A 49-year-old female suffering from right-sided triple-negative breast cancer and on active chemotherapy presented with left arm swelling for the past 10 days. She stated that her left arm swelling had progressed from the elbow up to the shoulder and also complained of heaviness and cramping pain in the left arm (5/10 in severity). Physical examination was remarkable for 4+ edema and tenderness along with a plethora at the level of the shoulder and upper left chest. She was not able to lift her hand above the shoulder and had a restricted range of motion of the left elbow due to swelling. She also had a left-sided CVC which, on assessment, was unable to be flushed or aspirated.
The patient was on an anthracycline-based regimen for her breast cancer for the past year. She had no personal or family history of previous DVT or hypercoagulable state and did not report the use of any hormonal therapy. Differential diagnoses at the time included catheter-associated deep and superficial vein thrombosis or malignant lymphedema.
The patient was admitted and preliminary investigations were remarkable for anemia (7.8 g/dl) and leukopenia (3200/mm3). Due to the likelihood of catheter-associated UEDVT, venous duplex ultrasonography was performed which showed acute occlusive DVT of the left subclavian and axillary veins, superficial venous thrombosis of the proximal left basilic, and antecubital veins, and short segment occlusion of the proximal left cephalic vein (Figure ).
As the diagnosis of catheter-associated UEDVT was confirmed, the patient was started on subcutaneous enoxaparin injection (1 mg/kg) every 12 hours, and the interventional cardiology service was consulted to discuss the need for possible intervention. Considering the patient’s severely progressive symptoms, high thrombotic burden extending from the subclavian to the axillary vein, acute presentation, severe anemia, and the need to treat the CVC malfunction, the decision was made to pursue mechanical thrombectomy with the ClotTriever System (Inari Medical, Irvine, CA).
Left brachial 5Fr venous access was obtained and diagnostic venography was performed. Thrombotic occlusion of the brachial, axillary, and subclavian veins was seen along with collateralization towards the superior vena cava (SVC) and the presence of a large thrombus at the location of the CVC extending into the subclavian vein (Figure ).
The occlusion was crossed, with the wire placed in the SVC and further navigated into the inferior vena cava past the right atrium. The wire was exchanged with an Amplatz Super Stiff wire that was placed in the right femoral vein and the ClotTriever 13Fr sheath was inserted into the left brachial vein after pre-insertion venoplasty with a 6.0 mm balloon. The ClotTriever catheter was then inserted through the sheath, advanced beyond the SVC, and deployed. After two passes with the ClotTriever catheter, repeat venography was performed which demonstrated continuous flow from the brachial vein to the subclavian vein. Mild contrast extravasation was noted in the proximal axillary vein and was treated with prolonged low-pressure balloon inflation with a 12 x 40 mm Conquest balloon. Repeat venography demonstrated > 90% patency of the brachial, axillary, and subclavian veins with minimal clot burden, no significant collaterals, and straight-line flow to the SVC (Figure ).
The patient was monitored overnight in the cardiac telemetry unit and was discharged the next day on full dose subcutaneous enoxaparin with scheduled follow-up after one week. At the follow-up visit, the patient had significant improvement in symptoms along with the resolution of venous engorgement without any sign of bleeding.


This patient is an 81-year-old male with a past medical history of COPD, CKD, and atrial fibrillation and a history of pneumonia treated by his primary care physician and pulmonary medicine specialist 3 months prior to presentation. Patient also had a 46-pack year smoking history who quit in 1998. He presented to the office with a mass of questionable soft tissue origin in his back that was causing discomfort and pain. The lesion was reported by the patient as a firm, slow-growing, and bothersome for him to lean back in his chair or car seat. Lying on his back was also painful. Initial examination the mass was 3 × 3 cm and mildly tender to palpation with no accompanying lymphadenopathy, redness, or discharge. After discussion of the risks, benefits, and alternative options, the shared physician-patient relationship decided to undergo surgical excision of the back mass. Informed consent was obtained.
The patient underwent LMAC anesthesia in the prone position with local application of 1% Xylocaine with epinephrine. An elliptical incision of the skin overlying the mass measuring was performed for grossly negative surgical margins. Circumferentially, the mass was taken down to the fascia and musculature. There were suspicious attachments of the mass to the surrounding musculature and fascia requiring excision for an en bloc resection. This was performed using cautery. The mass was removed, oriented, labelled, and sent to pathology.
