A 64-year-old man presented to the emergency department with acute onset abdominal pain. His medical history was unremarkable. Initial vital signs showed blood pressure of 87/43 mmHg and pulse rate of 110 beats per minute. His abdomen was distended, with generalised tenderness and guarding. The patient was stabilised with 1 L of crystalloid. Bedside ultrasonographic examination revealed intraperitoneal free fluid. Subsequent computed tomography of the abdomen demonstrated gross haemoperitoneum and multiple hepatic lesions highly suspicious of hepatocellular carcinoma (HCC). Active contrast extravasation was noted at the posterior aspect of segment 2/3 lesion, compatible with the diagnosis of ruptured HCC. The initial haemoglobin level was 8.7 g/dL. Transarterial embolisation was urgently arranged but the patient went into cardiac arrest. Spontaneous circulation returned after 8 minutes of cardiopulmonary resuscitation. Haemoglobin level fell to 5.5 g/dL and platelet count was normal. Prothrombin time and activated partial thromboplastin time were prolonged to 20.3 s and 62.1 s, respectively. International normalised ratio was 1.9. He was transfused with 2 units of pack cells and 4 units of plasma. Transarterial embolisation was successfully performed. Active contrast extravasation over a branch of the left hepatic artery was demonstrated but controlled by Gelfoam injection.

The patient was then transferred to the intensive care unit. Rotational thromboelastometry (ROTEM^®; Tem International GmbH, Munich, Germany) was performed to guide transfusion strategy (Fig a). Maximum lysis was shown to be 100%, indicating abnormally accelerated clot lysis. Maximum lysis over 15% is diagnostic of hyperfibrinolysis. The lysis index at 30 minutes was 5%, indicating almost complete clot dissolution 30 minutes after initial formation. No dysfunction in coagulation activation or clot propagation was otherwise detected. Tranexamic acid 1 g was administrated according to the interpretation of ROTEM results. A follow-up ROTEM analysis after antifibrinolytic treatment demonstrated restoration of normal fibrinolysis (Fig b). Haemostasis was achieved and no further blood transfusion was needed.

Testing for hepatitis B surface antigen was later revealed to be reactive. This patient probably had liver cirrhosis and HCC consequent to chronic hepatitis B infection. The occurrence of ruptured HCC tipped the balance in this vulnerable patient. He developed abdominal compartment syndrome and hepatic failure. The sequential organ failure assessment score was 13 with an estimated mortality of over 90%. The surgical team advised optimum medical supportive treatment in view of the extremely high operative risk. The patient succumbed 16 hours after hospital admission.

Haemocoagulation is a complex interaction of procoagulants, anticoagulants, fibrinolytic proteins, and cellular components. Platelets are activated in response to vascular injury, leading to primary haemostasis. Activated platelets adhere to damaged endothelium and aggregate to create a temporary platelet plug. Secondary haemostasis involves activation of the coagulation cascade, resulting in fibrin formation. The platelet plug is strengthened by the cross-linked fibrin to form a stable clot. Fibrinolysis serves as the final stage of coagulation to regulate the extent of clot formation and to maintain vascular patency. Cross-linked fibrin is broken down by plasmin and normal blood flow is restored.

Hyperfibrinolysis refers to excessive fibrinolytic activity that threatens clot integrity and leads to defective haemostasis. It is common in patients with chronic liver disease, major trauma, and obstetric complications. However, the incidence is not well studied and it has often been underdiagnosed due to an absence of appropriate tests.1 Conventional coagulation tests, such as prothrombin time, activated partial thromboplastin time, and thrombin time, are ineffective in detecting hyperfibrinolysis. Viscoelastic haemostatic assays are the only tests for rapid detection and quantification of hyperfibrinolysis.2

Rotational thromboelastometry is a form of viscoelastic assay. It provides a global haemostatic assessment from initial platelet activation, through platelet aggregation, clot strengthening by cross-linked fibrin, to clot dissolution. The degree of clot lysis is expressed numerically as maximum lysis. Hyperfibrinolysis is diagnosed when maximum lysis exceeds 15% within a 60-minute ROTEM analysis. Schöchl et al3 further quantified this condition based on the time course of clot dissolution, as reflected by the lysis index at 30 minutes and at 60 minutes. They categorised complete clot lysis within 30 minutes as fulminant hyperfibrinolysis; intermediate when complete clot lysis was within 30 to 60 minutes; and late when complete clot lysis exceeded 60 minutes. Prompt recognition of hyperfibrinolysis by ROTEM analysis guides appropriate antifibrinolytic therapy. Untreated hyperfibrinolysis has been shown to be associated with refractory bleeding and increased mortality.1

Rotational thromboelastometry has multiple advantages over conventional coagulation tests. In contrast to conventional coagulation tests that use plasma, ROTEM uses whole blood and can determine the contribution of both cellular and plasma components of haemostasis. Conventional coagulation tests provide only a quantitative assessment of individual procoagulation factors; results are not necessarily a good indication of the in vivo haemostatic process, especially in patients with chronic liver disease.4 Rotational thromboelastometry also provides real-time functional assessment of the haemostatic process, from clot formation to its lysis, and is useful for identifying hyperfibrinolysis. There is evidence that use of ROTEM-guided haemostatic strategy reduces transfusion requirement in different clinical settings.5 6 7

