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.

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.

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.

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.

All authors have disclosed no conflicts of interest.

The authors thank the Director General of Health Malaysia for his permission to publish this article.

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 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.

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

In September 2016, a 64-year-old man with intrathoracic oesophageal cancer underwent neoadjuvant chemoradiotherapy and minimally invasive esophagectomy with no pyloroplasty. The gastric conduit was placed in the posterior mediastinum. Pathology revealed a moderately differentiated squamous cell carcinoma (ypT2N1M0) with clear margins. One year later he underwent surgery for isolated right cervical lymph node recurrence and tolerated a normal diet after surgery with no gastrointestinal symptoms. At 22 months after the second surgery, the patient developed dysphagia and a cervical oesophageal cancer was identified. Completion pharyngo-laryngo-esophagectomy (PLE) with resection of the residual cervical oesophagus, pharyngo-laryngectomy, and reconstruction with a segment of free jejunum interposed between the neopharynx and gastric conduit was performed. After surgery, the patient developed delayed gastric conduit emptying (DGCE) and reported regurgitation of undigested food soon after diet introduction. There was a persistently high nasogastric output, and non-ionic contrast study showed hold-up of contrast at the level of pylorus (Fig 1a). The patient’s symptoms persisted and he relied on nasoduodenal feeding despite prokinetic agents and pyloric balloon dilatation.

Gastric peroral endoscopic myotomy (G-POEM) was performed in February 2020, 4 months after completion PLE. The procedure was performed with the patient in a supine position and under general anaesthesia with endotracheal intubation via end tracheostomy. A high-definition gastroscope (GIF-H190; Olympus, Tokyo, Japan) fitted with a conical shaped transparent cap (DH-28GR; Fujifilm, Tokyo, Japan) and carbon dioxide insufflation were used. After submucosal injection of a mixture of normal saline and indigo carmine at the posterior wall of the gastric conduit, 5 cm proximal to the pylorus, a 2-cm longitudinal mucosal incision was made with DualKnife J (Olympus) using Endocut Q mode (effect 3, cut-duration 2, cut-interval 4) [VIO® 300D; Erbe, Tübingen, Germany]. The endoscope entered the submucosal space to dissect a tunnel caudally until the pyloric ring was well exposed (Fig 2a). Pyloromyotomy was performed and the circular muscle ring completely divided and flattened (Fig 2b). Haemostasis was achieved and the mucosal opening closed with repositioning clips (Single Use Hemoclip; Mednova, Zhejiang, China) [Fig 2c]. The surgery time was 120 minutes and rapid contrast passage to the duodenum was demonstrated on postoperative contrast study (Fig 1b). He resumed an oral diet thereafter.

Pharyngo-laryngo-esophagectomy was first reported by Ong and Lee in 19601 and is regarded as standard treatment for hypopharyngeal and cervical oesophageal cancer. Chemoradiotherapy has gained popularity as an alternative therapeutic strategy to preserve the larynx, but salvage PLE due to incomplete response or cancer recurrence is not uncommonly required.2 Post-PLE DGCE is underreported and the incidence is unknown. Patients frequently complain of bloating, regurgitation, and poor oral intake. According to unpublished results from our prospectively collected database, DGCE was documented in five of 20 patients with PLE for cervical oesophageal cancer over the past 10 years. Of these five patients, pyloroplasty was performed in two, of whom symptoms improved with prokinetic agents alone in one, and endoscopic pyloric balloon dilation was required in the other. For those without pyloric drainage, two patients were managed by G-POEM. The remaining patient was an 83-year-old man on prolonged tube feeding who had pneumonia and died 10 weeks after the surgery.

