abdominal EP is very difficult in many cases. A systematic review by Poole et al3 showed that among patients with a final diagnosis of omental EP, none had a preoperative diagnosis of abdominal pregnancy. As a result of the diagnostic difficulty, there is usually a delay from presentation to definitive treatment with some cases requiring diagnosis by serial HCG monitoring supplemented with magnetic resonance imaging. A high level of vigilance is therefore vital when monitoring the symptoms and vital signs of a suspected case, and early surgical intervention should be considered if there is clinical deterioration. In our case, we elected to perform emergent laparoscopy in view of increased abdominal pain and free fluid in the pouch of Douglas.
 
Laparotomy with excision of the embryo has been the classic management for abdominal pregnancy.4 However, with its widespread availability, laparoscopy should be the modality of choice, especially when the patient is haemodynamically stable, as in our case, and the required expertise is available. Laparoscopic management is associated with fewer morbidities, reduced intraoperative blood loss and a shorter hospital stay. The importance of a general peritoneal survey is paramount; in cases of normal fallopian tubes and ovaries, extra care must be taken not to miss an EP elsewhere in the peritoneum and prematurely commit to a negative laparoscopy. If a difficult resection is encountered, the expertise of a general surgeon will be of benefit. Alternatives to surgical treatment have also been reported,3 such as intralesional methotrexate, intramuscular methotrexate, intracardiac potassium chloride injection and artery embolisation. However, the prerequisites for non-surgical treatment include reliable imaging and for the patient to be haemodynamically stable.
 
Assisted reproductive techniques are known to be associated with an increased risk of EP. Some reports state an incidence of up to 4.5% with assisted reproductive technology compared with a spontaneous pregnancy.5 With regard to IUI, the incidence of EP is reported to be 2.05% compared with 3.33% for in vitro fertilisation. A higher risk of EP is also associated with stimulated cycles (compared with natural cycles: 2.62% vs 0.99%) and use of husband sperm (compared with donor sperm: 3.54% vs 1.08%). Many postulations have been made regarding the mechanism of an abdominal EP.3 As ovarian induction was performed in this case, the risk of EP was increased. In the setting of IUI, it is possible that the fertilised embryo develops as a primary tubal pregnancy that subsequently passes through the fimbrial end and implants into the omentum.
 
Although omental EPs are extremely rare, and in our case, the first of such a condition found after IUI, clinical suspicion must be high in a patient who presents with symptoms suggestive of EP but with normal uterus and adnexa during intraoperative exploration. Clinicians should always be vigilant with regard to the patient’s clinical condition, and there should be a low threshold for surgical intervention if clinical deterioration is noted. In addition, with the rising application of assisted reproductive technology, the risk of EPs, and by extension the risk of abdominal EPs, is also increased, making the diagnosis and treatment of this potentially life-threatening condition evermore challenging.
 
Author contributions
All authors contributed to the design of the report, acquisition of data, drafting of the manuscript and critical revision 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.
 
Conflicts of interest
The authors have no conflicts of interest to disclose.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki. Informed consent was obtained for all treatment involved as well as for publication of this article and accompanying images.
 
References
1. Fylstra DL. Ectopic pregnancy not within the (distal) fallopian tube: etiology, diagnosis, and treatment. Am J Obstet Gynecol 2012;206:289-99. Crossref
2. Studdiford WE. Primary peritoneal pregnancy. Am J Obstet Gynecol 1942;44:487-91. Crossref
3. Poole A, Haas D, Magann EF. Early abdominal ectopic pregnancies: a systematic review of the literature. Gynecol Obstet Invest 2012;74:249-60. Crossref
4. Yip SL, Tan WK, Tan LK. Primary omental pregnancy. BMJ Case Rep 2016;2016: bcr2016217327. Crossref
5. Bu Z, Xiong Y, Wang K, Sun Y. Risk factors for ectopic pregnancy in assisted reproductive technology: a 6-year, single-center study. Fertil Steril 2016;106:90-4. Crossref

Cold agglutinin–mediated autoimmune haemolytic anaemia associated with COVID-19 infection: a case report

