Solitary lung nodules of <3 cm in diameter within the lung parenchyma and with no other abnormalities are often picked up incidentally during routine radiographic imaging. The incidence of cancer for such nodules has been estimated to be 10% to 70%. Management strategy depends on the clinical probability of cancer; nodule size, features, and growth rate ascertained by radiology; and the surgical risk to the patient. We report a case of such a nodule revealed by radiology and suspicious for malignancy. Subsequent excision and pathological examination revealed unexpected findings.

The index patient was a 61-year-old Chinese man from Northern China with history of laryngeal cancer treated successfully by local surgery and radiotherapy 6 years prior to present admission. Routine chest computed tomography (CT) scan revealed a peripheral lung nodule 9 mm in diameter in the right lower lobe. Follow-up CT scan 1 year later revealed minimal increase in size to 10 mm and the patient was referred to the Department of Thoracic Surgery, University of Hong Kong–Shenzhen Hospital in November 2015 for further treatment. The patient was a former chronic smoker for more than 10 years (10 cigarettes/day) but had stopped smoking upon diagnosis of laryngeal cancer.

Physical examination of the patient was unremarkable. High-resolution CT scan confirmed the presence of a peripheral lung nodule in his right lower lobe lateral-basal segment that was suspicious for malignancy. It measured 12 mm in diameter and had a spiculated border with a central cavity (Fig a). Another high-density 2-mm nodule was present in the right upper lobe subpleural region associated with apical fibrosis. There was pleural thickening and mildly increased peripheral lung markings in bilateral lower lobes. The peribronchiolar and hilar lymph nodes were not enlarged. After further examination and assessment of the surgical risk, video-assisted thoracoscopy was decided, with patient consent.

During video-assisted thoracoscopy, wedge excision of the nodule was done. Intra-operative frozen section consultation revealed a 10-mm papillary glandular tumour 8 mm away from the pleura. There was profuse mucin production and intra-alveolar extension suspicious for mucinous adenocarcinoma. Right lower lobectomy was subsequently performed, and the patient had an uneventful recovery. Microscopic examination of formalin-fixed paraffin-embedded sections from the nodule showed an arborising papillary tumour (Fig b) surrounded by intra-alveolar mucin. There was extension along the alveolar lining at its periphery (Fig b, inset) simulating ‘lepidic spread’ of adenocarcinoma. The papillary structures (Fig c and d) consisted of fibrous cores covered by single to multiple layers of mucin-secreting and ciliated (Fig d, inset) columnar cells and basal cells. There was focal tumour necrosis, rare mitoses, and mild nuclear atypia. Mucin and inflammatory cells filled the central cystic space. Origin from a dilated terminal bronchiole could be traced (Fig e). A batch of immunohistochemical studies showed CK7+/CK20- tumour cells mostly negative for thyroid transcription factor-1 except at the periphery, suggestive of residual alveolar lining cells. Monoclonal carcinoembryonic antigen highlighted the mucinous cells and p63 stained the basal cells. Proliferative index by Ki67 was low (5%). The overall picture was consistent with ciliated muconodular papillary tumour (CMNPT) of the lung. Examination of the lobectomy specimen showed focal peribronchiolar fibrosis compatible with the effect of smoking.1 These foci often contained peribronchiolar metaplasia featuring ciliated and mucinous columnar cells (Fig f) occasionally forming small papillae (Fig f, inset). The 2-mm lesion in the right upper lobe was a fibrotic nodule. The patient was well 1 year after surgery.

The term CMNPT of the lung was first used by Ishikawa in 2002 to describe a 1.5-cm peripheral lung nodule consisting of ciliated columnar cells, mucous cells and basal cells with papillary architecture. It was considered benign in view of indolent behaviour and bland-looking cells. Further reports by Ishikawa2 and others3 4 5 6 7 of similar tumours under various names (eg, solitary peripheral ciliated glandular papillomas, peripheral pulmonary papillary/glandular neoplasms with ciliated cells) supported this group of tumours as a specific entity that has not been included in the 2015 World Health Organization Classification of Lung Tumours.8 We searched the literature and reviewed 12 reports of 33 such tumours (online supplementary Appendix). Controversy exists whether CMNPT should be considered a benign tumour, a well-differentiated adenocarcinoma (in view of frequent intra-alveolar extension), or a spectrum of entities with possible progression. The consistent small size, slow growth rate, and lack of recurrence or metastasis after surgery support the benign nature of this tumour. Differentiation from mucinous adenocarcinoma is difficult for pathologists, especially during intra-operative frozen section, owing to the profuse mucin production and lepidic growth pattern. High-power examination revealing tripartite cell differentiation and lack of significant atypia in a clinically slow-growing lung nodule should raise suspicion of CMNPT. Wedge excision with clear margin is the treatment of choice. Our findings concur with a previous report3 of tumour origin from the terminal bronchiole. The finding of co-existing peribronchiolar metaplasia with similar cell components as CMNPT in the rest of the lung is unique. This suggests progression of disease from smoking-induced metaplasia to neoplasia during the pathogenesis. Although chronic smoking was noted in most male patients with CMNPT (14 out of 16 with smoking history specified in the online supplementary Appendix), co-existing peribronchiolar metaplasia was only briefly mentioned in one report,4 probably owing to limited sampling in wedge excision for most tumours. Molecular analysis for BRAF or EGFR mutations was not done in our case, because there was no therapeutic indication. Studies of CMNPT by Chuang et al5 and Lau et al6 yielded no KRAS or EGFR mutation. In contrast, Kamata et al7 reported mutations involving EGFR, BRAF, PTEN11, CTNNB1, IDH1, and TP53 in Asian patients and Liu et al4 reported mutations involving BRAF and AKT1 in one non-Asian patient. Because CMNPT is commonly reported in patients from East Asia, more reports are expected when awareness of this entity is raised among pathologists in this region. The pathogenesis, molecular characteristics, and natural behaviour of CMNPT can be better defined when more data are available.

