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.

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.

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.

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. The patient provided informed consent for the treatment/procedures and publication.

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

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.

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.

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.

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.

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.

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. Informed consent was obtained for all treatment involved as well as for publication of this article and accompanying images.

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

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.

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.

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.

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.

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

1. Stanley SL Jr. Amoebiasis. Lancet 2003;361:1025-34. Crossref

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

In October 2020, a 55-year-old Chinese man travelled from Hong Kong to Paris to attend a family funeral. He had psoriatic arthropathy in remission without chronic pain. In November 2020 while still in France, he and seven family members developed fever and upper respiratory symptoms, confirmed to be coronavirus disease 2019 (COVID-19). The family remained in home isolation and required no medical treatment. The patient self-treated with traditional Chinese medication: Lianhua Qingwen herbal capsules for 1 week. Two weeks later, he returned to Hong Kong after testing negative for COVID-19. In December 2020, during mandatory quarantine on re-entry to Hong Kong, the patient suddenly developed pain that extended from the neck and right interscapular region to the shoulder and down along the ulnar side of the right arm and forearm. The patient described the pain as shooting and drilling in nature, constantly severe, worst at the interscapular region, and aggravated by shoulder movement. He also reported disturbed sleep and numbness over his entire right arm and weakened right hand grip. He had no other joint pain, rash, vesicles, or fever. At this time, he was still resting alone in a quarantine hotel and performing no physical work. Most activities of daily living were manageable but some, such as bathing and dressing, were difficult. Diclofenac 100 mg daily and gabapentin 200 mg 3 times daily prescribed at a COVID-19 Clinic were ineffective. The patient’s younger sister who had recovered in France without medication reported similar symptoms in her left arm.

The patient presented to our pain clinic 1 month after pain onset. His motor symptoms had spontaneously improved although disturbing right shoulder and interscapular pain with paraesthesia persisted. There were no muscle wasting, scar, rash, or trophic changes. The patient’s right arm was slightly warmer than the left, and upper limb joints were not swollen or tender and there was full range of movement. He reported decreased sensation to light touch, cold and pinprick over the whole right arm, but his sense of vibration and proprioception were preserved. No touch or mechanical allodynia or hyperalgesia were noted. Apart from slightly weakened thumb opposition, other muscle strength, tendon reflexes and neck examination were unremarkable.

Analgesia was changed to pregabalin 75 mg twice per day and etoricoxib 90 mg daily as needed, and the patient was referred for occupational therapy for grip strengthening. Magnetic resonance imaging (MRI) in March 2021 revealed mild T2 hyperintensity at the right brachial plexus, suggestive of resolving neuritis (Fig). There was also cervical spondylosis without significant intervertebral foraminal narrowing or cord compression. Nerve conduction study in March 2021 was normal. Electromyography was not performed due to good neurological recovery.

At a subsequent 3-month follow-up examination in March 2021, the patient reported continued improvement with little or no pain. He reported only intermittent paraesthesia and mild weakness of his right hand and fingers. As a right-hander, he continued to have trouble turning keys and using chopsticks and pens. He coped with his office work with a speech-to-text converter to minimise keyboard usage. He could manage most household chores, including shopping for groceries, and slept well. He was calm and grieving appropriately for the loss of his mother. Pregabalin was gradually reduced, and he was weaned off etoricoxib.

The Coronavirus family is known for its neurotropism with 36% of COVID-19 infected patients reporting some form of neurological manifestation.1 Mechanisms involve direct neural infection, and indirect inflammatory and immunological reactions. Other possibilities are targeting of neuronal angiotensin-converting enzyme 2, vasculitis, thrombosis and iatrogenic, such as prone position-related effects or neuropathies.2

The pathophysiology of acute brachial neuritis is not well understood but the pre-existence of viral infection supports immunological mechanisms. Affected subjects have more lymphocytic activity to brachial (versus sacral) plexus nerve extracts and increased antibodies to peripheral nerve myelin. A hereditary form with mutation-related deficiency in proteins from the septin family has been identified.2 Our patient took Lianhua Qingwen, a traditional Chinese medicine prepared from 13 herbs, shown to bind to angiotensin-converting enzyme 2 and shorten the course of COVID-19 infection.3 Drug-induced plexopathy, although less likely, remains possible.