Hong Kong Med J 2022 Jun;28(3):257–9  |  Epub 27 Apr 2022
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Cold agglutinin–mediated autoimmune haemolytic anaemia associated with COVID-19 infection: a case report
CY Chang, MRCP (Medicine); HH Chin, MRCP (Medicine)2; PW Chin, MMed (Medicine)2; M Zaid, MMed (Medicine)1
1 Department of Medicine, Hospital Sultanah Aminah, Johor Bahru, Johor, Malaysia
2 Department of Medicine, Hospital Enche’ Besar Hajjah Kalsom, Kluang, Johor, Malaysia
 
Corresponding author: Dr CY Chang (ccyik28@gmail.com)
 
 Full paper in PDF
 
 
Case report
In November 2020, a 70-year-old woman with diabetes mellitus, hypertension, and dyslipidaemia presented with a 3-day history of fever, cough, and rhinorrhoea. She reported no chest pain, shortness of breath, anosmia, or ageusia. Physical examination revealed that she was awake and not tachypneic. There was mild pallor present, but no jaundice. The patient’s blood pressure was 118/56 mm Hg, pulse rate 62 beats per minute, and temperature 36.5°C. Respiratory rate was 16 breaths per minute and pulse oximetry revealed oxygen saturation of 98% on ambient air. Chest auscultation revealed bibasilar crackles. There were no signs of lymphadenopathy, splenomegaly, or autoimmune disease. Physical examination was otherwise unremarkable.
 
Haematological analysis revealed haemoglobin 8.1 g/dL, white cell count 9.6 × 109/L (absolute lymphocyte count 3.1 × 109/L) and platelet count 346 × 109/L. The peripheral blood film showed moderate anaemia with occasional spherocytes and marked red blood cell agglutination that dispersed when blood was heated to 37°C, indicating cold agglutinin (Fig). The absolute reticulocyte count was raised at 2.3% and direct antiglobulin test showed presence of anti-complement (C3d) antibodies but not anti-immunoglobulin G antibodies. Due to a lack of facilities at the district hospital, we were unable to conduct the following tests: serum haptoglobin, direct antiglobulin test performed with warm-washed red blood cells, cold agglutinin titre, and thermal amplitude testing. Mild hyperbilirubinaemia was present, with indirect bilirubin predominating (total bilirubin 26.2 mol/L, direct bilirubin 4.7 mol/L, indirect bilirubin 21.5 mol/L). Liver transaminases and renal profile were within the normal range. C-reactive protein, serum ferritin, and serum lactate dehydrogenase level was 5 mg/L, 2671 ?g/L, and 321 U/L, respectively. Mycoplasma serology, blood cultures, D-dimer, and autoimmune screening were all negative, as were tests for hepatitis B, hepatitis C, and human immunodeficiency virus.
 

Figure. (a) Peripheral blood smear prior to ‘pre-warm’ method. (b) Peripheral blood smear after the application of ‘pre-warm’ method. The smears show a leucoerythroblastic picture (dashed arrows). There are extensive red cell agglutinations (black arrows) in (a) that dispersed on warming of blood to 37°C. Occasional spherocytes are seen in (b) [arrowhead]. No abnormal lymphoid cells are present
 
Chest radiograph showed ground-glass opacities in both lower zones. Coronavirus disease 2019 (COVID-19) infection was confirmed by reverse transcriptase-polymerase chain reaction for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal and oropharyngeal swab samples (Ct value; E gene 16.09, RdRp gene 19.23). A diagnosis of cold agglutinin—mediated autoimmune haemolytic anaemia (AIHA) due to SARS-CoV-2 was made. On the seventh day of her illness, she developed hypoxaemic respiratory failure, necessitating 3 L/min supplemental oxygen administered via nasal cannula. At the time, inflammatory markers were elevated, and a new chest radiograph revealed worsening bilateral airspace opacities. The patient was prescribed intravenous methylprednisolone 500 mg as a single dose, followed by 2 mg/kg once daily for the next 5 days. She responded well and oxygen supplementation was discontinued 7 days later. Blood inflammatory marker levels (C-reactive protein 3.1 mg/L) and chest radiograph showed improved findings. The patient was prescribed a tapering dose of dexamethasone. One unit of packed cells was transfused on the third, fifth, tenth, and fourteenth day of hospitalisation due to ongoing low-grade haemolysis. In the absence of any constitutional symptoms, and no lymphadenopathy or organomegaly on physical examination, a computed tomography scan was not performed. She was discharged home on day 21 of her illness after her symptoms had resolved and she had been transfusion-independent with stable haemoglobin level for 1 week. At 1-month follow-up examination, the patient remained well: haemoglobin was 10 g/L and new peripheral blood film examination found no cold agglutinin haemolysis.
 