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.

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

The authors would like to thank Dr Siu-wah Pang for contributing to the diagnosis of this tumour.

All authors have disclosed no conflicts of interest.

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

This study was approved by the Ethics Committee of the University of Hong Kong–Shenzhen Hospital as original work with no infringement of personal privacy. The requirement for patient consent was waived by the Ethics Committee.

1. Katzenstein AL, Mukhopadhyay S, Zanardi C, Dexter E. Clinically occult interstitial fibrosis in smokers: classification and significance of a surprisingly common finding in lobectomy specimens. Hum Pathol 2010;41:316-25. Crossref

2. Ishikawa M, Sumitomo S, Imamura N, et al. Ciliated muconodular papillary tumor of the lung: report of five cases. J Surg Case Rep 2016;2016.pii:rjw144. Crossref

3. Aida S, Ohara I, Shimazaki H, et al. Solitary peripheral ciliated glandular papillomas of the lung: a report of 3 cases. Am J Surg Pathol 2008;32:1489-94. Crossref

4. Liu L, Aesif SW, Kipp BR, et al. Ciliated muconodular papillary tumors of the lung can occur in Western patients and show mutations in BRAF and AKT1. Am J Surg Pathol 2016;40:1631-6. Crossref

5. Chuang HW, Liao JB, Chang HC, Wang JS, Lin SL, Hsieh PP. Ciliated muconodular papillary tumor of the lung: a newly defined peripheral pulmonary tumor with conspicuous mucin pool mimicking colloid adenocarcinoma: a case report and review of literature. Pathol Int 2014;64:352-7. Crossref

6. Lau KW, Aubry MC, Tan GS, Lim CH, Takano AM. Ciliated muconodular papillary tumor: a solitary peripheral lung nodule in a teenage girl. Hum Pathol 2016;49:22-6. Crossref

7. Kamata T, Sunami K, Yoshida A, et al. Frequent BRAF or EGFR mutations in ciliated muconodular papillary tumors of the lung. J Thorac Oncol 2016;11:261-5. Crossref

8. Travis WD, Brambilla E, Burke AP, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: International Agency for Research on Cancer; 2015.

Intrauterine insemination (IUI) is a fertility treatment that involves injection of a processed semen sample into the uterus via a transvaginal catheter after the cervix has been swabbed clean. Sterile instruments are used to reduce the risk of infection.

Historically, Candida glabrata has been considered a relatively non-pathogenic saprophyte of the normal flora of healthy individuals, rarely causing serious infections in humans. Contrary to the more common vaginal coloniser Candida albicans, C glabrata is unable to penetrate intact fetal membranes in vitro.1 This explains the rarity of C glabrata chorioamnionitis although it is a common vaginal coloniser found in up to 8% of pregnant women.1

The present study describes a rare case of C glabrata chorioamnionitis and fungaemia in a pregnancy following IUI.

A 32-year-old healthy primigravida with a trichorionic-triamniotic triplet pregnancy conceived by IUI presented in December 2011 to Queen Mary Hospital, Hong Kong at 16 weeks’ gestation with leaking of liquor. Physical examination and ultrasonography confirmed rupture of membranes of one of the triplets. The patient was initially treated with oral erythromycin but 2 days later she developed a fever of 39℃. Empirical intravenous broad-spectrum antibiotics were given for presumptive bacterial chorioamnionitis. In view of the poor prognosis at such an early gestation and the risk of maternal sepsis, medical abortion with misoprostol was considered appropriate. Complete abortion was achieved and the patient’s fever subsided the next day.

Two days after abortion, blood culture and vaginal swab test results revealed the presence of C glabrata. Intravenous anidulafungin 200 mg stat, then 100 mg every 24 hours was prescribed. The patient remained well and was discharged from the hospital after 2 weeks of antifungal treatment. Results from a second blood culture taken 3 days after abortion were negative.

In view of the rarity of fungaemia in immunocompetent hosts, testing for human immunodeficiency virus antibodies, lymphocyte subset and dihydrorhodamine reduction test was performed. All results were normal. Histological examination of the three placentae showed polymorph infiltration and presence of fungal spores, confirming acute fungal chorioamnionitis.