Acute brachial neuritis is self-limiting but classically presents with excruciating pain at the shoulder, neck and interscapular region, followed by shoulder girdle weakness. Diagnosis is clinical and investigations are supportive. Cervical pathology is the major differential diagnosis but was excluded in our patient by MRI that revealed cervical spondylosis without nerve or cord compression or signal changes. Given the rheumatological history in our case, active autoimmune disease was also possible, but he had no such features.

To the best of our knowledge three cases of post-COVID-19 brachial neuritis4 5 6 have been reported but none in Hong Kong. Brachial neuritis is rare with an incidence of only 1.64 cases per 100 000 person-years, and underreporting is expected with isolation and restricted healthcare access during COVID-19. Compared to existing three cases, two cases similarly involved middle-aged men with delayed neuropathic symptoms 2 weeks after COVID-19 confirmation. One had similar symptoms to our patient, whereas the other two had either purely sensory components or solely proximal median nerve involvement. Our case and one existing case demonstrated classical MRI changes. Nerve conduction study in our patient did not demonstrate reduced action potential amplitude in affected nerves, which may have been related to its performance at a later course of the disease. Given the rarity of the entity and its occurrence in our patient and his sister, further research to investigate the role of genetic susceptibility to the acute form is warranted. Management of brachial neuritis is supportive and focused on pain control and functional rehabilitation with physiotherapy and occupational therapy. There is limited evidence that steroids and immunoglobulins will hasten recovery so their use should be balanced against the risk of viral replication. Currently, there are no established guidelines for pain management in patients with or recently recovered from COVID-19. Specific precautions should be taken in pain management of these cases.

Paracetamol has limited efficacy for neuropathic pain. Care should be taken for patients with severe COVID-19, because viral-induced cytokine storm can suppress cytochrome P450, increasing the risks of hepatotoxicity. Nonsteroidal anti-inflammatory drugs offer effective analgesia for brachial neuritis by suppressing cyclooxygenase and prostaglandin production. Although there were early concerns about ibuprofen-associated decompensation in patients with COVID-19, this has not been supported by the World Health Organization after data review. Meanwhile, cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs disturb the thromboxane A2–prostacyclin balance, potentially enhancing thrombotic tendency in patients with COVID-19. Our case illustrates the safe use of cyclooxygenase-2 inhibitors in a patient recently recovered from COVID-19. Among antineuropathic agents, gabapentinoids have relatively few adverse effects, lower cardiac toxicity, and fewer drug-drug interactions than tricyclic antidepressants and serotonin-noradrenaline reuptake inhibitors. Our patient was initially prescribed a relatively low dose of gabapentin that may account for its lack of effect. He was changed to pregabalin at a higher equivalent dose, with a better pharmacological profile with linear dose-response relationship and faster onset. Physicians should be alert to the sedative effects of analgesia that may worsen COVID-19-related ventilatory impairment. Opioids should be reserved for severe refractory pain.

Pain management for patients with or recently recovered from COVID-19 can be socially challenging. The need for quarantine delays presentation and management, and the associated mental stress and lack of social support may perpetuate pain. Although telemedicine enables remote medical care, controversies remain, and psychological engagement is less effective. Our patient’s appropriate grief reaction and illness coping mechanism minimises risk of chronic pain.

Our case report is the first to focus on the clinical management of brachial neuritis in patients with or recently recovered from COVID-19, and the first to identify a possible case series within a family. We hope our report of COVID-19-related brachial neuritis can promote awareness and understanding. Future research should focus on its pathophysiology including genetic susceptibility. Whether COVID-19 vaccination alters the course of acute brachial neuritis warrants further observation.

Concept or design: VYT Cheung, FPY Tsui.
Acquisition of data: VYT Cheung, JMK Cheng.
Analysis or interpretation of data: VYT Cheung.
Drafting of the manuscript: VYT Cheung.
Critical revision of the manuscript for important intellectual content: FPY Tsui, JMK Cheng.

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.