Discussion
This pandemic has taken the world by storm, with many new undocumented symptoms and treatment strategies. An increasing number of COVID-19-related complications involving various disciplines, particularly haematology, are being reported. Coronavirus disease 2019 is associated with prominent haematopoietic system manifestations, including leukopenia, lymphopenia, thrombocytopenia, disseminated intravascular coagulation, and prothrombotic state.1 An association between AIHA and COVID-19 infection has nonetheless been reported infrequently. The pathophysiology of this association is poorly understood with few cases reported worldwide.
 
Cold agglutinin disease (CAD) is a form of AIHA mediated by cold agglutinins that can agglutinate red blood cells at a temperature of 3°C to 4°C, resulting in complement-mediated haemolysis. Cold agglutinins arise from either primary (unknown) or secondary (when cold agglutinins are produced as a result of an underlying infection or haematological malignancy) conditions.2 The pathogenesis of CAD as a result of infectious agents is unclear. It may be the result of complement system activation, and associated with an inflammatory state, including the upregulation of pro-inflammatory cytokines.
 
In this case, our patient fulfilled the diagnostic criteria for CAD that include haemolytic anaemia, reticulocytosis, elevated lactate dehydrogenase, hyperbilirubinaemia, positive anti-C3d antibodies, and negative anti-immunoglobulin G antibodies.3 Other infections and autoimmune diseases were excluded, and no signs of malignancy were discovered. We concluded that the CAD in this case was caused by SARS-CoV-2 (COVID-19). Because of the ongoing haemolysis, our patient required packed cell transfusions on multiple occasions. We believe that her condition deteriorated due to the “cytokine storm” and complement cascade, necessitating oxygen supplementation and blood product transfusion.
 
Lazarian et al4 reported seven cases of AIHA (four cases of warm AIHA and three cases of cold AIHA) associated with COVID-19 infection. Extensive investigations into the three cases of cold AIHA revealed the presence of underlying malignancies (marginal zone lymphoma, 2 cases; prostate cancer, 1 case). No malignancy was evident in our patient. Patil et al5 reported a case of COVID-19 infection with AIHA and pulmonary embolism, and Maslov et al6 reported a patient with COVID-19 infection and cold agglutinin haemolytic anaemia complicated by stroke and bilateral upper extremity venous thrombosis. Our patient showed no signs of thromboembolism. Although patients infected with COVID-19 are at increased risk of thromboembolic complications, AIHA/CAD should be considered as a possible contributory factor.
 
Treatment of CAD is not recommended in patients who are asymptomatic with mild anaemia or compensated haemolysis and corticosteroids should not be used to treat CAD.7 However, in our patient, the use of methylprednisolone was indicated as treatment for severe COVID-19 pneumonia. Corticosteroid administration has been proposed to reduce the systemic inflammatory response that leads to lung injury and multiorgan failure in COVID-19. Prompt administration of methylprednisolone has been shown to significantly reduce mortality rate and ventilator dependence.8 The improvement of haemolysis in our patient coincided with a favourable treatment response of COVID-19 to corticosteroid. This was reflected in her need for fewer packed cell transfusions, as well as stabilisation of her haemoglobin and no need for blood transfusions for one week prior to discharge. Rituximab has also been used to treat COVID-19-associated AIHA in two reported cases following corticosteroid failure and marginal zone lymphoma, respectively.4 More research is needed to assess the safety and efficacy of these therapies in the treatment of COVID-19-associated AIHA.
 