The tissue sample which measured 3.7 × 2.8 × 2.5 cm was stained at the margins with black ink and was noted to have a somewhat circumscribed fleshy appearing area measuring 2.3 × 2 × 1.5 cm. Microscopically, this appeared to extend to the stained ink margins. The sample was sectioned in blocks A1-A9 and subsequently immunostained. Block A5 displayed positive staining for TTF-1, CK7, and CDX-2, with negative CK20. This immunostaining leads to a diagnosis of metastatic adenocarcinoma with micropapillary features from a lung primary. The sample was noted to be an incomplete excision with transection of the mass at the peripheral margin.
The patient was notified of the results, and oncology was consulted. Oncology recommends a staging workup and reexcision of the mass. The patient declined any surgical reexcision. The patient also refused to undergo further staging workup or medical or surgical treatment.


Method
This operation was performed on a 47-year-old female with a three-year history of hyperthyroidism resistant to medical management. Ultrasound imaging demonstrated an 8.2 cm multinodular goitre. The patient underwent a total thyroidectomy using the 4K 3D VITOM for the entire procedure.
The 4K 3D VITOM consists of a 4K endoscope and a 300W xenon fibreoptic light source. The VITOM is mounted external to the body cavity and is positioned using a pneumatic arm. The camera provides 8-30x magnification and a depth of field between 7-44 mm, allowing a working distance of 20-50 mm. The system projects to a 3D 55-inch monitor, with a maximum screen resolution of 1920 × 1080 in 16:9 image format, requiring the surgical team to wear 3D passive-polarised glasses. These have a different filtering system for each eye, meaning each eye only sees the image intended for it. They see the left and right image at the same time onto the area through polarised filters. These filters are oriented at right angles to each other. Each eye perceives a different image resulting in the 3D effect. The monitor is positioned to permit line-of-sight surgery, removing the necessity to physically interact with any magnifying device. The system is controlled by a slave unit comprising a wheel and joystick, which can be used to manipulate the micro-position, focus, and zoom of the camera.
The procedure was carried out with the patient in a supine position on a head ring and shoulder roll. The exoscope, within a sterile drape, was placed 50 cm from the patient to the right of the surgeon and outside the line of sight. It projected to a 3D monitor, placed 2.5 m from the surgeon, positioned at eye level directly opposite the operating surgeon. The control panel was placed to the left of the surgeon within reach, allowing adjustment of focus and fine position of the field of view. The scrub nurse was positioned at the head and the anaesthetist at the foot of the bed. (Figure , )
Surgical technique
The patient was intubated with a neural integrity monitor or NIM® (Medtronic, Minneapolis, USA) electromyogram endotracheal tube. Following a 5 cm transverse skin crease incision, the dissection was continued to the infrahyoid strap muscles. Continuous nerve monitoring was used by fitting an Automatic Periodic Stimulation (APS™)probe (Medtronic, Minneapolis, USA) to the ipsilateral vagus nerve in the carotid sheath []. The upper pole of the thyroid is first dissected using the LigaSure™ (Medtronic, Minneapolis, USA) followed by the lower pole and the position of the RLN is confirmed using a handheld probe. After the removal of both thyroid lobes, the APS probe was removed, the strap muscles were approximated, and the wound closed in layers. The procedure was recorded on the hard drive of the VITOM system. The procedure lasted 75 minutes. There were no immediate complications and the patient was discharged the next day on a standard post-operative regime of calcium and thyroxine supplementation. The histological diagnosis confirmed benign multinodular goitre. Follow up at four weeks revealed a well-healed incision, normal vocal cord movements, and a normal calcium level.