To the best of our knowledge, this is the first report of C glabrata chorioamnionitis and fungaemia in a pregnancy following IUI. A search of the literature revealed 18 articles reporting 22 cases of C glabrata chorioamnionitis (online supplementary Appendix 1). Fifteen of the reported cases were associated with in-vitro fertilisation (IVF) and four with a foreign body (intrauterine contraceptive device or cervical cerclage). The growing number of reports may be partly due to improved diagnostic methods, but the increasing use of assisted reproductive technologies also appears to be an important factor. Contamination of the embryo by infected semen or the mother’s cervicovaginal Candida during transvaginal oocyte harvest, or direct inoculation of C glabrata into the uterus during embryo transfer are possible aetiological mechanisms.2 The only two reported cases of the rare Candida lusitaniae chorioamnionitis in the literature were also associated with IVF (online supplementary Appendix 2), further supporting the hypothesis.

Most of the reported cases were associated with preterm labour or preterm premature rupture of membranes (PPROM); therefore, it is also possible that intrauterine C glabrata infection was a result of ascending infection after PPROM and preterm labour, since assisted reproductive technologies are associated with multiple pregnancy, preterm labour, and PPROM. However, PPROM and preterm labour occur in about 6% of births and there have been only 23 reported cases (including the current report) of C glabrata chorioamnionitis. Sixteen of the 23 reported cases were associated with IVF and IUI. We conclude that C glabrata chorioamnionitis is more likely due to inoculation of the fungus into the uterus during IVF and IUI procedures, rather than a result of preterm labour and PPROM. The present case supports this hypothesis.

Although maternal outcome was good in the published cases, this fungal chorioamnionitis was often associated with poor fetal outcome. Only 30% (7 of 23 cases, including the present case) of the published affected pregnancies had any neonatal survival as they usually presented with PPROM or preterm labour in the second or early third trimester.

There are no guidelines for screening for vaginitis before assisted reproductive procedures. If asymptomatic C glabrata or other fungal colonisation is identified, there is no consensus on whether treatment should be given. One case of a successful IVF pregnancy following eradication of C glabrata by topical boric acid treatment had been preceded by an IVF pregnancy that ended in C glabrata sepsis and fetal loss.3 The authors suggested routine vaginal culture for yeast and treatment of positive culture results prior to embryo transfer, and commented that such an inexpensive test adds little to the overall costs and procedures associated with IVF.3 On the contrary, some authors suggest that a comprehensive screening programme may not be justified given the rarity of invasive disease despite widespread use of IVF and the relatively high rates of C glabrata carriage among pregnant women.2 The true incidence of C glabrata chorioamnionitis is unknown because it is likely to be underdiagnosed due to the difficulty in laboratory diagnosis.2 Treatment cost-effectiveness cannot be estimated, but the number needed to treat to prevent one C glabrata–related adverse outcome is likely to be large in view of the relatively high carrier rate and the rarity of C glabrata chorioamnionitis. Further research is needed to evaluate the cost-effectiveness of such a screen-and-treat programme before it can be recommended. In addition, there have been reports of emergence of antifungal resistance. If all asymptomatic carriers are treated prior to embryo transfer, emergence of drug resistance will become a concern. Similarly, whether it is worth screening men for any asymptomatic carriage is uncertain.

The possibility of C glabrata chorioamnionitis should be considered in pregnant women who develop chorioamnionitis after conceiving with assisted reproductive techniques. The reporting of this potentially devastating condition should be encouraged so as to improve our knowledge about its incidence, risk factors, pathogenesis, and management. Further research is needed to determine the incidence of fungal infection–related adverse outcomes and the cost-effectiveness of a screen-and-treat approach prior to assisted reproduction.

All authors contributed to the concept of the paper. SSF Yung, MMC Cheng, and PWS Ma contributed to the acquisition, analysis, and interpretation of data. SSF Yung drafted the article.

All authors have disclosed no conflicts of interest. 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. This paper was presented as a poster in the 25th Asian & Oceanic Congress of Obstetrics and Gynaecology (AOCOG), Hong Kong, on 15-18 June 2017.

1. Ganer Herman H, Mevorach Zussman N, Krajden Haratz K, Bar J, Sagiv R. Candida glabrata chorioamnionitis following in vitro fertilization: review of the literature. Gynecol Obstet Invest 2015;80:145-7. Crossref

2. Jackel D, Lai K. Candida glabrata sepsis associated with chorioamnionitis in an in vitro fertilization pregnancy: case report and review. Clin Infect Dis 2013;56:555-8. Crossref

3. Asemota OA, Nyirjesy P, Fox R, Sobel JD. Candida glabrata complicating in vitro pregnancy: successful management of subsequent pregnancy. Fertil Steril 2011;95:803.e1-2. Crossref

Acute appendicitis is a common surgical emergency that can cause severe complications if diagnosis and management are delayed.1 Necrotising fasciitis (NF) is a necrotic infection involving deeper layers of the skin and subcutaneous tissue that spreads rapidly along the fascia, progressing to systemic sepsis. It is most commonly induced by injury and is an extremely rare complication of acute appendicitis. In this article, we present a case of perforated appendicitis complicated by right thigh and scrotal NF. Since the condition runs a fulminant clinical course, prompt diagnosis and early surgical intervention are crucial to reduce mortality.