Author contributions
Concept or design: CY Chang.
Acquisition of data: CY Chang, HH Chin.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: CY Chang, HH Chin.
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.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Acknowledgement
The authors thank the Director General of Health Malaysia for his permission to publish this article.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patients were treated in accordance with the tenets of the Declaration of Helsinki. The patient(s) provided written informed consent for all treatments and procedures and for publication of this case report.
 
References
1. Terpos E, Ntanasis-Stathopoulos I, Elalamy I, et al. Hematological findings and complications of COVID-19. Am J Hematol 2020;95:834-47. Crossref
2. Berentsen S. New insights in the pathogenesis and therapy of cold agglutinin-mediated autoimmune hemolytic anemia. Front Immunol 2020;11:590. Crossref
3. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood 2013;122:1114-21. Crossref
4. Lazarian G, Quinquenel A, Bellal M, et al. Autoimmune haemolytic anaemia associated with COVID-19 infection. Br J Haematol 2020;190:29-31. Crossref
5. Patil NR, Herc ES, Girgis M. Cold agglutinin disease and autoimmune hemolytic anemia with pulmonary embolism as a presentation of COVID-19 infection. Hematol Oncol Stem Cell Ther 2020:S1658-3876(20)30116-3. Crossref
6. Maslov DV, Simenson V, Jain S, Badari A. COVID-19 and cold agglutinin hemolytic anomie. TH Open 2020;4:e175-7. Crossref
7. Berentsen S. How I treat cold agglutinin disease. Blood 2021;137:1295-303. Crossref
8. Salton F, Confalonieri P, Meduri GU, et al. Prolonged low-dose methylprednisolone in patients with severe COVID-19 pneumonia. Open Forum Infect Dis 2020;7:ofaa421. Crossref

Fulminant necrotising amoebic colitis: a report of two cases

Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Fulminant necrotising amoebic colitis: a report of two cases
LM Tam, MB, BS1; KC Ng, MB, BS, FRCS1; CH Man, MB, BS FRCS1; FY Cheng, MB, BS2; Y Gao, LMCHK2
1 Department of Surgery, Caritas Medical Centre, Hong Kong
2 Department of Pathology, Caritas Medical Centre, Hong Kong
 
Corresponding author: Dr LM Tam (tammy520@connect.hku.hk)
 
 Full paper in PDF
 
Case report
Case 1
In January 2019, a 31-year-old man with a history of amphetamine abuse presented with a 10-day history of watery diarrhoea and abdominal pain. On admission, he had a fever of 38.1°C and tachycardia but normal blood pressure. Abdominal examination revealed tenderness and guarding over the lower abdomen. The patient was resuscitated and intravenous antibiotics prescribed since an infective cause was considered most likely. Abdominal plain radiograph showed grossly dilated small and especially large bowel (diameter up to 9 cm). White cell count was 22×109/L (neutrophil differential count 19×109/L), liver and renal function were unremarkable. Contrast computed tomography (CT) scan of the abdomen and pelvis revealed extensive colitis, suggesting pseudomembranous colitis or diffuse colitis. Stool culture for Clostridium difficile was negative and stool microscopy revealed no ova or cysts. Human immunodeficiency virus (HIV), hepatitis B and C virus serologies were non-reactive. He was treated as pseudomembranous colitis by the medical gastrointestinal team and commenced on oral vancomycin. Later sigmoidoscopy revealed inflamed mucosa with multiple ulcers, especially at the sigmoid colon (Fig 1). Biopsies were taken. The patient’s condition deteriorated and he developed septic shock. A new contrast CT scan showed pneumoperitoneum. Emergency laparotomy was performed and revealed generalised faecal peritonitis with the whole colon necrosed and communicating with the peritoneal cavity. Debridement of necrotic tissue and multiple segmental resections of bowel with end ileostomy were performed in stages. The diagnosis of fulminant amoebic colitis (FAC) was made on histopathological evaluation of the biopsy and resection specimen (Fig 2). Antibiotics were switched to metronidazole accordingly. The patient’s condition was later complicated by an intra-abdominal fluid collection and image guided drainage was performed. He was initially nursed in the intensive care unit and then transferred to a surgical ward for rehabilitation. He was discharged from hospital 4 months later.
 