Understanding its limitations is equally important in the interpretation of ROTEM analysis. It is insensitive to the effect of platelet inhibitors such as aspirin and clopidogrel. Thrombin, the strongest activator of platelets, is produced in large amounts during ROTEM analysis, masking the inhibitory effects of antiplatelet agents.8 It is also poor at detecting conditions that affect platelet adhesion and aggregation, with Von Willebrand’s disease being a well-known example.9 The ROTEM analysis is undertaken at 37°C to mimic physiological conditions so the negative effect of hypothermia on coagulation is not reflected by the analysis.9

In conclusion, owing to the limitations of conventional coagulation tests, hyperfibrinolysis is frequently underdiagnosed. With its ability of real-time functional haemostatic assessment from clot formation to lysis, ROTEM analysis allows better insight into the complex haemocoagulation process. The rapid detection of hyperfibrinolysis by ROTEM can guide prompt antifibrinolytic treatment, possibly reducing the transfusion requirement in bleeding patients.

Concept or design: KM Kwok, KL Lee, SY Lam, T Liong, KI Law.
Acquisition of data: KM Kwok.
Analysis or interpretation of data: KM Kwok, KL Lee, SY Lam, T Liong, KI Law.
Drafting of the manuscript: KM Kwok.
Critical revision of the manuscript for important intellectual content: All authors.

The authors have no conflicts of interest to disclose.

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

The patient was treated in accordance with the Declaration of Helsinki. Patient was incapable to provide informed consent for publication.

1. Theusinger OM, Wanner GA, Emmert MY, et al. Hyperfibrinolysis diagnosed by rotational thromboelastometry (ROTEM) is associated with higher mortality in patients with severe trauma. Anesth Analg 2011;113:1003-12. Crossref

2. Yeung MC, Tong SY, Tong PY, Cheung BH, Ng JY, Leung GK. Use of viscoelastic haemostatic assay in emergency and elective surgery. Hong Kong Med J 2015;21:45-51. Crossref

3. Schöchl H, Frietsch T, Pavelka M, Jámbor C. Hyperfibrinolysis after major trauma: differential diagnosis of lysis patterns and prognostic value of thrombelastometry. J Trauma 2009;67:125-31. Crossref

4. Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011;365:147-56. Crossref

5. De Pietri L, Bianchini M, Montalti R, et al. Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: a randomized, controlled trial. Hepatology 2016;63:566-73. Crossref

6. Veigas PV, Callum J, Rizoli S, Nascimento B, da Luz LT. A systematic review on the rotational thrombelastometry (ROTEM®) values for the diagnosis of coagulopathy, prediction and guidance of blood transfusion and prediction of mortality in trauma patients. Scand J Trauma Resusc Emerg Med 2016;24:114. Crossref

7. Vymazal T, Astraverkhava M, Durila M. Rotational thromboelastometry helps to reduce blood product consumption in critically ill patients during small surgical procedures at the intensive care unit—a retrospective clinical analysis and literature search. Transfus Med Hemother 2018;45:385-7. Crossref

8. Lang T, von Depka M. Possibilities and limitations of thrombelastometry/-graphy [in German]. Hamostaseologie 2006;26(3 Suppl 1):S20-9. Crossref

9. Srivastava A, Kelleher A. Point-of-care coagulation testing. Continuing Educ Anaesthesia Crit Care Pain 2013;13:12-6. Crossref

A 79-year-old man presented with left-sided weakness, drowsiness and dysphasia following left atrial appendage occlusion implantation in a cardiac intensive care unit. A sudden drop in systolic blood pressure to 40 mmHg was noted. Echocardiogram and angiogram revealed no obvious coronary artery disease. Computed tomography (CT) of the brain showed no major vessel occlusion or gas pocket. A new CT of the brain showed more established infarct and oedema. Four sessions of hyperbaric oxygen therapy (HBOT) were conducted in accordance with United States Navy Treatment Tables (USNTT)1: two USNTT6 and two USNTT5.

A 40-year-old woman was admitted to a surgical unit for suspected acute appendicitis. Urgent CT of the abdomen with contrast was performed, but approximately 60 mL of air was injected intravenously during the procedure and gas was evident in the right ventricle. Luckily, she was asymptomatic as the gas emboli had entered only the venous system and remained in the heart. One session of HBOT was conducted with USNTT6.

A 57-year-old woman underwent fine needle aspiration cytology under CT guidance for lung mass. The patient developed sudden onset bilateral anopia and left upper limb weakness during the procedure. Computed tomography brain and thorax identified a small gas embolism in the pulmonary vein with pulmonary haemorrhage. No obvious gas bubble was noted in the brain. A total of four sessions of HBOT were conducted with two USNTT6 and two USNTT5.

An 84-year-old man underwent CT-guided lung biopsy for right lung mass but experienced an acute deterioration in Glasgow Coma Scale (GCS) score. Urgent CT of the brain showed multiple acute gas emboli and confirmed the diagnosis of cerebral arterial gas embolism (AGE). On arrival at the HBOT centre, he had GCS of 13/15 and right limb weakness with power of 1/5 and 3/5, respectively. Two sessions of HBOT were conducted with USNTT6.