A 60-year-old man with good past health presented to the Accident and Emergency Department of Queen Elizabeth Hospital, Hong Kong, in December 2015 with a 6-day history of fever and lower abdominal pain.

His vital signs on presentation were as follows: systolic blood pressure 97 mm Hg; diastolic blood pressure 59 mm Hg; pulse 90 beats per minute; and body temperature 38.3°C. Physical examination revealed lower abdominal and right thigh tenderness without subcutaneous emphysema. Laboratory data showed leucocytosis (15.5 × 10⁹/L) with neutrophilia (neutrophils 88.7%) and evidence of acute kidney injury (estimated glomerular filtration rate 38 mL/min/1.73 m², serum creatinine 171 μmol/L).

Abdominal, pelvic, and right hip radiographs were unremarkable. Urgent abdominal and pelvic computed tomographic (CT) scan revealed a dilated retrocaecal appendix with heterogeneous wall enhancement, compatible with acute gangrenous appendicitis. There was rupture at the appendiceal tip, contiguous with a 2.8- × 4.5- × 8.0-cm gas-containing abscess posterolateral to the ascending colon and caecum (Fig 1). Increased peri-appendiceal and pericaecal stranding and free gas were noted. Multiple smaller pelvic abscesses were also observed. An incidental finding of abnormal swelling of the right upper thigh was noted in the limited coverage of the thigh in the original CT scan. Another CT scan including the whole right thigh was performed by the on-site radiologist. Abnormal high-density fluid and fat stranding were noted in the subcutaneous layer and intermuscular fascial planes in the anterior, adductor, and posterior compartments of the right thigh (Fig 2). The thigh muscles were swollen without discrete abscess formation. No gas density was detected along the fasciae. The initial overall imaging diagnosis was ruptured acute appendicitis with peri-appendiceal abscess, complicated by right thigh NF.

Subsequent urgent laparotomy revealed a ruptured inflamed retrocaecal appendix and an 8-cm retrocolic abscess. Appendectomy and abscess drainage were performed. These were followed by exploration of the right thigh that revealed oedematous and necrotic subcutaneous and deep soft tissues mainly involving the adductor compartment. Multiple intramuscular abscesses were seen with turbid fluid tracing along the femoral neurovascular bundles proximally to the pelvic region. Overall features were compatible with NF. Right above-knee amputation with excisional debridement was performed in view of the patient’s poor general condition and extensive involvement.

Culture of the debrided muscle and fascial tissue yielded Escherichia coli, Bacteroides fragilis, and Streptococcus milleri. A combination of antibiotics was given, including amikacin, ampicillin, levofloxacin, linezolid, meropenem, and penicillin G. However, septic shock persisted with development of multi-organ dysfunction despite multiple inotropes. Another CT scan of the abdomen and pelvis was performed on postoperative day 1, revealing a grossly swollen scrotum with hydrocoele (not shown). No intrascrotal gas density was detected. In view of the patient’s clinical deterioration, urgent scrotal exploration was performed and revealed extensive scrotal skin necrosis with copious serous fluid draining from the perineum.

After the second surgery, the patient had persistent multi-organ failure with clinical deterioration despite supportive management. He developed acute respiratory distress syndrome with respiratory failure and disseminated intravascular coagulation with severe anaemia, further complicated by acute coronary syndrome. The patient succumbed on the fourth day of hospital admission.

The incidence of NF has risen recently owing to an increased prevalence of patients who are immunocompromised secondary to diabetes mellitus or treatment for malignancy or human immunodeficiency virus infection.1 The mortality rate for NF is high, despite significant advances in antibiotic treatment, owing to its rapid progression to septic shock and multi-organ failure.1

Common causes of NF include minor trauma, skin infection, intravenous drug use, and surgical complication.1 The abdomen, groin, and extremities are the regions most commonly affected by NF.1 2 3 4 5 Necrotising fasciitis is commonly polymicrobial, caused by virulent toxin-producing bacteria such as Group A haemolytic streptococci and Staphylococcus aureus. Other causative bacteria include Bacteroides, Clostridium, Enterobacteriaceae, Peptostreptococcus, Proteus, Pseudomonas, and Klebsiella.1

The diagnosis of NF is challenging due to its rarity and non-specific presentation. Usually the early manifestations are local inflammatory signs and symptoms such as swelling, erythema, and tenderness, occasionally with fever. However, NF should be suspected when the severity of pain or clinical status are disproportional to local findings.5 Laboratory studies show leucocytosis with predominant neutrophilia,1 but is unfortunately non-specific.5 Presence of soft tissue gas in the absence of penetrating trauma suggests a diagnosis of NF,2 although the absence of soft tissue gas does not exclude the diagnosis, as evidenced by our case.