The pathogenesis of DGCE after PLE may differ to that after oesophagectomy without pharyngo-laryngectomy although data are lacking. Experience in the management of DGCE after oesophagectomy (without pharyngo-laryngectomy) serves to guide treatment of post-PLE DGCE. Proposed contributing factors include gastropyloric denervation, dysfunctional gastric peristalsis and use of the whole stomach for reconstruction.3 4

The application of G-POEM in PLE patients has not been reported. We report a patient with prior oesophagectomy who developed DGCE only after completion PLE. Symptoms resolved after G-POEM. We postulate that removal of the upper oesophageal sphincter in PLE limits build-up of intragastric pressure, compounding DGCE. Pyloromyotomy reduces pyloric channel pressure and expedites gastric emptying, G-POEM accomplishes this as a minimally invasive method. We hypothesise that gastric conduit emptying after PLE can be viewed as a two-stage process. In the first stage, the food bolus passes passively from the proximal stomach to the antrum. In the second stage, food is evacuated from the antrum through the pylorus to the duodenum. A sufficient pressure gradient within the gastric conduit is required to overcome pyloric resistance. Resection of the pharynx and larynx results in equalisation of pressure between the gastric conduit and the atmosphere. The stomach is also exposed to negative intrathoracic pressure. The outflow resistance due to the intact pylorus assumes more importance after PLE since the paretic stomach fails to build up internal pressure. This explains why symptoms of delayed emptying in our patient emerged only after the pharyngo-laryngectomy, not after the initial oesophagectomy.

Pyloroplasty and pyloromyotomy have both been shown effective and safe drainage procedures for gastric conduit after oesophagectomy.5 The G-POEM disrupts the pylorus and improves gastric emptying, theoretically achieving the same outcome and serving as a salvage option for DGCE after PLE. We perform G-POEM according to the same principle applied to POEM for achalasia. The submucosal tunnel is dissected close to the muscle layer for precise pyloromyotomy. Secure mucosal closure permits early diet resumption. However, the aim of pyloromyotomy is to overcome the outlet obstruction without alleviating gastroparesis. Despite improved gastric emptying, symptoms of our patient were not completely eliminated. Patients need to make dietary adjustments to accommodate the new conduit over time while maintaining satisfactory nutrition and body weight.

To the best of our knowledge, this is the first report of successful management of DGCE after PLE by G-POEM. A pyloric drainage procedure is advocated since resection of the upper oesophageal sphincter, an integral part of PLE, limits pressure build-up and food emptying within the gastric conduit.

Concept or design: FSY Chan, S Law.
Acquisition of data: FSY Chan.
Analysis or interpretation of data: FSY Chan.
Drafting of the manuscript: FSY 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.

As an editor of the journal, VLY Chow was not involved in the peer review process. Other 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 study was approved by the Institutional Review Board of The University of Hong Kong/Hospital Authority Hong Kong West Cluster (Ref: UW 16-2023). Consent from patient was obtained.

1. Ong GB, Lee TC. Pharyngogastric anastomosis after oesophago-pharyngectomy for carcinoma of the hypopharynx and cervical oesophagus. Br J Surg 1960;48:193-200. Crossref

2. Tong DK, Law S, Kwong DL, Wei WI, Ng RW, Wong KH. Current management of cervical esophageal cancer. World J Surg 2011;35:600-7. Crossref

3. Konradsson M, Nilsson M. Delayed emptying of the gastric conduit after esophagectomy. J Thorac Dis 2019;11:S835-44. Crossref

4. Akkerman RD, Haverkamp L, van Hillegersberg R, Ruurda JP. Surgical techniques to prevent delayed gastric emptying after esophagectomy with gastric interposition: a systematic review. Ann Thorac Surg 2014;98:1512-9. Crossref

5. Law S, Cheung MC, Fok M, Chu KM, Wong J. Pyloroplasty and pyloromyotomy in gastric replacement of the esophagus after esophagectomy: a randomized controlled trial. J Am Coll Surg 1997;184:630-6.

In July 2020, a 17-year-old Pakistani boy presented with pain in his right foot unrelated to trauma or insect bite, after returning from Pakistan. The following day he tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. He had no previous medial history but was obese with a body mass index of 32.4 kg/m². He denied any camping, water-trekking, or outdoor barefoot walking while in Pakistan. Physical examination revealed multiple purplish, flat, dry lesions <5 mm in diameter on his right toes and dorsum of the foot. They were tender on palpation but there was no surrounding erythema (Fig). No lesions were evident on the left foot or elsewhere and he had no symptoms or signs suggestive of any systemic autoimmune disorder. Pain associated with the lesions subsided by day 4 of illness. Some lesions spontaneously resolved but some became raised and crusted after day 3 (Fig). Topical fusidic acid for 1 week was prescribed to treat any potential bacterial infection. Of note, he developed a fever up to 39°C on day 8 and a productive cough. Vital signs remained stable with no respiratory distress or need for oxygen therapy. Chest X-ray did not show pneumonic changes and fever subsided within 24 hours. White blood cell count and differential were normal and C-reactive protein was 28 mg/L. Alanine aminotransferase was initially elevated at 131 U/L but showed a downward trend on rechecking. Clotting profile and D-dimer were normal. On day 12, SARS-COV-2 immunoglobulin G was detected and the patient was discharged from the hospital. His toe lesions resolved completely a few days later.