A 66-year-old man with biliary pancreatitis underwent urgent endoscopic retrograde cholangiopancreatography. After the procedure he developed left-sided weakness with limb power of 0/5 after 5 minutes. Urgent CT of the brain revealed branching gas densities at the sulcal space of his right frontal and parietal lobes (Fig 1). Two sessions of HBOT with USNTT6 were conducted and the patient’s symptoms considerably improved.

A 72-year-old man underwent CT-guided fine needle aspiration cytology for a lung lesion. The patient developed transient hypotension on needle removal and CT of the thorax revealed gas embolism in his left ventricle with no pneumothorax (Fig 2). The patient remained asymptomatic with no neurological deficit. Gas embolism had been introduced through the pulmonary circulation but remained in the heart, avoiding the complication of cerebral arterial occlusion. One session of HBOT was conducted with USNTT6.

Gas embolism is a serious and life-threatening condition. It is usually iatrogenic and should be treated promptly to prevent serious complications such as cerebral AGE. It presents with sudden deterioration in neurological and haemodynamic status following risky medical procedures, most notably lung biopsy and cardiac interventions. This case report revealed six patients with gas embolism: five with AGE and one with venous gas embolism. Four patients with AGE manifested as cerebral AGE with neurological deficits such as limb weakness and anopia (Table).

As soon as AGE is suspected, the patient should start receiving 100% high-flow oxygen and be placed in the right lateral decubitus position. The definitive treatment for AGE is HBOT with 100% oxygen, although no randomised controlled trials have been conducted to confirm its efficacy in this disease. Hyperbaric oxygen therapy “crushes” the bubbles with pressure, accelerates gas diffusion and bubble resolution with oxygen, oxygenates ischaemic tissue, reduces cerebral oedema, and decreases neutrophil adhesion to the endothelium.1 2 A retrospective study in France showed that the initial neurological symptoms were impaired consciousness (70%), focal motor deficits (60%), seizures (11%), visual disturbance (10%), dysarthria/aphasia (5%) and vertigo (5%). In all, 26% of patients were haemodynamically unstable and subject to hypotension, circulatory collapse, and cardiac arrest. Respiratory disturbances such as dyspnoea, cough or chest pain were present in 23% of patients.3

In a study of 45 patients with AGE, good neurological outcome was achieved in 27 (60%) of them.4 Time to receipt of HBOT was the only statistically significant factor predictive of a good outcome with mean delay 8.8 hours.4 Although probability of a good outcome is highest when HBOT is administered as soon as possible, a good response can still be obtained if treatment is delayed for longer than 24 hours.3 5 There is a tendency for patients with AGE to deteriorate after their initial apparent recovery; thus, early HBOT is still recommended for patients with a seemingly spontaneous recovery.6 Although identification of gas bubbles on CT of the brain is not a prerequisite to HBOT, early treatment can also attenuate leucocyte adherence to damaged endothelium and secondary inflammation that in turn facilitate the return of blood flow. However, gas bubbles can persist for several days, and many case reports have demonstrated the benefit of HBOT after delays ranging from hours to days. Complete recovery has been reported in one patient in whom treatment was delayed for 28 hours. In 2017, another patient who was deeply comatose with AGE recovered and was able to lead a functional life after HBOT had been delayed for 6 days.7 8 In our cases, all the patients were treated within 7 hours onset of symptoms. Most fully recovered except for Patient 1. The aetiology of neurological deterioration in Patient 1 was likely due to a combination of gas embolism, clots, and hypotension.

According to the United States Navy Diving Manual,9 USNTT6 is the standard initial compression therapy for AGE. It is a table with maximum pressure up to 2.8 atmospheres absolute (ATA) for 1 hour 15 minutes with slow depressurisation to 1.9 ATA lasting for 2.5 hours. Total treatment time is approximately 4 hours 45 minutes. There is no conclusive evidence that use of pressure higher than 2.8 ATA has any advantage. Use of pressure up to 6 ATA poses further risks to the patient and attending staff, including gas toxicity and decompression sickness. Typically, one to three hyperbaric treatments are required to treat AGE; the clinical condition should be monitored until there is no further stepwise improvement. There are reports that up to 10 treatments have been required to reach a stable condition.10 11

The USNTT5, which is a shorter treatment used to treat mild decompression sickness, may be used together with USNTT6 for AGE when prolonged treatment is required. This treatment table advises a maximum pressure up to 2.8 ATA for 45 minutes with slow depressurisation to 1.9 ATA for 30 minutes. Total treatment time is approximately 2 hours 15 minutes. According to the Royal Navy Diving manual,12 which is commonly used in Europe, RN62 Table is the standard to treat AGE. This treatment is similar to USNTT6 with a maximum pressure of 2.8 ATA.

Arterial gas embolism presents in highly variable ways with no pathognomonic signs or symptoms. It is uncommon to achieve complete consensus on the diagnosis, and it is common practice to err on the side of caution. Hyperbaric oxygen therapy should be initiated as early as possible although delayed treatment is also effective. Failure to administer treatment can result in long-term disability. Hyperbaric oxygen therapy should be considered for any suspected AGE.

Concept or design: JCW Chau.
Acquisition of data: JCW Chau.
Analysis or interpretation of data: JCW Chau.
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.

All authors have disclosed no conflicts of interest.

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

The patients were treated in accordance with the Declaration of Helsinki. The patients provided informed consent for the treatment/procedures, and verbal consent for publication.