Plain radiographs are usually unhelpful for initial diagnosis as soft tissue gas is seldom detected until late in the disease process.1 Magnetic resonance imaging is superior in delineating soft tissue pathology but is a suboptimal modality for critically ill patients.2 Computed tomography is the preferred imaging modality, with reported findings including asymmetric fascial thickening with fat stranding and subcutaneous gas tracking along fascial planes.2 It also delineates the extent of tissue involvement well and is useful for monitoring treatment response.

Necrotising fasciitis secondary to perforated appendicitis is rarely reported. We have found only 18 case reports of NF caused by acute appendicitis published in the English literature.1 2 3 4 5 The affected regions included the abdominal wall (most commonly involved), perineum, and thigh. According to Taif and Alrawi,5 there have been only three reported cases of appendicitis complicated by NF predominantly involving the lower limb. All cases involved the right thigh, likely from more direct infective spread along the right femoral neurovascular bundles than the left.

Our case represents a rare but life-threatening consequence of a common disease despite the absence of risk factors. Early clinical changes of NF can be subtle. Early recognition, broad-spectrum antibiotic treatment, and aggressive surgical debridement are the cornerstones of management for this potentially lethal disease.1 A high index of suspicion is needed in diagnosis such that emergent surgical intervention can be initiated to improve clinical outcome.

All authors contributed to the design, acquisition and interpretation of data, drafting of the article, and critical revision for important intellectual content.

We would like to thank the staff radiographers of the Department of Radiology and Imaging, Queen Elizabeth Hospital for their assistance in acquisition of the images.

All authors have disclosed no conflicts of interest. 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.

1. Chen CW, Hsiao CW, Wu CC, Jao SW, Lee TY, Kang JC. Necrotizing fasciitis due to acute perforated appendicitis: case report. J Emerg Med 2010;39:178-80. Crossref

2. Hung YC, Yang FS. Necrotizing fasciitis—a rare but severe complication of perforated appendicitis. Radiol Infect Dis 2015;2:81-3. Crossref

3. Hua J, Yao L, He ZG, Xu B, Song ZS. Necrotizing fasciitis caused by perforated appendicitis: a case report. Int J Clin Exp Pathol 2015;8:3334-8.

4. Wanis M, Nafie S, Mellon JK. A case of Fournier’s gangrene in a young immunocompetent male patient resulting from a delayed diagnosis of appendicitis. J Surg Case Rep 2016;2016:rjw058. Crossref

5. Taif S, Alrawi A. Missed acute appendicitis presenting as necrotising fasciitis of the thigh. BMJ Case Rep 2014;2014:bcr2014204247. Crossref

A 24-year-old Chinese man was referred to the Chest Unit of Grantham Hospital, Hong Kong in June 2016 for management of bronchiectasis. The patient had experienced his first episode of lower respiratory tract infection (LRTI) at age 17 years, which required hospital admission for intravenous antibiotics. He had since developed four to five episodes of LRTI annually and subsequently developed bronchiectasis with daily copious sputum and occasional haemoptysis.

Review of the patient’s records revealed a history of autoimmune hypothyroidism since age 12 years, which was based on thyroid scintigraphy and high titres of antithyroid autoantibodies and required thyroxine replacement. At age 21 years, after an incidental finding of iron deficiency anaemia, the patient underwent upper endoscopy, which revealed oesophageal candidiasis (Fig 1). The patient had recurrent and chronic oral ulcers, and excisional biopsy with Grocott staining displayed fungal spores and pseudohyphae consistent with candidiasis.

Further questioning of the patient revealed frequent tinea infections and orogenital candidiasis since early childhood. The patient had had childhood chickenpox with two further episodes of zoster reactivation during his teens. There were no features suggestive of atopy nor any history of recurrent abscesses. The patient had difficulty attending his frequent medical appointments and often required sick leave from his work as a technician. He was a never smoker and social drinker. The patient was born and raised in Hong Kong, and had received all routine vaccinations without problems. The family history was unremarkable with no history of consanguinity. The patient lived with his parents and younger brother, none of whom had candidiasis.

High-resolution computed tomography revealed bilateral lower lobe bronchiectasis (Fig 2) and bronchoscopy again showed extensive candidiasis with no airway abnormalities. Pulmonary function test results and serum alpha-1-antitrypsin level were normal. Sputum cultures were negative for acid-fast bacilli and yeasts, and aerobic culture yielded commensals only. The patient’s complete blood counts were grossly normal apart from a persistently low absolute lymphocyte count (0.5-0.7 × 109 /L). Immunoglobulin (Ig) levels (IgG/IgM/IgA/IgE) were all within normal limits. Screening for diabetes mellitus and testing for human immunodeficiency virus (HIV) was negative. Complement levels and the dihydrorhodamine assay were normal. A serology panel also found positive anti-nuclear antibodies with a titre of 1:320, in addition to previously documented thyroid autoantibodies. Repeated lymphocyte subsets showed persistent panlymphocytopenia (CD19:43/μL[n:91-452], CD3:491/μL[n:938-2311], CD4:206/μL[n:437-1226], CD8:263/μL[n:322-1104] and CD16/56:115/μL[n:177-1059]), with impaired lymphocyte proliferation after phytohaemagglutinin and pokeweed mitogen stimulation.