Figure 1. Endoscopy photos showing severely inflamed mucosa in Case 1
 

Figure 2. Histological examinations from Case 1. (a) Perforated ulcer. Haematoxylin and eosin (H&E) stain ×100. (b) Amoebae labelled with arrows in the lamina propria. H&E stain ×100
 
Case 2
In February 2020, a 61-year-old man presented with a ≥1-week history of diarrhoea, abdominal pain, high fever of 39°C and tachycardia with normal blood pressure. Abdominal examination showed diffuse tenderness, but without peritoneal signs. The patient’s medical history was otherwise good, and initial investigations including blood tests and plain radiographs were all unremarkable. In view of the progressive abdominal distension, urgent contrast CT was arranged and showed a suspected perforated caecum. Emergency surgery found ischaemic colon extending from the caecum to mid sigmoid, with perforations over the proximal transverse colon and hepatic flexure. Subtotal colectomy with end ileostomy was performed. He was transferred to the intensive care unit after surgery and required vasopressor and continuous venovenous haemofiltration due to severe sepsis. He showed a good response and was weaned off vasopressor support on postoperative day 4. Pathology of the surgical specimen later confirmed amoebic colitis with extensive ulcer and perforation (Fig 3). There were no features of atherosclerosis, vasculitis, thromboembolism, or inflammatory bowel disease. Microscopic results were also available after surgery. Stool culture for C difficile, stool microscopy for amoeba, stool microscopy for ova or cysts, stool polymerase chain reaction for virus, and HIV serology test results were all negative, but Entamoeba histolytica serology test was positive. He was prescribed metronidazole for 14 days and then oral diloxanide furoate for 10 days as suggested by the microbiologist. The patient’s recovery was later complicated by wound dehiscence and abdominal cocoon. Repeat surgery for debridement was performed and skin closure changed to an ABTHERA temporary abdominal closure system. The patient recovered gradually and was transferred to a rehabilitation unit 3 months after surgery.
 

Figure 3. Histological examinations from Case 2. (a) Presence of Entamoeba histolytica, stained purple due to glycogen content, in necrotic ulcer debris. Periodic acid-Schiff ×200. (b) Deep penetrating ulcer, with extensive necrosis, down to the muscularis propria. H&E stain ×10
 
Discussion
Entamoeba histolytica is a protozoan parasite and the cause of amoebiasis in humans.1 Early diagnosis and treatment are essential to avoid progression to fulminant colitis. Amoebic dysentery is classified as a notifiable disease in Hong Kong. Prevalence of amoebiasis is higher in developing countries such as India, Mexico, and parts of Central and South America,2 mainly related to poor socioeconomic and sanitary conditions. In developed countries, where faecal-oral transmission is unusual, amoebiasis is more often seen in immigrants from or individuals with a travel history to endemic areas. Other groups at risk include male homosexuals3 with or without HIV, infants, pregnant women, and those taking immunosuppressants, especially corticosteroids.1 Neither of our two cases had a relevant travel history in the past year, and they presented several months apart, so they are unlikely to be imported cases or to have had the same source of infection. Case 1 had some risk factors for amoebiasis: he was a male homosexual living in rental housing with shared rooms. A detailed history taking from patients who present with severe diarrhoea is crucial. Prompt initiation of anti-amoebic treatment should be considered in cases where there is a high index of suspicion.
 