A 23-year-old non-alcoholic man without past medical history presented with a high fever of 38.0°C and sore throat. He was diagnosed with infectious mononucleosis by EBV infection on serological testing, showing positivity for the EBV-IgM viral capsid antigen but negativity for the EBV-IgG viral capsid antigen and early antigen. His symptoms had improved with supportive care. However, 6 weeks later, he presented with a persistent fever of 40.0°C. His consciousness level was clear. Computed tomography scans showed a hepatosplenomegaly but no fatty liver or lymphadenopathy (Fig. ). Laboratory results showed elevated liver function tests (aspartate transaminase 696 IU/L, alanine transaminase 336 IU/L, lactate dehydrogenase 1862 IU/L, alkaline phosphatase 630 IU/L, and total bilirubin 4.9 mg/day), hypofibrinogenemia (100 mg/dL), increased ferritin (5833 ng/mL), increased sIL-2R (3785 U/mL), elevated prothrombin time (56%), and pancytopenia (white blood cell count 1200/μL, hemoglobin 8.9 g/dL, platelet 21 × 103/μL). All autoimmune testing was negative, and serological testing for hepatitis B and C viruses and human immunodeficiency virus (HIV) was also negative. Bone marrow examination for evaluation of pancytopenia revealed that macrophages had phagocytosed mature erythrocytes (Fig. , arrows). Based on these findings, we suspected an HLH triggered by EBV infection (EBV-HLH). To distinguish from HLH triggered by malignant lymphomas accompanying EBV infection, we performed a percutaneous liver biopsy. The biopsy revealed that atypical T-lymphocytes (CD3+, CD8+, CD56−, and CD20−) had markedly infiltrated the hepatic lobules, Glisson's capsules, and sinusoids (Fig. , 100×, d, 200×). The T-lymphocytes were positive for EBV-encoded RNA in situ hybridization (Fig. ). No distinct monoclonal T-cell receptor chain gene rearrangement was detected. Collectively, these findings indicated an EBV hepatitis, and malignant lymphoma was ruled out. The number of copies of EBV DNA in the peripheral blood had increased (1.3 × 106 copies/mL), and he met seven of the eight diagnostic criteria of the HLH-2004. Therefore, we finally made a diagnosis of EBV-HLH. The patient was treated with corticosteroid and etoposide according to the HLH-2004 guideline recommendations. The treatments went well, and the patient was discharged. Thereafter, he remained asymptomatic, and there was no recurrence.


A 4-year old Sri Lankan boy presented with gradually worsening difficulty in walking and unsteadiness for two weeks duration. He was the first child of non-consanguineous parents without a significant family history. He was investigated for anaemia since 18 months of age when he presented with haemoglobin of 8.0 g/dL, mean corpuscular volume (MCV) of 57.8fL, mean corpuscular haemoglobin of 17.6 pg and hypochromic microcytic red blood cells (RBC) in the blood film. His serum ferritin, serum iron and haemoglobin high-performance liquid chromatography were normal. Peripheral blood film showed haemoglobin H inclusion bodies, and the DNA analysis revealed a compound heterozygous state for 3.7 kb α-globin gene deletion and triplicated α-globin genes (-α3.7/ααα). Complete blood counts of both parents were normal however, the α-globin genotype of mother revealed α-thalassaemia trait (-α3.7/αα). He was managed as non-transfusion dependent α-thalassaemia due to haemoglobin H disease with infrequent RBC transfusions and folic acid 1 mg daily.
During 3-months preceding the current presentation, his haemoglobin level frequently dropped below 7 g/dL thus requiring monthly blood transfusions. Then he started to lose motor developmental milestones in the two weeks before admission. At the time of admission, his gross motor development corresponded to the age of 9–12 months; he could sit unaided and stand with support, however, was not able to walk even with support. He was taking a normal balanced diet with food of both animal and plant origin and did not have any chronic illnesses.
On examination, the child had low mood, poor appetite, irritability and hypopigmented hair, which were of recent onset (Fig. a). His weight was 11 kg (at -3SD), and the growth chart showed weight loss of 2 kg over the past six months. His height was 92 cm (between − 2SD to -3SD) and BMI was 12.9 kg/m2 (between − 2SD to -3SD). There were multiple petechiae in the body. Neurological examination revealed generalised hypotonia, grade 4 muscle power in lower limbs and exaggerated knee jerk and extensor plantar response bilaterally. Examination of the upper limbs was normal except for hypotonia. Glasgow coma scale and intellectual functions were unaffected. Examination of other systems was normal.
His complete blood count revealed; haemoglobin- 6.8 g/dL, white cell count- 2800/mm3 (neutrophils-9 % and lymphocytes-89 %) and platelet- 53,000/mm3 (Table ). Blood film showed pancytopenia and haemoglobin H inclusion bodies remained positive. His reticulocyte count was 0.6 %, and the bone marrow biopsy revealed mildly suppressed megaloblastic erythropoiesis with partial maturation arrest of RBC precursors. Granulopoietic progenitor cells were hypercellular with giant metamyelocytes (Fig. ).