1. United States Navy. Diagnosis and treatment of decompression sickness and arterial gas embolism. In: US Navy Diving Manual. Revision 7. Vol 5. Available from: https://www.navsea.navy.mil/Portals/103/Documents/SUPSALV/Diving/US%20DIVING%20MANUAL_REV7.pdf?ver=2017-01-11-102354-393. Accessed 30 Sep 2020.

2. Grim PS, Gottlieb LJ, Boddie A, Batson E. Hyperbaric oxygen therapy. JAMA 1990;263:2216-20. Crossref

3. Blanc P, Boussuges A, Henriette K, Sainty JM, Deleflie M. Iatrogenic cerebral air embolism: importance of an early hyperbaric oxygenation. Intensive Care Med 2002;28:559-63.Crossref

4. Beevor H, Frawley G. Iatrogenic cerebral gas embolism: analysis of the presentation, management and outcomes of patients referred to The Alfred Hospital Hyperbaric Unit. Diving Hyperb Med 2016;46:15-21.

5. Massey EW, Moon RE, Shelton D, Camporesi EM. Hyperbaric oxygen therapy of iatrogenic air embolism. J Hyperb Med 1990;5:15-21.

6. Pearson RR, Goad RF. Delayed cerebral edema complicating cerebral arterial gas embolism: case histories. Undersea Biomed Res 1982;9:283-96.

7. Benson J, Adkinson C, Colier R. Hyperbaric oxygen therapy of iatrogenic cerebral arterial gas embolism. Undersea Hyperb Med 2003;30:117-26.

8. Perez MF, Ongkeko Perez JV, Serrano AR, Andal MP, Aldover MC. Delayed hyperbaric intervention in lifethreatening decompression illness. Diving Hyperb Med 2017;47:257-9 Crossref

9. United States Navy. US Navy Diving Manual. Revision 7. Vol 5: Diving medicine and recompression chamber operations. 2016. Available from: https://www.navsea.navy.mil/Portals/103/Documents/SUPSALV/Diving/US%20DIVING%20MANUAL_REV7.pdf?ver=2017-01-11-102354-393. Accessed 30 Sep 2020.

10. Vann RD, Butler FK, Mitchell SJ, Moon RE. Decompression illness. Lancet 2011;377:153-64.Crossref

11. Undersea & Hyperbaric Medical Society. UHMA Best Practice Guidelines: Prevention and Treatment of Decompression sickness and arterial gas embolism. Available from: https://www.uhms.org/images/DCS-AGE-Committee/dcsandage_prevandmgt_uhms-fi.pdf. Accessed 30 Sep 2020.

12. Royal Navy, Ministry of Defence. Diving Manual. HM Stationery Office, London; 1972.

In July 2017, a 28-month-old boy presented to a private outpatient clinic with a 2-day history of fever and coryzal symptoms (Table). He had enjoyed good past health and his family history was unremarkable. On clinical examination, he was noted to have respiratory distress and tachycardia. Plain radiograph of the chest (CXR) showed perihilar haziness but no consolidation. He was transferred to Queen Mary Hospital, Hong Kong, to exclude myocarditis in view of elevated serum troponin in blood taken in the private clinic. On admission, he was noted to have diffuse crepitations and wheeze suggestive of pneumonitis. Nebulised salbutamol, hypertonic saline, and intravenous cefotaxime were administered. Complete blood count revealed neutrophilia, normal liver and renal function, and normal creatine kinase level. Venous blood gas showed no acidosis. Troponin was high initially but then gradually normalised. Echocardiogram showed no features of myocarditis. Nasopharyngeal aspirate and throat swab test results were positive for enterovirus (EV)/rhinovirus ribonucleic acid (RNA) using reverse transcriptase-polymerase chain reaction (RT-PCR) detection method. EV71 RNA was not evident. Nasopharyngeal aspirate for mycoplasma, throat swab and blood culture were all negative. He then developed progressive respiratory distress with increased cough and high fever up to 40°C on day 7 of illness and CXR showed worsening of bilateral perihilar haziness. In view of the progressive respiratory failure, the child was admitted to the paediatric intensive care unit 2 days later (day 9).

On admission to paediatric intensive care unit, he was noted to have generalised muscle weakness with a weak voice and an inability to sit up. Gag reflex and jerks were preserved. He was then intubated and ventilated under sedation. On reassessment, chest auscultation revealed decreased air entry over the left side, corresponding to the left lower zone collapse evident on CXR. He was prescribed piperacillin-tazobactam and levofloxacin. On day 10, throat swab culture grew only commensals while endotracheal aspirate revealed scanty growth of alpha-haemolytic streptococci with negative fungal smear and culture, and RT-PCR identified EV/rhinovirus. Broncho-alveolar lavage was also performed but results were unremarkable: Pneumocystis jiroveci (carinii), smear and culture for bacteria, fungus and acid-fast bacilli, and RT-PCR for cytomegalovirus, herpes simplex virus, Mycoplasma, Legionella, were all negative. Urine culture was negative for Legionella antigen.