Rash is an uncommon symptom in coronavirus disease 2019 (COVID-19) infection.1 It has been described in Italy where 20% of COVID-19 patients developed cutaneous signs, including erythematous rash and widespread urticarial or vesicular lesions, at disease onset or following hospitalisation. The lesions usually subsided after a few days and there was no correlation with disease severity.2 Cutaneous manifestations included pseudo-chilblain (pernio-like), vesicular eruptions, urticarial lesions, maculopapular eruptions, and livedo or necrosis.2 3

Classic chilblains (or pernios) are inflammatory skin lesions that occur on the dorsal surface of the fingers and toes. They form painful and itchy erythematous and oedematous nodules that may ulcerate. They are triggered by cold and usually recur yearly during winter.3 Since March 2020, cases of acral lesions resembling chilblains have been reported across Europe, coinciding with the beginning of the COVID-19 outbreak. These lesions have differed to classic ones, showing an equal sex distribution, absence of obvious triggering factors, and involvement of the feet and distal third of the legs.3 They have been seen more commonly in previously healthy children or adolescents aged >10 years, almost always (74%-100%) on the feet but occasionally on the hands and fingers. The lesions were multiple and varied in size from a few millimetres to centimetres and were described as erythematous, violaceous, swollen, or purpuric. Itchiness and mild pain were frequently reported but required only symptomatic treatment. Lesions started to regress within 12 days to 8 weeks with complete resolution. The appearance of chilblain-like lesions was not thought to be associated with a poor disease outcome.2 3 A major limitation of these reports is that only 11% of cases hospitalised tested positive for SARS-CoV-2 by polymerase chain reaction (PCR), with the remainder untested or testing negative. Some authors have attributed this to the low sensitivity of tests or low viral load in children.3 The pathophysiological relationship between COVID-19 infection and chilblain-like lesions remains poorly understood, but has been hypothesised to be related to type 1 interferonopathies.3

Our patient is one of the few reported cases of laboratory-confirmed SARS-CoV-2 infection with chilblain-like lesions. To date, our patient is the only child in Hong Kong to present with SARS-CoV-2 infection as well as so-called “COVID toe”.1 Currently, there are insufficient data to determine a clear relationship between these dermatological symptoms and COVID-19. Rash is a common manifestation of many diseases and may not be associated COVID-19 infection. A recent case series of 17 adolescents in Italy who developed chilblain-like lesions during the first wave of COVID-19 screened negative on SARS-CoV-2 PCR of nasopharyngeal swabs, negative for SARS-CoV-2 immunoglobulin M and immunoglobulin G, and had no viral genome in biopsy specimens. However, this report was limited by its small sample size and did not compare data with an age- and gender-standardised background incidence of chilblains in the population.4 Most patients with dermatological manifestations were not confirmed to be infected with SARS-CoV-2. Another systematic review also concluded that some, but not all paediatric cases, who developed chilblain-like lesions during the COVID-19 pandemic had positive SARS-CoV-2 PCR, serology or viral particles confirmed in electron microscopy.5 Larger-scale epidemiological study is needed to confirm an association between these chilblain-like lesions and COVID-19 infection. Reported manifestations and histological findings were too heterogeneous to ascertain the pathophysiology. Nevertheless, physicians should remain vigilant since dermatological manifestations may be the first or only symptom in patients with COVID-19 infection,2 3 enabling a timely diagnosis of COVID-19 infection to reduce transmission. Physicians should also consider the possibility of coagulopathies and interferonopathies.