Based on the megaloblastic changes and neurological manifestations, vitamin B12 deficiency was suspected. Subsequent investigations revealed; low serum vitamin B12 (116 pg/ml; normal 187–883 pg/ml) and RBC folate (91 µg/L; normal 126–650 µg/L) levels. MRI of the spine revealed symmetrical T2-weighted high signal intensity in the posterior column from cervico-medullary junction to the 12th thoracic vertebra suggesting subacute combined degeneration of the spinal cord (Fig. ). Axial T2-weighted images showed ‘inverted V sign’ with symmetrical bilateral hyperintense signal in posterior columns (Fig. ). MRI of the brain revealed multiple bilateral patchy T2-weighted high signal intensity in the centrum semiovale and deep white matter areas with mild cerebral and cerebellar atrophy. The ventricular system, extra-axial cerebrospinal fluid spaces and cerebellar folia were prominent. His nerve conduction study was normal, anti-intrinsic factor antibody titre was 14.7U (Normal < 20.0), and anti-parietal cell antibodies were negative. Urine analysis revealed urine albumin 2 + with normal microscopy. Urine protein: creatinine ratio was 225 mg/mmol suggesting non-nephrotic range proteinuria. His liver and renal function tests, serum electrolytes, serum calcium, serum protein and renal ultrasonography were normal; however, 25-hydroxy vitamin D level was 27.3 ng/mL (normal 30–100 ng/mL).
Due to the presence of non-nutritional vitamin B12 deficiency and proteinuria in the absence of renal pathology, the diagnosis of Imerslund-Gräsbeck syndrome was made. Genetic testing was not done due to its unavailability locally and difficulties in getting it done internationally. He was commenced on intramuscular hydroxocobalamin 1 mg daily for two weeks followed by 1 mg weekly for eight weeks and then 1 mg monthly. With treatment, he demonstrated rapid improvement of general well-being, hair pigmentation, neurological functions, and haematological manifestations over 4–8 weeks (Fig. b; Table ). He could walk unaided after two weeks and was transfusion independent after two months.


Case1: Patient A, 3-month-old female, developed a fever first measured 38.2 °C at 7 am on January 26, 2020. According to the parents’ description, she did not develop any respiratory or digestive symptoms, had a good appetite, good mental response and loud crying. 4 h after the onset of fever, she was transferred to the hospital for treatment via ambulance. She was healthy previously, immunizations up to date, and had no underlying disease. Her temperature at admission was 38 °C, heart rate 130 beats/min, respiratory rate 30 breaths/min, and body weight 7 kg. Physical examination was unremarkable. Laboratory tests of peripheral blood showed white blood cells were 9.68 × 109/L, 44.3% lymphocytes, 44.6% neutrophil, hemoglobin level 113 g/L, platelets 494 × 109/L, C-reactive protein 5.66 mg/L. Urine routine test was normal. Feces routine test showed lipid drop +. Throat swab specimens were negative for influenza A and B viral antigens. There were no abnormal changes in blood, liver and kidney functions, electrolytes, myocardial enzymes, and antistreptolysin O titer (ASO). She was quarantined in a single room and breastfeeding was continued. She received peramivir antiviral therapy, azithromycin, ceftazidime, and other symptomatic treatments. On January 27, she was afebrile, and her throat swab test from admission returned positive for SARS-CoV-2 nucleic acid. She was transferred to a negative pressure ward for isolation. On day three of hospitalization, she developed a productive cough. Her symptoms improved after being supportively managed with ambroxol, nebulization, and sputum suction. On January 31st, her chest CT showed slightly thickened interstitial lungs and thickened lung markings. Repeat pharyngeal swabs on February 3, 5, and 9 were negative for SARS-CoV-2. Additional sampling from February 5 detected SARS-CoV-2 RNA in feces, and sputum but not urine. On February 9, her fecal specimen test for SARS-CoV-2 RNA remained positive, but throat swab test turned negative.
On February 11, she was discharged from the hospital because she remained afebrile for more than 3 days, improved respiratory symptoms, and tested negative on two consecutive throat swabs. On February 13, her throat swab testing remained negative, but her rectal swab remained positive. The rectal swab ultimately turned negative on March 16 and 18. Follow-up health check on March 7showed that no abnormal changes in blood biochemistry tests, liver and kidney functions, electrolytes, or myocardial enzyme spectrum. However, she continued to have an intermittent cough, wheezing and phlegm. On April 12, she underwent lung function testing with measuring nitric oxide concentration in exhaled gas. Time-to-peak ratio was moderately decreased to 15.1%, volume-to-peak ratio was moderately decreased to 19.4%, tidal volume was 7.2 mL/kg, average breath was 31.1 times/min, and respiration ratio was 0.56. Chest CT (Fig. ) showed the limited “mosaic” signs at the posterior segment of the left upper lobe. There was moderate obstructive tidal breathing dysfunction with a time-to-peak change rate of 27.9% after diastole and a volume-to-peak change rate was of 19.8%. Chest CT showed local mosaic sign in the posterior segment of the left upper lobe, diffusely increased pulmonary volume in the right lung parenchyma, and worsening distal tracheal continuity.