In view of his chronic mucocutaneous candidiasis (CMC), autoimmunity and combined immunodeficiency, the patient was referred to us for further evaluation. An interleukin (IL)-17–related defect was suspected and sequencing of the signal transducer and activator of transcription (STAT) 1 gene was performed. A previously reported gain-of-function (GOF) mutation of p.G384D in the DNA-binding domain was identified.1 The patient was counselled and long-term itraconazole and co-trimoxazole prophylaxis treatment was started. Measurement of pneumococcal antibody responses were scheduled. The patient continues to receive multidisciplinary care between immunology, pulmonology, and internal medicine after a unifying diagnosis for his wide spectrum of disease manifestations was made.

That primary immunodeficiencies (PIDs) only affect children is a common misconception. Diagnoses are also made in adulthood due to genuine adult-onset types, as in our case, or delayed disease recognition. We describe the first reported adult case of STAT1-GOF mutation in our locality. The patient had a typical history of CMC, complicated by recurrent infections, bronchiectasis, and autoimmune hypothyroidism. The patient also had panlymphocytopenia, which is reported in 20% to 30% of STAT1-GOF patients and associated with LRTIs.2 The first possible indication of STAT1-GOF mutation was the autoimmune hypothyroidism in the context of CMC.

Typically, CMC is characterised by persistent/recurrent non-invasive Candida infections of the skin, nails, and mucous membranes. Candidiasis is usually an opportunistic infection and associated with immunosuppression acquired through diabetes mellitus or HIV, or use of chemotherapy, glucocorticoids, or antibiotics. Candidiasis is also associated with a variety of PIDs, usually with an underlying IL-17 pathway defect. Examples include hyper-IgE syndromes, autoimmune polyendocrinopathy syndrome type 1, CARD9 deficiency, in addition to IL-17F and IL-17RA deficiencies.3

Since 2011, STAT1-GOF mutations have been discovered that cause autosomal dominant familial CMC. These mutations are now established as the most common genetic cause of inherited CMC. Such STAT1-GOF mutations have also been reported in paediatric patients in Hong Kong with CMC and penicilliosis.4 These mutations impair STAT1 dephosphorylation and enhance the production of STAT1-dependent cytokines (interferon-α/β, interferon-γ and IL-27). In turn, this likely represses STAT3-dependent gene transcription and impairs the development of IL-17–producing T cells, although the exact mechanisms remain unclear.5

A recent analysis of the clinical manifestations in 274 individuals with 76 different STAT1-GOF mutations revealed an extremely broad disease phenotype.2 In addition to CMC, patients were also prone to other fungal, bacterial (usually LRTIs), and viral infections. Results of immunological investigations were variable, but abnormalities were significantly associated with increased infections. More than a third of patients had autoimmune/inflammatory disorders, most commonly hypothyroidism, and 21% of patients had bronchiectasis.2 Most patients with autoimmunity had positive autoantibodies. Alarmingly, these patients are more likely to develop other autoimmune disorders, cerebral/abdominal aneurysms, and squamous cell carcinomas (likely secondary to chronic mucocutaneous inflammation).

The outcome for patients with STAT1-GOF mutations remains poor, with most deaths resulting from infection, aneurysms, or malignancies. Long-term (as opposed to intermittent) systemic antifungal therapy remains the mainstay of treatment, aiming to reduce the development of antifungal resistance and malignancy. Additional antibiotic prophylaxis and intravenous Ig should be considered for patients with recurrent infections. In our patient, intravenous Ig would have been indicated if his response to pneumococcal vaccination was suboptimal in the context of bronchiectasis. Furthermore, autoimmune hypothyroidism is associated with cerebral aneurysms and baseline magnetic resonance angiography may be indicated. Lastly, any ear, nose, and throat or gastrointestinal symptoms should alert the physician to a need for regular monitoring of such malignancies with biopsy. Experimental therapies such as colony-stimulating factors and ruxolitinib, a Janus kinase 1/2 inhibitor, have been reported to successfully improve CMC and will merit a trial if his CMC worsens with time.6

For other PIDs, the main goals are to reduce the incidence of infections and to prevent development of complications; with the ultimate aim of cure. Improved awareness and further development of adult clinical immunology in Hong Kong is required, so that adult patients with PID receive more timely and comprehensive care.

All authors have made substantial contributions to the concept; acquisition of data; interpretation of data; drafting of the article; and critical revision for important intellectual content.

All authors have disclosed no conflicts of interest. 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.