On day 11, the patient exhibited paradoxical breathing on weaning of sedation along with hypotonia and paralysis of four limbs. Urgent sagittal T2-weighted magnetic resonance imaging of spine (day 11) showed mild T2 hyperintensity with mild expansion within the central portion of the cervical cord from C3 to C6 (Fig). No intraspinal mass or collection could be seen. Neurology examination was performed on day 12. Creatine kinase was normal and anti-acetylcholine receptor and anti-aquaporin-4 were negative. Eye examination the following day showed no evidence of optic neuritis. Immunoglobulin G and immunoglobulin M of anti-gangliosides were all negative. Lumbar puncture revealed normal cerebrospinal fluid level of glucose and protein. Total cell count was 100 × 10⁶/L with predominantly (80%) neutrophils. Cerebrospinal fluid culture was negative for viruses, including EV, herpes simplex virus or varicella-zoster virus. Cerebrospinal fluid levels of oligoclonal protein and immunoglobulin G were unremarkable. The working diagnosis was transverse myelitis affecting cervical cord C3 to C6. He was prescribed pulse methylprednisolone 30 mg/kg for 5 days (day 12 to 16) followed by a tapering oral dose of prednisolone together with intravenous immunoglobulin 2 g/kg over 2 days (day 16 and 17). He was also treated with therapeutic plasma exchange with 1.5-times plasma volume for five courses over 2 weeks (day 22, 24, 26, 30, 32). His condition gradually improved and he was extubated (day 47) after 38 days of invasive ventilation. The child was successfully discharged from the paediatric intensive care unit after 2 months (day 64) and achieved full neurological recovery with intensive training by physiotherapists. Subsequent review by a microbiologist using gene sequencing of initial specimens obtained on day 3 of admission to Queen Mary Hospital revealed EV-D68 RNA in nasopharyngeal aspirate, endotracheal aspirate and stool samples. Samples remained positive for 4 weeks (day 30, during acute deterioration warranting intensive care unit admission) and were negative after 6 weeks (day 55). The definitive diagnosis was EV-D68-associated acute flaccid paralysis (AFP) although EV-D68 was not present in the cerebrospinal fluid and plasma/serum samples were not tested for EV-D68 by RT-PCR.

Acute flaccid paralysis is defined by the World Health Organization as a clinical syndrome of diverse aetiology characterised by acute-onset limb weakness or paralysis with varying degrees of autonomic and somatic nervous system dysfunction that reaches maximum severity over a period of days or weeks in a child younger than 15 years of age.1 It is a diagnosis of exclusion. In 1962, a new strain of EV, EV-D68, was identified in Berkeley, California. In 2014, EV-D68 outbreaks were reported in 20 countries including the United States, Canada, Europe, and Asia with a total of over 2000 cases. This corresponded to an increased global incidence of AFP.2 A casual association between EV-D68 and AFP is supported by Bradford Hill criteria.3 Despite public health attempts in 1988 to eliminate AFP through the Global Polio Eradication Initiative4 and roll-out of the oral polio vaccine5 to prevent vaccine-associated poliomyelitis, the emergence of EV-D68-associated AFP has become a significant cause of neurological deficits in children since 2014. Owing to its impact on the healthcare system, a comprehensive literature review and further detailed studies are warranted. This is the first case encountered in our department. It is important for clinicians in Hong Kong to be alert for the disease.

As a newly emerging disease manifestation, a high index of suspicion and clinical awareness is advocated to facilitate earlier recognition and diagnosis through appropriate investigations, and presumably, improved clinical outcomes. The optimum treatment strategy has yet to be defined and preventive strategies are still being developed. Local and international notification systems as well as comprehensive surveillance are suggested since disease outbreaks may occur at any time and may have a serious impact on affected children.

Acquisition of data: WYK Chan, SHY Chim, DML Tse.
Analysis or interpretation of data: WYK Chan, DML Tse, PL Ho.
Drafting of the manuscript: WYK Chan.
Critical revision of the manuscript for important intellectual content: All authors.

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

All authors have disclosed no conflicts of interest.

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

The parents of the patient gave consent for publication.

1. Bitnun A, Yeh EA. Acute flaccid paralysis and enteroviral infections. Curr Infect Dis Rep 2018;20:34. Crossref

2. Holm-Hansen CC, Midgley SE, Fischer TK. Global emergence of enterovirus D68: a systematic review. Lancet Infect Dis 2016;16:e64-75. Crossref

3. Messacar K, Asturias EJ, Hixon AM, et al. Enterovirus D68 and acute flaccid myelitis-evaluating the evidence for causality. Lancet Infect Dis 2018;18:e239-47. Crossref

4. World Health Organization. Global Polio Eradication Initiative. 2018. Available from: http://polioeradication.org/where-we-work/polio-endemic-countries/. Accessed 24 Mar 2018.

5. World Health Organization. Global Polio Eradication Initiative. Circulating vaccine-derived poliovirus. 2018. Available from: http://polioeradication.org/polio-today/polio-now/this-week/circulating-vaccine-derived-poliovirus/. Accessed 24 Mar 2018.

In January 2018, a 21-year-old man with good past health presented with a 2-week history of left forearm painless lump. He had no fever. The lump was 30 mm in diameter with no evidence of inflammation. Preoperative diagnosis was a sebaceous cyst and preoperative blood tests were not routinely performed.

Surgical excision was performed under local anaesthesia with lidocaine and application of a tourniquet. Intra-operatively, a whitish-yellowish 25-mm subcutaneous nodule surrounded by dense adhesions without a definite border was removed. The nodule was firm and multi-lobulated with multiple feeding vessels. Although en bloc excision with a 5-mm margin was attempted, the dense fibrous mass was partially breached during dissection due to scarring.