Concept or design: MYW Kwan, P Ip.
Acquisition of data: C Wan, SH Lau, SCS Ho, JS Rosa Duque.
Analysis or interpretation of data: C Wan, SH Lau, SCS Ho, JS Rosa Duque.
Drafting of the manuscript: JSC Wong, TS Wong, GT Chua.
Critical revision of the manuscript for important intellectual content: ICK Wong, KKW To, WWY Tso, CS Wong, MHK Ho, J Kwok, CB Chow, PKH Tam, GCF Chan, WH Leung, YL Lau.

All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

This study is supported by the Collaborative Research Fund (CRF) 2020/21 and One-off CRF Coronavirus and Novel Infectious Diseases Research Exercises (Ref: C7149-20G). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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

1. Chua GT, Wong JS, Lam I, et al. Clinical characteristics and transmission of COVID-19 in children and youths during 3 waves of outbreaks in Hong Kong. JAMA Network Open 2021;4:e218824. Crossref

2. Andina D, Belloni-Fortina A, Bodemer C, et al. Skin manifestations of COVID-19 in children: Part 2. Clin Exp Dermatol 2021;46:451-61. Crossref

3. Andina D, Belloni-Fortina A, Bodemer C, et al. Skin manifestations of COVID-19 in children: Part 1. Clin Exp Dermatol 2021;46:444-50. Crossref

4. Discepolo V, Catzola A, Pierri L, et al. Bilateral chilblain-like lesions of the toes characterized by microvascular remodeling in adolescents during the COVID-19 pandemic. JAMA Network Open 2021;4:e2111369. Crossref

5. Koschitzky M, Oyola RR, Lee-Wong M, Abittan B, Silverberg N. Pediatric COVID toes and fingers. Clin Dermatol 2021;39:84-91. Crossref

In July 2021, a 1.5-kg baby girl presented with polyhydramnios on antenatal ultrasound scan at 27 weeks that had resolved by 35 weeks. Physical examination showed no dysmorphic features. She was born by caesarean section at 35 weeks due to discordant growth in a dichorionic diamniotic twin pregnancy. She was intubated at birth but resistance was noted during orogastric tube insertion. Chest X-ray revealed coiling of the gastric tube at the upper pouch of the oesophagus with the presence of intestinal gas, which is a classic feature of type C oesophageal atresia (Fig 1). Echocardiogram revealed several cardiac anomalies including a ventricular septal defect, a moderate patent ductus arteriosus, and a large atrial septal defect.

Thoracoscopic repair of oesophageal atresia was scheduled for the next day following stabilisation. The patient was positioned in a semi-prone position with the right chest slightly elevated. She was put on conventional ventilation without single lung ventilation, as per our practice. A camera port was inserted at the 5th intercostal space and two further 5-mm working ports were inserted under direct vision. Pneumothorax of 3 to 4 mm Hg was created using CO₂. The azygous vein was cauterised and divided with monopolar diathermy and the tracheoesophageal fistula readily identified. This was closed by Weck Hem-o-lok (Teleflex; Wayne [PA], United States) and divided (Fig 2). The proximal oesophageal stump was identified and opened with scissors. End-to-end esophago-oesophagostomy was performed using single-layer interrupted 5/0 polydioxanone sutures (Ethicon; Bridgewater [NJ], United States). A 12-Fr chest drain was inserted at the end of the procedure. The operation was uneventful and completed in 145 minutes.

After surgery, the patient was managed in the neonatal intensive care unit according to our usual protocol. On day 1 after surgery she developed sudden profound desaturation with CO₂ retention when the endotracheal tube was secured at 8 cm from the upper lip. Bedside bronchoscopy showed a tracheal pouch (fistula remnant) close to the tip of the endotracheal tube. The tip completely entered the pouch with minimal advancement of the endotracheal tube. The endotracheal tube was then withdrawn to 7.5 cm from the upper lip and no further desaturation was noted.

A contrast swallow study on day 18 after surgery showed an intact anastomosis. The patient was extubated successfully on day 19 after surgery. Bolus feeding via a feeding tube was established after extubation, and oromotor training was commenced. She was transferred back to the referring hospital for management of her cardiac disorders. At 6 weeks after surgery, she had good weight gain with full oral feeding and no clinical gastroesophageal reflux.