1. Yamazaki Y, Yamada M, Kawai T, et al. Two novel gain-of-function mutations of STAT1 responsible for chronic mucocutaneous candidiasis disease: impaired production of IL-17A and IL-22, and the presence of anti-IL-17F autoantibody. J Immunol 2014;193:4880-7. Crossref

2. Toubiana J, Okada S, Hiller J, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood 2016;127:3154-64. Crossref

3. Puel A, Cypowyj S, Maródi L, Abel L, Picard C, Casanova JL. Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis. Curr Opin Allergy Clin Immunol 2012;12:616-22. Crossref

4. Lee PP, Mao H, Yang W, et al. Penicillium marneffei infection and impaired IFN-γ immunity in humans with autosomal-dominant gain-of-phosphorylation STAT1 mutations. J Allergy Clin Immunol 2014;133:894-6.e5. Crossref

5. Zheng J, van de Veerdonk FL, Crossland KL, et al. Gain-of- function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC). Eur J Immunol 2015;45:2834-46. Crossref

6. van de Veerdonk FL, Netea MG. Treatment options for chronic mucocutaneous candidiasis. J Infect 2016;72 Suppl:S56-60. Crossref

Despite the advances in neuroscience and medical therapy for epilepsy, status epilepticus, especially when refractory or super-refractory (defined as seizure that continues or recurs ≥24 hours after onset of anaesthetic therapy, including cases that recur on reduction or withdrawal of anaesthesia),1 remains an enormous challenge. Multiple and high-dose drug loading is usually prescribed but may be futile. New modalities of treatment including hypothermia and ketogenic diets have been tried with some success in reported case series.2 We report a case of new-onset super-refractory status epilepticus treated successfully with electroconvulsive therapy (ECT).

A 31-year-old male with a history of childhood asthma presented to Tuen Mun Hospital in November 2012 following onset of generalised tonic-clonic seizure at home. He had upper respiratory symptoms with fever, myalgia, and cough for a week previously. There was no history of recent travel or drug abuse.

Physical examination revealed no focal neurological abnormalities. Investigations showed a normal routine blood picture and renal function except mild liver impairment with alanine aminotransferase level of 72 U/L. General autoimmune (antinuclear antibodies, anti–early nuclear antigen antibodies, C3/C4 and antithyroid antibodies) and toxicology screening were negative. Dried blood spot test for neurometabolic screening was also negative. Examination of cerebrospinal fluid showed white blood cell count 9 per mm3, red blood cell 2 per mm3, protein 0.54 g/dL, and glucose 5.4 g/dL. Microbiological investigations (herpes simplex virus, human immunodeficiency virus, Japanese encephalitis virus, varicella zoster virus, and enteroviruses) were negative. Serology for neurosyphilis and leptospirosis was also negative. Serum anti-CASPR2 Ab, anti-LGI1 Ab, anti-VGKC Ab, and anti-NMDAR Ab (serum and cerebrospinal fluid) were all negative.

He was initially treated with intravenous acyclovir and ceftriaxone for presumed acute infectious meningoencephalitis. Routine electroencephalogram (EEG) showed a generalised slow background of 4 to 6 Hz without epileptiform discharges. He developed a clustering of generalised tonic-clonic seizures 2 days later and was admitted to the intensive care unit. He underwent mechanical ventilation and aggressive treatment with medication at the maximal tolerable dosage including intravenous phenytoin (300 mg/d), valproate (1200 mg/d), midazolam (~60 mg/h), propofol (up to 110 mg/h), phenobarbitone (300 mg/d), and levetiracetam (3000 mg/d). Despite treatment he remained convulsive with seizures evident on EEG. Intravenous immunoglobulin was first given 8 days following admission for possible autoimmune encephalitis but was unsuccessful. Electroencephalogram showed generalised epilepti-form discharges and runs of EEG seizure activity over the bitemporal and bifrontocentral regions. His condition was later complicated by rhabdomyolysis and renal failure (creatine phosphokinase up to 47 000 U/L) that was controlled by aggressive intravenous fluid administration.

Magnetic resonance imaging of the brain (Fig 1) showed multiple patchy areas of cortical T2 hyperintensity bilaterally that were more indicative of epileptic changes with the possibility of encephalitis. Electroencephalogram finally reached burst suppression and seizure suppression following infusion of thiopentone (300 mg/h) and ketamine (220 mg/h). The former was withdrawn because of sepsis that was treated with ticarcillin/sulbactam and meropenem/ertapenem. The generalised epileptiform discharges and seizures returned 8 days later despite such aggressive treatment.

Hypothermia by external cooling (18 days after admission) with body temperature reduced to 32°C with a ketogenic diet (81% lipid, 4.7% Chinese hamster ovary and 13.9% protein) and urine ketosis had no effect. Plasmapheresis was attempted on day 22 but also failed.

Finally, ECT was attempted using the spECTrum 5000Q (Techsan, Czech Republic) and followed the standard psychiatric protocol for treatment of refractory major depression. Ketamine and propofol continued throughout the procedure. The first course of ECT commenced 30 days after admission, and was administered 3 times per day for 3 days:

• Day 1: pulse width at 0.5 ms, frequency 40 Hz × 1 and 60 Hz × 2, duration of 8 seconds, current 800 mA, 200 J
• Day 2: pulse width at 0.5 ms, frequency 60 Hz × 2 and 80 Hz × 1, duration of 8 seconds, current 800 mA, 200 J (tonic seizure, EEG seizure, and R arm clonus-induced)
• Day 3: pulse width at 0.5 ms, frequency 80 Hz × 3, duration of 8 seconds, current 800 mA, 200 J (tonic seizure–induced and EEG showed spindle coma)

Attenuation and abolition of continuous lateralised epileptiform discharges and seizures were achieved with interictal focal epileptiform discharge over the right frontal region only. The EEG seizure induced by stimulation comprised generalised fast beta activities different to the patient’s own seizure activities.