Case 2: Patient B, the father of patient A, a 29-year-old male. A throat swab specimen was collected and tested for SARS-CoV-2 on January 26 due to his close contact with patient A during the car ride and hotel stay. His initial test was negative. On February 2, he developed fatigue but without coughing, rhinorrhea, shortness of breath or other respiratory symptoms, and his temperature was 37.4 °C. Interferon α2b was sprayed on his mouth and bilateral nasal cavities. He continued to complain of low-grade fever, but his whole blood cell count was normal. Chest CT was concerning for infection in the lingula with micronodules. His throat swab specimen tested positive for SARS-CoV-2 on February 2. He was then transferred to the infectious disease isolation ward for further treatment. He met discharge criteria and was discharged on February 14.


Case 3: Patient C, the grandmother of patient A, a 58-year-old female. Her throat swab specimen was collected and tested on January 26 for SARS-CoV-2 given she had the same car ride exposure to patient A. Her test result returned negative. Due to the concentrated quarantine, she had no contact with patient A or patient A’s parents from January 26 to February 10. She did not develop any symptoms during her quarantine in the hotel. She took care of patient A after discharge from hospital on February 11. 2 days later, patient C developed fever and presented for evaluation. Chest CT showed changes indicative of COVID-19. On February 14, patient C was tested positive for SARS-CoV-2. As a confirmed COVID-19 patient, she was transferred to the isolation ward and treated immediately. On February 29, she was discharged.


Patient D, the mother of patient A, a 27-year-old female. Her throat swab specimen was collected and tested for SARS-CoV-2 on January 26 due to travel with patient A from Hubei to Hainan and stay in the same hotel room. Her test returned negative. Patient D continued to have close contact with patient A as she provided care and breastfeed her. On February 3 and 4, patient D had two consecutive throat swab specimens, and tests were positive for SARS-CoV-2 which was also confirmed by the Hainan provincial reference laboratory on February 5. Chest CT imaging showed bilateral upper lung exudative lesions; however, patient D did not demonstrate any clinical symptoms. Based on above evidence, patient D was identified as an asymptomatic carrier. She was isolated for observation. On March 1, her SARS-CoV-2 test returned negative and she was released from isolation.
There were 5 people in this family (Infant A, Father B, Grandmother C, Mother D, and Grandfather E). Grandfather E lived in Xiaogan, Hubei before January 21while the rest of family members were residents of Wuhan, Hubei. Patient B was admitted to the Third People’s Hospital of Wuhan on January 11 for a tonsillectomy and was discharged on January 21. During the hospitalization of patient B, patient C went downstairs to purchase food without protection. Patient D delivered meals to patient B daily with mask protection. On January 20, patient B was discharged and back home. He took patient A to a local private indoor swimming pool for infants with patient D. On their way to swimming pool, patients B and D wore masks but patient A had no mask protection. Patient A was able to use the pool privately and no other customer was present. On January 21, patients A, B, C and D drove to Xiaogan to pick up grandfather E. The family then traveled in the same vehicle to Haikou where they were immediately quarantined. Patients A, B and D stayed in the same room and patients C and E stayed in another. All of them denied history of wild animal exposure or consumption.
After patient A became the first confirmed COVID-19 case in this family, the other four family members were identified as close contacts. They were tracked and three of them were infected. The attack rate of this family cluster outbreak was determined to be 80% (4/5).
According to the epidemiological investigation, patients B, C, D, and E were all in close contacts with patient A. Her exposure to COVID-19 determined to be unprotected swimming in Wuhan, and she was considered as the most identifiable source of infection in this transmission chain. On February 2, patient B, was diagnosed as a confirmed case, on February 5, patient D was identified as an asymptomatic carrier. On February 13, patient C was diagnosed with COVID-19. Patients B, C, D were considered second-generation transmission. Figures and depict the timeline of these events.