Although E histolytica can be cultured in vitro, this is neither routinely performed nor is it a gold standard in the diagnosis of amoebic colitis because amoebic culture is insensitive (25%). The most commonly used laboratory test is stool microscopy to identify trophozoites or cysts, although this also has low sensitivity (<60%) and specificity (10%-50%). As exemplified by our two cases, both had negative stool microscopy. In some laboratories, stool antigen detection of E histolytica might be available. However, neither stool microscopy (in the absence of ingested erythrocytes in the trophozoites) nor some antigen detection kits can distinguish between pathogenic E histolytica and commensal Entamoeba dispar. Serum antibody is commonly positive in patients with invasive amoebiasis,4 especially in endemic areas. It may be difficult to differentiate past from active infection since antibodies may persist for some time. Recent commercially available multiplex polymerase chain reaction systems offer a rapid and sensitive way of detecting E histolytica DNA in stool; however, cost and availability limit their application in most patients.
 
Another popular non-invasive investigation is different modalities of imaging, especially contrast CT scan. Some CT features specific to amoebic colitis have been reported. These include extended submucosal ulcers with intramural dissection caused by flask-shaped ulcers typical of amoebiasis and omental “wrapping” indicating adhesions with neovascularisation due to ischaemic foci of transmural amoebic colitis.5 Other non-specific findings include pancolitis with areas of target signs, discontinuous bowel necrosis and coexistence of liver abscess. None of these features were evident on CT scans in our patients. In clinical practice, CT scan is not sensitive and has a small role in diagnosing FAC. It is mainly used to distinguish the severity of colitis, looking for complications such as bowel perforation or ischaemia.
 
Sigmoidoscopy and/or colonoscopy with biopsy can also be performed as a diagnostic tool. However, there is a high risk of perforation, especially of inflamed or even ischaemic bowel. We do not recommend endoscopic investigations in cases of severe colitis or in patients with high fever.
 
Preoperative diagnosis of FAC remains a challenge and detailed history taking plays an important role in identifying high-risk cases.
 
Mild cases of amoebic colitis can be treated medically with metronidazole to control systemic invasion and diloxanide furoate, a luminal agent, in addition to eliminating luminal cysts. If the condition becomes transmural, conservative treatment is no longer appropriate. Early diagnosis and extensive surgical treatment are important to reduce morbidity and mortality.1 In both our cases, with both complicated by bowel perforation, extensive bowel resection was immediately performed.
 
Intra-operatively, skipped lesions with multiple transmural perforations of bowel were noticed. However, some gross features make differentiation from other pathology difficult, especially Crohn’s disease. In our patients, necrotic tissue was more friable with little bleeding from the necrotic bowel wall. These features are quite unique compared with other causes of bowel ischaemia. This may be related to severe necrosis with consequent poor vascular supply to the bowel. In the worst case, the necrotic bowel wall communicates with the peritoneal cavity, making bowel resection more difficult as the dissection planes may be disrupted. Therefore, extensive debridement of necrotic tissue or even staged operations are required. Special gross features of FAC are seldom mentioned in other case reports. Early identification of these features enables early commencement of empirical anti-amoebic treatment and aids the recovery of patients.
 
Author contributions
Concept or design: LM Tam, KC Ng, CH Man.
Acquisition of data: LM Tam
Analysis or interpretation of data: LM Tam, FY Cheng, Y Gao.
Drafting of the manuscript: LM Tam.
Critical revision of the manuscript for important intellectual content: KC Ng, CH Man.
 
Conflicts of interest
The authors have no conflicts of interest to disclose.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patients were treated in accordance with the Declaration of Helsinki. The patients provided verbal informed consent for the treatment/procedures and consent for publication.
 
References
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2. Haque R, Huston CD, Hughes M, Houpt E, Petri WA Jr. Amebiasis. N Engl J Med 2003;348:1565-73. Crossref
3. Roure S, Valerio L, Soldevila L, et al. Approach to amoebic colitis: epidemiological, clinical and diagnostic considerations in a non-endemic context (Barcelona, 2007-2017). PLoS One 2019;14:e0212791. Crossref
4. Tanyuksel M, Petri WA Jr. Laboratory diagnosis of amebiasis. Clin Microbiol Rev 2003;16:713-29. Crossref
5. Kinoo SM, Ramkelawon VV, Maharajh J, Singh B. Fulminant amoebic colitis in the era of computed tomography scan: a case report and review of the literature. SA J Radiol 2018;22:1354. Crossref

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