The EEG from the first day of the first course stimulation is shown in FIgure 2.3 4 The second course was given 8 days later (again thrice per day for 3 days) as there was no sustainable improvement. In this course, all therapies were given with pulse width 0.5 ms, frequency 80 Hz, duration of 8 seconds, and current 800 mA, 200 J after referencing the EEG response of the last stimulation. Arm clonus, with one arm paralysed with muscle relaxants and the other for observing EEG-induced seizure and threshold titration, was observed in 10 of the 15 stimulations.

Electroencephalogram 1 week after completion of the second course showed a triphasic wave pattern rather than the previous generalised periodic discharges with EEG seizures over the right frontocentral and right hemisphere. The patient had hyperammonaemia, likely secondary to hepatotoxicity due to the prolonged use of multiple antiepileptics and anaesthetics, and was treated with sodium benzoate.

Oxcarbazepine and lacosamide were added for focal electrographic seizures. Electroencephalogram 10 days after ECT continued to show generalised continuous slow waves with intermittent rhythmic slowing of 1 Hz. There was some eye blinking but no ictal EEG changes.

Electroencephalogram 1 month after ECT showed an improved background of 6 to 8 Hz and occasional EEG seizures over the right frontocentral region, as well as clinically automotor seizures.

The patient was transferred back to the general ward 1 month later and commenced active rehabilitation. He was discharged home 3 months later, although he continued to require a frame for walking and experienced short duration of breakthrough seizures. His positron emission tomography scan later showed no evidence of malignancy. One year later, the patient remained ambulatory with aids but with cognitive decline and personality changes. He was able to self-care, but his seizures remained pharmacoresistant.

This is the first case of super-refractory status epilepticus, defined as status epilepticus that continues or recur ≥24 hours after the onset of anaesthetic therapy including those cases that recur on reduction or withdrawal of anaesthesia,1 that has been treated with ECT successfully in our locality.

There are only individual reports describing the use of ECT for status epilepticus over the last 30 years,5 6 although its use was first described in the 1940s. It was not until the introduction of super-refractory status epilepticus7 that the role of multiple exploratory therapies (those without support from systemic investigations or clinical trials including use of ketamine, hypothermia, ketogenic diet, and ECT) were added to the management protocol.8 The most promising news for this specific seizure status nonetheless comes from the recent discovery of the treatable autoimmune encephalitic nature of many such cases with specific identifiable antibodies such as anti-NMDAR Ab, anti-LGI1 Ab, and anti-VGKC Ab.

The term NORSE (new-onset refractory status epilepticus) was introduced in 20059 for patients with refractory status epilepticus and no history of seizures and no identifiable aetiology. Reviewing the limited literature, these cases reported usually have features suggestive of an infectious or inflammatory nature with febrile episodes or abnormal cerebrospinal fluid pleocytosis.10 These cases are most likely to be autoimmune encephalitis, but the antibodies are not available or have not yet been identified. Our patient was likely true NORSE, although the possibility of a postinfectious or autoimmune mechanism cannot be excluded as the panel of testing has not been exhausted.

Electroconvulsive therapy in status epilepticus was first described by Carrasco González et al in 1997 and Viparelli and Viparelli in 1992.5 11 Since then, there have been other case reports or series reporting success of this therapy, both in adult and paediatric patients.12 13 It is usually applied with the withdrawal of anticonvulsants or anaesthetics. Mechanisms suggested include enhanced gamma-aminobutyric acid inhibition, the effect of paradoxical stimulation of status epilepticus and electrical modulation.14 In our patient, anticonvulsants or anaesthetic agents were given without an end date and we applied ECT in addition to, not instead of, such drug therapy. The EEG epileptiform discharges showed immediate attenuation following electrical stimulation, and supports the possibility of enhancing the seizure threshold or an inhibitory mechanism. The later EEG changes were related to significant metabolic encephalopathy (hyperammonaemia) rather than previous runs of epileptiform discharges, also suggested the modulatory effect of ECT when a course was given rather than just a few shots. Of course, one would also argue that the improvement could be the late effect of previous intravenous immunoglobulin or plasmapheresis although these had no immediate effect on the EEG or clinical seizures or epileptiform discharges.

Despite the apparent successful outcome for our patient following the addition of ECT, we require more cases, both adult and paediatric, with such treatment applied as well as a clear definition of the status epilepticus stages (early, refractory or super-refractory) and specific categorisation of the syndrome and aetiology (autoimmune or cryptogenic to be NORSE) before we can confidently support the role and effectiveness of this physical therapy.

The authors have no conflicts of interest to disclose.

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