On January 26, throat swabs from this family were collected. The nucleic acid test of SARS-Cov-2 showed that the baby was positive, but the other four members were negative. Afterwards, more throat swab tests were done and Table shows the details.
Rectal swabs from patient A were collected and tested for SARS-CoV-2, which remained positive or intermittently positive for 37 days after she was discharged. On March 16 and March 18., the tests were consecutively negative indicating clearance of SARS-CoV-2. Table shows the details.
On June 13, blood samples of patient A, B, C, D and Grandfather E were collected for IgG and IgM tests of SARS-CoV-2 by chemiluminescence and GICA. The results showed Patients A, B, C, D had positive serum IgG and negative IgM, but grandfather E’s serum IgG and IgM were negative. Table shows the details.
The urine sample of Patient A and the breast milk sample of Patient D were collected on February 6 for the nucleic acid tests of SARS-Cov-2. All test results showed negative.
Cluster outbreak identification is essential for infectious diseases monitoring and containment, such as COVID-19. Symptoms and outbreaks of clustering cases are used to determine the possible transmission chain and risk factors throughout the community to prevent further outbreaks [, ]. Regarding COVID-19, the definition of cluster outbreak emphasizes two or more confirmed cases following the same small space exposure in a contained timeframe of 2 weeks [].
Studies had shown that although the main sources of infection for children were other family members. It is rare for an infant to be the source of infection in a family []. In this reported family cluster outbreak, SARS-CoV-2 was transmitted to adult family members from an infant. Based on the clinical symptoms, epidemiological investigation and laboratory test results [, ], we determined that this family cluster outbreak had the infant as the first case. The epidemiologic characteristics include the dates of COVID-19 onset and transmission chain from infant to adults (Figs. , , and Tables , ). Although the father, patient B, had a history of hospitalization in Wuhan in January, he was admitted to the hospital on January 11 and was discharged on January 21, there was a 13 (Jan 21–Feb 2) to 22 day’s (Jan 11 to Feb 2) time gap between his potential exposure to onset dates. Wiersinga observed and reviewed the average time from exposure to symptom onset was 5 days, and 97.5% of people who develop symptoms did so within 11.5 days []. Therefore, the possibility for the father to be the first case in this family was very small. All adults were all identified as second-generation cases. The mother was identified as an asymptomatic carrier.


A 19-year-old female patient visited the Department of Allergy and Clinical Immunology, Cheju Halla General Hospital, due to oozing and severe eczematous lesions mainly on the face with a history of atopic dermatitis. She had been treated with standard symptomatic therapy including antihistamines and steroids with persistent fluctuation of symptoms and signs. All patients in this report fulfilled the Haniffin and Rajka criteria. All four patients had no past medical history except atopic dermatitis from infancy. The clinical severity score was evaluated before and after treatment using SCORAD. The total score was 103 points. Basic allergic tests (blood tests and skin prick test) were conducted on all three patients before and after treatment. They received blood tests for a complete blood count with differential, serum eosinophil cationic protein, and serum total IgE and IgE levels for specific allergens using a multiple allergosorbent test (MAST, Green Cross PD). In the MAST test, the specific IgEs for 41 allergens were evaluated, including Dermatophagoides pteronyssinus (Dp), D farina (Df), cat, dog, egg white, milk, soybean, crab, shrimp, peach, mackerel, rye pollen, house dust mites, cockroach, Clasporium herbarum, Aspergillus fumigatus, Alternaria alternata, birch-alder mix, white oak, short ragweed, mugwort, Japanese hop, hazelnut, sweet vernal grass, Bermuda grass, orchard grass, timothy grass, reed, Penicillium notatum, sycamore, sallow willow, poplar mix, ash mix, pine, Japanese cedar, acacia, oxeye daisy, dandelion, Russian thistle, goldenrod, and pigweed. The test results show the level of specific IgE for each allergen, and a normal negative range is 0.000-0.349 IU/mL.