The introduction of minimally invasive surgery has undoubtedly revolutionised the treatment of many surgical disorders. The role of minimally invasive surgery in common neonatal procedures such as inguinal hernia repair and pyloromyotomy is well established. However, this operative approach in more complex procedures is still limited by various factors including equipment size, surgical expertise, and perioperative support.

Among all the neonatal operations, repair of oesophageal atresia is one of the most challenging. In addition to the need for meticulous surgical skill, adequate support from a dedicated neonatal intensive care unit and expert paediatric anaesthetists are equally important. The first successful thoracoscopic repair of oesophageal atresia was reported in 1999.1 A subsequent international multicentre study published 15 years ago further confirmed that thoracoscopic repair of oesophageal atresia was at least as good as traditional thoracotomy.2 However, this operative approach is still not widely practised.

In our unit, we started to perform thoracoscopic surgery in 2007. In our early experience reported in 2012,3 we selected patients with a reasonably large body size for minimally invasive surgery. With the accumulation of neonatal operative experience, we became confident performing these operations on smaller-sized babies. Prior to our case, Son et al4 published their experience in thoracoscopic repair of oesophageal atresia in babies <2 kg, and Rothenberg1 reported a successful experience in a 1.2-kg baby. We believe that thoracoscopic repair of oesophageal atresia in neonates can be performed safely in experienced centres with proper case selection.

Traditionally, the Spitz classification has been considered the prognostic indicator. Neonates with oesophageal atresia with birth weight <1.5 kg and major cardiac anomalies (as in our patient) are predicted to have only a 50% survival rate with a traditional open surgical approach. However, advances in surgical skills, neonatal care, and anaesthesia combined with the ability to optimise the surgical approach have resulted in improved surgical outcomes and consequent survival rates.1 4

The challenges faced in this operation included the patient’s small size and presence of cardiopulmonary complications before and during surgery. The pneumothorax created during thoracoscopy may compress the lung causing difficulty in ventilation and compromise cardiac function, further increasing the complexity of anaesthesia. We overcame this by limiting the pressure to 3 to 4 mm Hg, resulting in less operative space but better patient tolerance. In our opinion, the reduced working space is not a major hurdle for a surgeon competent in minimally invasive surgery. In a baby with congenital heart disease, an anaesthetist who has experience in neonatal thoracic surgery is essential for optimum intra-operative management.

Holcomb et al2 demonstrated in a multi-institutional study that there were no significant differences in reported postoperative complication rates between minimally invasive surgery and open repair. A minimally invasive approach has the additional benefits of smaller wounds and less pain. More specifically, thoracoscopic repair allows for clearer magnification. Although CO₂ pneumothorax will compress the right lung during surgery, its effect is significantly less than that of manual compression during open surgery. Long-term studies of musculoskeletal problems also reveal a superior outcome for thoracoscopic surgery.1

In conclusion, we report a successful thoracoscopic repair of oesophageal atresia in a high-risk neonate with very low birth weight. To the best of our knowledge, this is the smallest baby with oesophageal atresia in Hong Kong to have this operation. While proper case selection to ensure patient safety remains the top priority, small body size should not preclude a thoracoscopic surgical approach. The combined efforts and advances in surgery, anaesthesia and neonatal care are key to success.

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

As the editor of the journal, KKY Wong was not involved in the peer review process for this article. Other 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. The patient’s parents provided informed consent for all treatments and procedures and provided consent for publication.

1. Rothenberg SS. Thoracoscopic repair of esophageal atresia and tracheo-esophageal fistula in neonates: evolution of a technique. J Laparoendosc Adv Surg Tech A 2012;22:195-9. Crossref

2. Holcomb GW 3rd, Rothenberg SS, Bax KM, et al. Thoracoscopic repair of esophageal atresia and tracheoesophageal fistula: a multi-institutional analysis. Ann Surg 2005;242:422-8. Crossref

3. Huang J, Tao J, Chen K, et al. Thoracoscopic repair of oesophageal atresia: experience of 33 patients from two tertiary referral centres. J Pediatr Surg 2012;47:2224-7. Crossref

4. Son J, Jang Y, Kim W, et al. Thoracoscopic repair of esophageal atresia with distal tracheoesophageal fistula: is it a safe procedure in infants weighing less than 2000 g? Surg Endosc 2021;35:1597-601. Crossref