After tourniquet release, the patient developed flushing, dizziness, diarrhoea, hypotension, and sinus tachycardia. He had no respiratory distress but the clinical diagnosis was anaphylactic shock. He was stabilised with fluid resuscitation and intravenous adrenaline. Laboratory tests showed an elevated white blood cell count (WBC) at 13.6 × 10⁹/L (reference range: 3.9-10.7 × 10⁹/L), neutrophil predominance at 85.9% (reference: 38%-76%), and low eosinophil count of only 0.027 × 10⁹/L (reference: <0.45 × 10⁹/L) and 0.2% of total WBC. Blood tests were otherwise unremarkable. Serum mast cell tryptase level was 46.2 μg/L immediately after surgery but dropped to 3.3 μg/L after 24 hours. Erythrocyte sedimentation rate or C-reactive protein were not measured. The patient remained well and was discharged home the next day.

The patient had no known history of allergy and skin allergy test for exposed agents including lidocaine was negative. On further questioning, he revealed regular contact with horses located in a countryside barn but no contact with other animals. He reported skin erythema (Fig 1) prior to swelling onset but had presumed this was due to a mosquito bite.

Microscopy of the nodule revealed a piece of fibro-fatty tissue with mixed inflammatory cell infiltrate and dense eosinophilic infiltrate (Fig 2a), and a 0.72 mm × 0.29 mm fragment of degenerated parasite rimmed by foamy histiocytes (Fig 2b). There was no evidence of malignancy. The surgical margin measured from the edge of the surrounding granulomatous inflammation to the closest edge of the excised specimen was 0.82 mm. Further molecular study by polymerase chain reaction and DNA sequencing based on Filarioidea cytochrome oxidase subunit I (cox1) and specific 12S ribosomal RNA (12S rRNA) gene revealed the parasite to be Dirofilaria hongkongensis.1

The patient remained symptom-free and differential WBC and C-reactive protein were normal at 6 months after surgery. No antiparasitic therapy was deemed necessary by microbiologists.

Dirofilaria hongkongensis has been proposed as a novel species causing zoonotic filariasis in humans and is a possible cause of unresolved subcutaneous nodules in Hong Kong.2 This is the first reported case worldwide of anaphylactic shock following excision of subcutaneous dirofilariasis in a human.

Zoonotic filariae are transmitted to humans through the bite of an infected arthropod such as mosquitoes. However, they cannot grow to maturity in accidental hosts such as humans.3 The pathogenesis is localised foreign body reaction around a moribund parasite. The absence of a host inflammatory response in the asymptomatic period suggests death of the worm due to an unfavourable host environment, rather than host immunity.3 Asymptomatic survival and growth of the parasite may continue for ≥6 months. The lesion becomes clinically noticeable due to granulomatous reaction with tissue scarring and can present as a subcutaneous or ocular lesion, and rarely as lymphadenopathy and nodules in deeper tissues such as the lungs. In our patient, the subcutaneous dirofilariasis presented as a painless lump in his forearm, without any symptoms or signs of inflammation. The patient reported some skin erythema prior to the onset of the swelling. The erythema could have been caused by a mosquito bite, which is a possible route of parasite transmission. The absence of pain, warmth, or erythema over the mass would suggest the parasite did not trigger a significant inflammatory response in our patient. After the parasite’s death, the remaining material could be shielded off from the host tissue by a dense fibrous tissue envelope, producing a lump which was otherwise asymptomatic.

Careful history taking may reveal exposure to animals. Subcutaneous infections are small (0.5-1.5 cm) and discrete. Pain or sense of a moving worm may be present. Blood tests for eosinophilia and elevated inflammatory markers might be useful, but the absence of systemic inflammation is common3 and blood test results may be unremarkable. In our patient, blood tests were not taken preoperatively, as the clinical impression of the mass was a sebaceous cyst, with the absence of signs of inflammation. Postoperative blood tests showed neutrophilia instead of eosinophilia, but the results were likely affected by the anaphylaxis.

Among around 40 species of Dirofilaria, D immitis and D repens account for most cases of infection in humans. Dirofilaria immitis is commonly known as “dog heartworm” and has a cosmopolitan distribution. Hou et al4 reported seropositivity in 30.6% of stray dogs and 15.6% of domestic dogs in north-eastern China. Wang et al5 reported a 0% to 7.4% seroprevalence in dogs in coastal cities in south-eastern China. Dirofilaria repens is prevalent worldwide including Southeast Asia. Dirofilaria hongkongensis was first proposed as a distinct species in 2012, following three cases of human infection.2 In stray dogs in Hong Kong, the seroprevalence of D hongkongensis is 3%,2 and that of D immitis is 10%.6

Molecular study in nucleotide sequencing of cytochrome oxidase subunit 1 (cox1) gene and the 12S ribosomal RNA (12S rRNA) gene is useful in the identification of Dirofilaria species, taking reference from GenBank data. The cox1 gene and 12S rRNA gene specific to D hongkongensis were identified (GenBank accession number NC_031365). Simpler diagnostic tests would be less reliable; for example, morphological identification depends on the quality of histopathological specimen, and in our case only parasitic fragments were found. Retrospective molecular study could also be performed on the stored specimen for epidemiological studies.