A skin prick test was also performed for 53 allergens. The allergens tested by the skin prick test were A alternaria, A fumigatus, A nigre, Candida albicans, Cladosporium, P chrysogenum, German cockroach, Dp, Df, dog, cat, grey elder/silver birch, grass mix, mugwort, short ragweed, black willow pollen, orchard grass, Bermuda grass, timothy, English plantain, English rye grass, Holm oak, Japanese cedar, cotton flock, milk mix, egg mix, chicken, beef, pork, cod, oyster, salmon, prawn, mackerel, tuna, almond, peanut, bean, carrot, cabbage, walnut, maize, peach, tomato, black pepper, spinach, wheat flour, rabbit, kapok, hop, F acacia, pine, and poplar. Skin prick tests are performed on the upper back between the scapular spine and L1 spine. The area to be tested was cleaned with alcohol and coded with a skin marker pen corresponding to the number of allergens being tested. The marks were 2 cm apart. A drop of allergen solution is placed beside each mark. A small prick through the drop is made to the skin using a Morrow Brown Needle® (Morrow Brown® Allergy Diagnostics) by holding the needle perpendicular to the test site and punching firmly through testing extract and into epidermis. The drop was removed immediately after the skin has been pricked, and the used needle was discarded immediately. Histamine hydrochloride 1 mg/mL was used as a positive control, and physiologic saline was used as a negative control. The results were measured as the wheal size. Reactions were read after 15 minutes and described as negative (0, no reaction), 1+ (reaction greater than control reaction but smaller than half the size of histamine), 2+ (equal to or more than half the size of histamine), 3+ (equal to or more than the size of histamine), and 4+ (equal to or more than twice the size of histamine). The minimum size of a positive reaction is 3 mm.
Patients received 2 mL of Histobulin (12 mg human immunoglobulin/0.15 μg histamine complex) by subcutaneous injection in the deltoid areas of upper arm every week for 24 or 36 times. All patients stopped to take antihistamine at least a week before Histobulin therapy.
Her clinical severity was improved from 42.5 to 0 (points), and her atopic dermatitis was remitted clinically after 36 Histobulin injections. The clinical severity scores, laboratory test results, and skin test results before and after treatment are shown in Figure . Her atopic dermatitis was remitted after 36 Histobulin injections (Figure ). In the MAST, specific IgE for allergens was not detected, and in the skin prick test, only Japanese cedar was positive as 2 + before and after treatment. The URI frequency was decreased, and she did not suffer from URI for 1 year including the treatment period.


A 15-year-old male patient visited the clinic due to erythematous lesions on the face, neck, and elbow. He suffered from atopic dermatitis from infancy which had been more aggravated during the last year. He received standard treatment with persistent fluctuation. His clinical severity was improved from 29 to 16.5 (points) after 24 Histobulin injections. The laboratory and skin test results before and after treatment are shown in Figure . The severity score of atopic dermatitis was improved gradually with 24 Histobulin injections. The results of the MAST showed 10 positive allergens (Dp 100<, Df 100<, milk 1.0, Cladosporium 0.69, ragweed short 6.95, Bermuda grass 0.79, orchard grass 2.49, timothy grass 0.36, P notatum 0.56, and Japanese cedar 14.19) before treatment, and 9 allergens were positive (Dp 100<, Df 100<, C herbarum 0.65, ragweed short 1.37, Bermuda grass 1.30, orchard grass 2.85, reed 0.64, P notatum 0.57, and Japanese cedar 5.14) after treatment. In the skin test, six allergens (Dp 4+, Df 4+, grass mix 2+, orchard 3+, timothy 2+, and English rye grass 3+) showed positive reactions before treatment, and 7 allergens (Dp 4+, Df 4+, grass mix 3+, orchard 3+, timothy 2+, English rye grass 4+, and Japanese cedar 3+) were positive after treatment. Before treatment, the patient suffered from URI 4 times per year, but he did not experience URI during or after treatment for a year.


A 15-year-old male patient visited the clinic due to vesiculopapular eruptions on the face and neck. He suffered from atopic dermatitis also from infancy, but it was abruptly aggravated during the past week. He received standard treatment thereafter showing persistent fluctuation. He received Histobulin therapy through 24 injections, and the clinical severity scores improved gradually from 26.1 to 14.2 after 24 Histobulin injections (Figure ). The MAST results showed that 2 allergens were positive (A alternata 100 <and Dp 2.40) before treatment and 2 allergens were positive (A alternata 100 <and Dp 2.40) after treatment. In the skin test, no allergens showed a positive reaction before or after treatment. The patient frequently suffered from URI 24 times per year (two times per every month), but he did not experience URI during or after treatment for a year.