We would like to thank Dr Annie Chu for contributing to the clinical management, and Drs Mandy Au Yeung and Kendrick Tang for the investigations.

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 informed consent for the treatment/procedures, and for publication.

1. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020;77:683-90. Crossref

2. Fernandez CE, Franz CK, Ko JH, et al. Imaging review of peripheral nerve injuries in patients with COVID-19. Radiology 2021;298:E117-30. Crossref

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A 10-year-old ethnic-Russian boy was confirmed to have severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the second wave of the coronavirus disease 2019 (COVID-19) outbreak in Hong Kong.1 He had a past medical history of coarctation of the aorta with corrective surgery performed at age 2 months. He returned from Russia on 6 June 2020 and his first deep throat saliva specimen saved on arrival at Hong Kong International Airport tested negative for SARS-CoV-2. Four days later, he developed fever, malaise, and headache. On 13 June 2021, he was admitted to our Paediatric Infectious Disease Unit and a new deep throat saliva specimen was positive for SARS-CoV-2. He did not require oxygen during his hospital stay. He was discharged from the hospital after being tested positive for SARS-CoV-2 anti-nucleoprotein immunoglobulin G antibodies 17 days after admission. This complied with the discharge criteria set by the Department of Health, the Government of Hong Kong Special Administrative Region.1

On 16 July, 16 days after being discharged, he returned to our Paediatric Infectious Disease Unit with a 2-day history of high fever and right cervical tender lymphadenopathy. Repeat nasal pharyngeal swab for SARS-CoV-2 polymerase chain reaction was negative. He was presumed to have bacterial lymphadenitis and was prescribed intravenous antibiotics but symptoms progressed. Ultrasound of the neck showed evidence of lymphadenitis but no signs of abscess formation. His fever and lymphadenitis persisted for 5 days and he also developed bilateral non-purulent conjunctivitis with peri-limbic sparing, erythematous and cracked lips, strawberry tongue and blanchable erythema over the trunk (Fig). Serial blood tests showed mild thrombocytopenia (trough 110 × 10⁹/L), and raised erythrocyte sedimentation rate (peak 60 mm/Hr), C-reactive protein (peak 102 mg/L; range, <5.0), lactate dehydrogenase (270 U/L; range, <270), ferritin (1568 pmol/L; range, 31-279), highly sensitive troponin I (peak 643 ng/L; range, <21), N-terminal prohormone of brain natriuretic peptide (peak 3213 ng/L; range, <112), and interleukin-6 (IL-6) (peak 480.9 pg/mL; range, <4). Electrocardiogram and echocardiogram were unremarkable. His clinical presentation was compatible with Kawasaki-like disease. Since he had been infected with COVID-19 approximately 4 weeks previously, he was suspected to have PIMS-TS (paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2).2 Other differential diagnoses were excluded but included streptococcal and staphylococcal infection, Epstein–Barr virus infection and infection-related myocarditis. Owing to the rarity of PIMS-TS in East Asia, the clinical team discussed the case with experts from the United Kingdom who concurred with the diagnosis. He was treated with two doses of intravenous immunoglobulin (IVIG) at 2 g/kg/dose as his fever resurged 1 day after the first dose. Fever and other symptoms subsequently subsided after the second dose of IVIG, and serial echocardiograms did not reveal any coronary lesions. Whole exome sequencing performed to look for the possibility of an underlying monogenic immune dysregulation syndrome because of the rarity of this condition was unremarkable.

Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 is one of the most severe complications of COVID-19 infection in children. It was initially described in several case series in Europe and North America among children who presented with Kawasaki-like illness and were confirmed or known to have been in contact with another SARS-CoV-2–infected individual.2 3 Kawasaki disease (KD) is most prevalent among East Asians but rare in other parts of the world.3 On the contrary, paediatric cross-sectional clinical studies from East Asia have reported that PIMS-TS is rare among East Asians.1 We present the first, and so far, the only case of PIMS-TS in China. The case was an ethnic Russian boy who showed features of KD approximately 4 weeks after confirmation of SARS-CoV-2 infection. There is no consensus on the treatment regimen at present. In our patient, IVIG alone, instead of steroid or immunomodulators, was effective in treating the condition.