Parasitic materials are foreign antigens that may trigger a type I immunoglobulin E–mediated hypersensitivity reaction. Dirofilaria immitis extract can result in shock and elevated plasma histamine level in dogs,7 while hydatid cyst (Echinococcus spp) rupture has been associated with anaphylactic shock.8 We believe the partial breach of the parasitic tissue envelope during our surgical dissection led to contact of parasitic material with host tissue. This contact, in turn, caused the hypersensitivity reaction and anaphylactic shock in our patient.

We recommend complete en bloc excision of lesions suspected to be caused by dirofilariasis to prevent anaphylaxis, especially when surgeons encounter dense adhesions or multiple feeding vessels. Further study is required to ascertain the necessary margin of excision to avoid inadvertent breakage of the tissue envelope. Up to 75.4% of parasitised humans experience chronic urticaria.9 In our patient, the capsule was breached during dissection and sudden allergen release may have triggered the anaphylactic cascade. Antiparasitic medication is likely unnecessary if the parasite can be removed intact.

Anaphylactic shock can cause sudden haemodynamic collapse. It is characterised by acute onset of hypotension after allergen exposure, or the combination of cutaneous, cardiopulmonary or gastrointestinal manifestations.10 The importance of routine monitoring, timely detection and cardiopulmonary stabilisation cannot be overemphasised. Plasma tryptase or histamine level may serve as a diagnostic adjunct in doubtful cases. Fluid resuscitation, supplemental oxygen, and epinephrine injection are indicated as effective treatments of anaphylactic shock.

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

All authors have disclosed no conflicts of interest.

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

The patient was treated in accordance with the Declaration of Helsinki. The patient provided verbal informed consent for publication of this de-identified case report, including clinical photos.

1. Dang TC, Nguyen TH, Do TD, et al. A human case of subcutaneous dirofilariasis caused by Dirofilaria repens in Vietnam: histologic and molecular confirmation. Parasitol Res 2010;107:1003-7. Crossref

2. To KK, Wong SS, Poon RW, et al. A novel Dirofilaria species causing human and canine infections in Hong Kong. J Clin Microbiol 2012;50:3534-41. Crossref

3. Eberhard ML. Zoonotic filariasis. In: Guerrant R, Walker D, Weller P, editors. Tropical Infectious Diseases: Principles, Pathogens, and Practice. 3rd ed. New York: Elsevier; 2011: 750-8. Crossref

4. Hou H, Shen G, Wu W, et al. Prevalence of Dirofilaria immitis infection in dogs from Dandong, China. Vet Parasitol 2011;183:189-93. Crossref

5. Wang J, Zhu X, Ying Z, et al. Prevalence of Dirofilaria immitis infections in dogs and cats in Hainan Island/Province and three other coastal cities of China based on antigen testing and PCR. J Parasitol 2019;105:199-202. Crossref

6. Wong SS, Teng JL, Poon RW, et al. Comparative evaluation of a point-of-care immunochromatographic test SNAP 4DX with molecular detection tests for vector-borne canine pathogens in Hong Kong. Vector Borne Zoonotic Dis 2011;11:1269-77. Crossref

7. Kitoh K, Katoh H, Kitagawa H, Nagase M, Sasaki N, Sasaki Y. Role of histamine in heartworm extract-induced shock in dogs. Am J Vet Res 2001;62:770-4. Crossref

8. Khanna P, Garg R, Pawar D. Intraoperative anaphylaxis caused by a hepatic hydatid cyst. Singapore Med J 2011;52:e18-9.

9. Minciullo PL, Cascio A, Gangemi S. Association between urticaria and nematode infections. Allergy Asthma Proc 2018;39:86-95. Crossref

10. Simons FE, Ardusso LR, Bilò MB, et al. World allergy organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J 2011;4:13-37. Crossref

A 51-year-old lady with a history of congenital diaphragmatic hernia repair during infancy presented to the emergency department with increasing abdominal pain and repeated vomiting. Posteroanterior chest plain radiograph revealed dilated small bowel loops in the right thoracic cavity. Computed tomography scan revealed two closely related small bowel loops trapped within a narrow hernia neck orifice across the diaphragm, suggestive of closed loop intestinal obstruction (Fig 1). Blood test results revealed metabolic acidosis and elevated lactate level.

Emergency laparotomy via a subcostal incision revealed a right-sided large diaphragmatic defect with bowel herniating into the thoracic cavity. Transabdominal reduction of the bowel was difficult owing to adhesion of bowel to the lung so an additional posterolateral thoracotomy was performed by a cardiothoracic team. Adhesiolysis was performed and the small bowel freed and reduced to the abdominal cavity via the transthoracic approach. Examination through the thoracotomy revealed minimal residual diaphragmatic tissue (Fig 2a). Primary closure was not possible and repair with a patch posed a technical challenge in the absence of sufficient residual diaphragmatic tissue to enable secure anchorage. For the anterolateral portion, multiple pledgetted 3-O sutures were passed through the intercostal space for anchorage (Fig 2b). A neo-diaphragm was reconstructed using a porcine dermal collagen implant of size 150 mm × 200 mm × 1 mm (Permacol^TM; Medtronic, Minneapolis [MN], United States). The patch was then parachuted down to cover the defect and secured. A 4-cm flutter-valve patch was directed downwards and medially to avoid suturing and injury to the oesophagus and inferior vena cava (Fig 2c). We believe this design permits peristalsis of oesophageal content without causing stricture while also preventing future intestinal herniation.