In June 2020, a previously healthy 7-year-old boy presented with a 1-week history of persistent fever. He had an unremarkable medical history, and had gone hiking a week before the onset of his fever. He was initially treated for a presumed viral illness but his condition worsened over the subsequent 2 days. His fever became high and fluctuating, with a peak of 39°C, and he developed dyspnoea without cough. He had no headache or body aches. Physical examination revealed crepitations with diminished breath sounds over both lung fields and tachypnoea with a respiratory rate of 30 per minute. Cervical lymphadenopathy and hepatomegaly were present. There was no eschar. He had distributive shock with hypotension (80/40 mm Hg) and tachycardia (150 beats per minute) and a norepinephrine infusion was commenced. Within one day, type I respiratory failure became evident with increasing oxygen requirement from room air to FiO₂ 0.4 and continuous positive airway pressure of 6 cmH₂O to maintain oxygen saturation above 90%. The PaO₂:FiO₂ ratio was 232.5 mm Hg. Plain radiograph of the chest revealed bilateral opacities and peribronchial thickening (Fig). Echocardiography and lung ultrasound confirmed normal heart function and the absence of pleural effusion. By definition, the boy was diagnosed with paediatric acute respiratory distress syndrome (PARDS: an acute lung injury occurring within 7 days of a known clinical insult, with acute hypoxaemia of PaO₂:FiO₂ ratio ≤300 when the child is on non-invasive ventilation, and new infiltrates consistent with acute pulmonary parenchymal disease on chest radiograph, which cannot be explained by acute left ventricular heart failure or fluid overload), where he had progressive respiratory failure and bilateral diffuse infiltration on chest radiography.1 Further blood tests and bone marrow findings met the diagnostic criteria for haemophagocytic lymphohistiocytosis (HLH: a life-threatening clinical syndrome of systemic hyperinflammation and progressive immune-mediated organ damage due to excessive immune activation): anaemia (haemoglobin 8.3 g/dL), thrombocytopenia (45 × 10⁹/L), hypertriglyceridaemia (4.5 mmol/L), high ferritin (4467 pmol/L), hypofibrinogenaemia (0.9 g/L), and elevated soluble CD25 (8569 pg/mL).2 Bone marrow aspiration and trephine biopsy showed haemophagocytosis. There was no evidence of Epstein–Barr virus association on immunohistochemical analysis. Orientia tsutsugamushi antibody titre of 512 increased to 4096 (ie, more than a fourfold increase) after 2 weeks. The child was diagnosed with PARDS and secondary HLH associated with scrub typhus infection and prescribed oral doxycycline 50 mg twice daily (~3.7 mg/kg/day) for the scrub typhus. Intravenous dexamethasone 5 g every 12 hours (10 mg/m²/day) was commenced as treatment of HLH with a starting dose as per the HLH-2004 study protocol. He became afebrile within 1 day of commencing treatment and respiratory distress gradually resolved. He was weaned off continuous positive airway pressure ventilation after 3 days. Platelet count rose to >100 × 10⁹/L after 4 days. Ferritin lowered the day after treatment and was within normal range after 2 weeks. The boy completed a 1-week course of doxycycline and dexamethasone was also tapered off in 1 week.

Our patient presented with non-specific symptoms of scrub typhus and developed severe complications including PARDS and HLH without the pathognomonic eschar. Scrub typhus is caused by the bacterium O tsutsugamushi and is spread to humans through the bites of infected chiggers, Leptotrombidium mites, that can be both a vector and a reservoir for O tsutsugamushi.3 It is a notifiable disease in Hong Kong with between 7 and 28 cases reported each year over the past 10 years.4 Symptoms of scrub typhus usually begin within 10 days of being bitten and can range from non-specific signs including fever, headache, body aches and rash, to multiorgan failure and death with a median mortality rate of 6% if left untreated.3 Although eschar is pathognomonic for scrub typhus, it is rare among Southeast Asian patients. Laboratory confirmation of the diagnosis usually requires indirect fluorescent antibody test and is the mainstay of serologic diagnosis. Polymerase chain reaction assay of whole blood sample if available can speed the diagnosis.