The pathophysiology of PIMS-TS remains uncertain. Studies have shown significant clinical and laboratory differences between PIMS-TS and KD, despite some similarities in clinical presentation. Patients with PIMS-TS are generally older than those with KD (median age, 8.3-9 years vs 2.7 years).2 3 They also have a higher white blood cell and neutrophil count and C-reactive protein, and a greater degree of lymphopenia and anaemia and tendency to develop thrombocytopenia in contrast to thrombocytosis in KD. In addition, fibrinogen and troponin levels are more elevated in PIMS-TS.2 These factors are associated with an increased risk of intensive care admission among children with PIMS-TS.2 These findings imply that PIMS-TS is a different entity to KD, with a greater degree of inflammation and myocardial injury. Studies have shown that certain cytokines, such as IL-6, appear to be particularly elevated in patients with PIMS-TS and may be involved in myocardial depression.2 Studies have also suggested that life-threatening COVID-19 pneumonia may be associated with monogenic inborn errors of immunity related to type 1 interferonopathies or type 1 interferon neutralising antibodies.4 Certain human leukocyte antigens, which are prevalent in East Asians but not Caucasians, have been associated with KD.4 However, no genes have been identified to cause PIMS-TS. Future studies will continue to explore the genetic factors related to PIMS-TS and the possible associated leukocyte antigen that explains the ethnic differences in PIMS-TS prevalence.

The treatment for PIMS-TS is similar to that for KD. A recent observational study demonstrated that patients who received IVIG and methylprednisolone together were less likely to require second-line biological agents, and were at lower risk of secondary acute left ventricular dysfunction and need for haemodynamic support with a shorter length of stay in the intensive care unit.5 Interleukin-1 and IL-6 receptor monoclonal antibodies have been used as second-line biological agents and have been shown to achieve remission when first-line therapies fail.2 5 Short-term outcomes of PIMS-TS are generally good. Immediate cardiac complications include coronary abnormalities, transient valvular regurgitation and myocardial dysfunction.2 The majority of patients recover without sequelae, but mortality has been reported.2 Data on the long-term outcomes of PIMS-TS are lacking.

The PIMS-TS remains a rare disease among East Asian patients.1 Nevertheless, frontline paediatricians in East Asia should remain vigilant when looking after ethnic non-East Asian children with COVID-19 infection in case they develop PIMS-TS after their initial recovery. Paediatricians should advise parents about the symptoms and signs of PIMS-TS so that timely medical consultation can be sought.

Concept or design: GT Chua, JSC Wong, P Ip, MYW Kwan.
Acquisition of data: J Chung, I Lam, J Kwong, K Leung, CY Law, CW Lam, J Kwok, PWK Chu, EYL Au, CK Lam, MYW Kwan.
Analysis or interpretation of data: D Mak, NC Fong, D Leung, WHS Wong, MHK Ho, SSL Tsao, CS Wong, JC Yam, WWY Tso, KKW To, PKH Tam, GCF Chan, WH Leung, KY Yuen, V Novelli, N Klein, M Levin, E Whitaker, YL Lau.
Drafting of the manuscript: GT Chua, JSC Wong, I Lam, J Chung.
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 work was supported by the Collaborative Research Fund (CRF) 2020/21 and One-off CRF Coronavirus and Novel Infectious Diseases Research Exercises (Ref: C7149-20G). The funding source was not involved in the study design, collection, analysis or interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.

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

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 Netw Open 2021;4:e218824. Crossref

2. Whittaker E, Bamford A, Kenny J, et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA 2020;324:259-69. Crossref

3. To KK, Chua GT, Kwok KL, et al. False-positive SARS-CoV-2 serology in 3 children with Kawasaki disease. Diagn Microbiol Infect Dis 2020;98:115141. Crossref

4. Sancho-Shimizu V, Brodin P, Cobat A, et al. SARS-CoV-2-r elated MIS-C: A key to the viral and genetic causes of Kawasaki disease? J Exp Med 2021;218:e20210446.

5. Ouldali N, Toubiana J, Antona D, et al. Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children. JAMA 2021;325:855-64.Crossref