Postoperatively the patient was prescribed total parenteral nutrition for 10 days and gradually tolerated a normal diet. A computed tomography scan at 10 days after surgery confirmed an intact neo-diaphragm with no recurrence of hernia. The patient was discharged home 13 days after surgery. She was well at follow-up examinations at 1 month and 12 months after surgery. Chest plain radiograph confirmed no recurrence of hernia (Fig 3).

Diaphragmatic hernia is a rare but serious condition associated with respiratory and gastrointestinal complications and increased mortality.

Surgical repair is the gold standard treatment to prevent complications. However, patients with a previously repaired congenital diaphragmatic hernia are more prone to respiratory complications during childhood and occasionally develop recurrences.1 However, the long-term success rate of repair is good with patients surviving well into adulthood with a normal life expectancy.

Surgical options for repair include a primary repair and a patch repair. A patch repair is associated with higher risks of complications and recurrence.2 However, for a hernia with large defects in which a primary repair is not possible, repair with surgical mesh (xenograft or synthetic) is an effective and safe method.3 In conventional patch repair, the hernia sac is repositioned and resected. The hernia defect is sized and the Permacol trimmed to cover the defect. The flap is then fixed to the remaining rim of diaphragmatic tissue with absorbable sutures.4 The lack of an adequate rim of tissue in our patient presented a unique challenge for construction of the neo-diaphragm relative to most instances of diaphragmatic hernia where a remnant of diaphragmatic tissue is present for anchorage. Although the pleura and adjacent chest wall offer good support for anchoring the neo-diaphragm posteriorly and anterolaterally, there is often a lack of strong tissue medially with consequent substantial risk of inadvertent injury to the oesophagus if sutures are placed too deeply. Travers et al5 reported an incidence of oesophageal injury up to 3.9% in their series of surgical repair of para-oesophageal hernia using porcine dermal collagen biologic mesh (Permacol). Innovative designs in the creation of the neo-diaphragm have been reported, but most studies have been in paediatric patients.6 The technique described in this case report is novel and has not been reported elsewhere. The design of a flutter valve mechanism in the reconstruction of the medial aspect of the neo-diaphragm serves to create a tension-free repair near the mediastinum and oesophagus while also creating a seal to separate the pleural cavity from the abdominal contents. No sutures were applied near the oesophagus or the medial side of the neo-diaphragm. This technique avoids inadvertent visceral injury and is currently our preferred technique of neo-diaphragm construction in patients with a large diaphragmatic defect and insufficient rim.

In our case, we utilised the acellular dermal matrix Permacol for hernia repair. Permacol is a cross-linked graft comprised of acellular collagen matrix. Compared with other collagen-based implants, it offers long-lasting dimensional stability and avoids loss of tensile strength as well as increased tissue laxity resulting in lower rates of recurrence. Acellular dermal matrix is a developing technology and studies have shown promising results for its efficacy.7

In conclusion, repair of diaphragmatic hernia with a xenograft composed of dermal collagen implant and a medial flutter-valve design is safe and effective. It avoids inadvertent injury to mediastinal structures while allowing satisfactory prevention of recurrence of diaphragmatic herniation of intestines.

Concept or design: All authors.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: THY Wong, SCY Chow, RHL Wong.
Critical revision of the manuscript for important intellectual content: All authors.

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

All authors have disclosed no conflicts of interest.

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

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

1. Jancelewicz T, Chiang M, Oliveira C, Chiu PP. Late surgical outcomes among congenital diaphragmatic hernia (CDH) patients: why long-term follow-up with surgeons is recommended. J Pediatr Surg 2013;48:935-41. Crossref

2. Jancelewicz T, Vu LT, Keller RL, et al. Long-term surgical outcomes in congenital diaphragmatic hernia: observations from a single institution. J Pediatr Surg 2010;45:155-60. Crossref

3. Kuhn R, Schubert D, Wolff St, Marusch F, Lippert H, Pross M. Repair of diaphragmatic rupture by laparoscopic implantation of a polytetrafluoroethylene patch. Surg Endosc 2002;16:1495. Crossref

4. Lingohr P, Galetin T, Vestweber B, Matthaei H, Kalff JC, Vestweber KH. Conventional mesh repair of a giant iatrogenic bilateral diaphragmatic hernia with an enterothorax. Int Med Case Rep J 2014;7:23-5. Crossref

5. Travers HC, Brewer JO, Smart NJ, Wajed SA. Diaphragmatic crural augmentation utilising cross-linked porcine dermal collagen biologic mesh (Permacol) in the repair of large and complex para-oesophageal herniation: a retrospective cohort study. Hernia 2016;20:311-20. Crossref

6. Loff S, Wirth H, Jester I, et al. Implantation of a cone-shaped double-fixed patch increases abdominal space and prevents recurrence of large defects in congenital diaphragmatic hernia. J Pediatr Surg 2005;40:1701-5. Crossref

7. Buinewicz B, Rosen B. Acellular cadaveric dermis (AlloDerm): a new alternative for abdominal hernia repair. Ann Plast Surg 2004;52:188-94. Crossref