Acute respiratory distress syndrome is a serious complication of scrub typhus; it has been reported in 4% to 22% of cases,5 6 and can involve over 50% of children who developed secondary HLH associated with scrub typhus infection.7 The pulmonary manifestations vary from bronchitis and interstitial pneumonitis to acute respiratory distress.5 6 Acute respiratory distress has also manifested in many patients with HLH due to other causes and has been reported as the initial manifestation of HLH. Nahum et al8 reported that 7 of 11 children with HLH and multiple organ failure exhibited PARDS after HLH was diagnosed, highlighting the importance of close monitoring and early intervention for children with PARDS and HLH. The presentation of acute respiratory distress syndrome in children differs from that in adults and a consensus on a formal PARDS definition was reached in 2015 by the Paediatric Acute Lung Injury Consensus Conference.1

In some cases, HLH can cause cytokine release syndrome, a life-threatening disorder of severe excessive inflammation (hyperinflammation) caused by uncontrolled proliferation of activated lymphocytes, macrophages and secretion of inflammatory cytokines.9 Although rare, O tsutsugamushi is a significant cause of HLH, especially in Asia.7 The HLH-2004 protocol, which includes etoposide, dexamethasone and cyclosporine as the initial therapy, is designed for treatment of patients with primary HLH.2 For patients with secondary HLH, treatment of the underlying infection or malignancy may help control the HLH and avoid the need for cyclosporine and etoposide. Single antibiotic therapy with doxycycline, minocycline, chloramphenicol, azithromycin or clarithromycin has been reported to result in rapid defervescence in patients with HLH associated with scrub typhus.10 Thus, an accurate diagnosis of scrub typhus in patients with HLH can help timely targeted antibiotic therapy with subsequent rapid clinical improvement.

This case illustrates an atypical severe manifestation of scrub typhus presenting with non-specific signs and symptoms resulting in complications including PARDS and HLH. Early diagnosis and treatment with doxycycline are crucial to prevent complications. Physicians should be vigilant for scrub typhus as a potential diagnosis in a child who presents with pyrexia of unknown origin and a history of participation in rural outdoor activities.

Concept or design: RCM Fung, KKY Leung, CC Au, KL Hon.
Acquisition of data: RCM Fung, KL Hon.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: RCM Fung, KKY Leung, KL Hon.
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.

As an editor of the journal, KL Hon was not involved in the peer review process. Other 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’s parents provided written informed consent for all treatments and procedures and consent for publication.

1. Pediatric Acute Lung Injury Consensus Conference Group. Pediatric acute respiratory distress syndrome: consensus recommendations from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med 2015;16:428-39. Crossref

2. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31. Crossref

3. Peesapati N, Rohit T, Sunitha S, Pv S. Clinical manifestations and complications of scrub typhus: a hospital-based study from North Andhra. J Assoc Physicians India 2019;67:22-4.

4. Center for Health Protection, Department of Health, Hong Kong SAR Government. Number of notifiable infectious diseases by month. 2020. Available from: https://www.chp.gov.hk/en/statistics/data/10/26/43/6896.html. Accessed 25 Jun 2020.

5. Sankuratri S, Kalagara P, Samala KB, Veledandi PK, Crossref

6. Kumar Bhat N, Dhar M, Mittal G, et al. Scrub typhus in children at a tertiary hospital in north India: clinical profile and complications. Iran J Pediatr 2014;24:387-92.

7. Naoi T, Morita M, Kawakami T, Fujimoto S. Hemophagocytic lymphohistiocytosis associated with scrub typhus: Systematic review and comparison between pediatric and adult cases. Trop Med Infect Dis 2018;3:19. Crossref

8. Nahum E, Ben-Ari J, Stain J, Schonfeld T. Hemophagocytic lymphohistiocytic syndrome: Unrecognized cause of multiple organ failure. Pediatr Crit Care Med 2000;1:51-4. Crossref

9. Hon KL, Leung KK, Oberender F, Leung AK. Paediatrics: how to manage septic shock. Drugs Context 2021;10:2021-1-5. Crossref

10. Hon KL, Leung AS, Cheung KL, et al. Typical or atypical pneumonia and severe acute respiratory symptoms in PICU. Clin Respir J 2015;9:366-71. Crossref