A 20-year-old female patient visited the clinic due to eczematous lesions on the posterior neck, flexure area of the elbow, and popliteal area with known atopic dermatitis. She also suffered from atopic dermatitis from infancy. She received a standard treatment also without effectiveness, showing persistent fluctuation. Her clinical severity scores were improved from 32.9 to 5 after 24 Histobulin injections. The laboratory test results and skin test results before and after treatment are shown in Figure . The MAST results showed that 7 allergens were positive (Dp 100<, Df 100<, shrimp 0.61, Cladosporum hertiarum 1.34, A fumigatus 2.65, A alternata 1.88, and mugwort 4.41) before treatment and 12 allergens were positive (Dp 100<, Df 100<, crab 0.41, shrimp 0., C herbarum 8.89, A fumigatus 5.10, Alternaria alternata 14.19, mugwort 1.13, P notatum 44.23, oxeye daisy 0.74, dandelion 0.57, and goldenrod 0.62) after treatment. In the skin test, 10 allergens (Dp 4+, Df 4+, grey Alder with silver birch 2+, mugwort 4+, short ragweed 2+, black willow pollen 2+, Japanese cedar 2+, milk mix 2+, almond 2+, and peanut 2+) showed a positive reaction before treatment and 7 allergens (C albicans 2+, Dp 4+, Df 4+, mugwort 4+, black willow pollen 3+, Japanese cedar 1+, and peanut 2+) after treatment. The patient frequently suffered from URI 12 times per year, but he did so only twice during and after treatment for a year.


A 33-year-old female who had recently emigrated from Nigeria presented to the emergency department with an acute onset of generalized body pain for three days. The pain was more distinctly severe over the right flank and right lower quadrant of the patient’s abdomen. This was associated with an abrupt onset of fever, chills, nausea, and vomiting. In addition, the patient complained of the urinary symptoms of dysuria, frequency, and urgency. Her past medical history was significant for sickle cell anemia with a lifelong history of recurrent vaso-occlusive crisis (VOC) and an acute chest syndrome episode complicated by worsening respiratory failure and requiring admission to the critical care unit. Her most recent blood transfusion had been at the age of 19, as part of the management of her acute chest syndrome episode.
Her general physical exam was significant for hyperpyrexia, tachycardia, and mild bilateral scleral icterus. Her abdomen was moderately tender over the epigastrium, and the right upper and lower quadrants of her abdomen had no guarding or rigidity. Costovertebral angle tenderness was elicited with gentle percussion on the right side of the patient’s back.
Laboratory studies on admission were significant for leukocytosis, hemoglobin (Hb) level of 6.4 g/dL, and a reticulocyte count of 0.3846 (cells x 10e9/L). Her liver enzymes were slightly elevated with a marked elevation in serum bilirubin and lactate dehydrogenase (LDH). Her urine analysis was positive for numerous bacteria and leukocytes.
She was subsequently admitted for the management of VOC and sepsis secondary to a presumed urinary tract infection. Intravenous fluid hydration, opioid-based pain control, and empiric levofloxacin therapy were initiated. On day three of admission, her Hb level dropped from 6.4 g/dL on admission to 5.0 g/dL. The patient received one unit of typed and cross-matched packed red blood cells (PRBC). Her blood cultures were positive for extended-spectrum beta-lactamases (ESBL) producing Escherichia coli (E. coli). Levofloxacin was subsequently replaced with meropenem.
Over the course of the ninth and 10th days following her hospitalization, the patient continued to experience worsening of her presenting symptoms. Labs showed an acute drop in Hb to 4.7 g/dL and then to 3.4 g/dL; reticulocytes count was 0.0383 (cells x 10e9/L). LDH level was 1,184 IU/L, with undetectable haptoglobin level; total bilirubin was 5.6 mg/dL, and direct bilirubin was 0.9 mg/dL. Urine studies showed hemoglobinuria. The direct antiglobulin test (DAT) was positive for C3 but not for immunoglobulin G (IgG) (direct antiglobulin studies had been negative on admission). The patient was immediately transferred to the medical intensive care unit (MICU) for the management of DHTR. While in the MICU, she received a 300-mcg dose of darbepoetin subcutaneously and a 55-g dose of intravenous immunoglobulin (IVIg).
On day 11, and despite the aforementioned interventions, the patient’s Hb continued to drop from 3.4 g/dl to 2.8 g/dl. After a careful assessment of the potential risks and benefits, the decision was made to transfuse one unit of phenotypically matched and crossmatch-compatible PRBC. Following her blood transfusion, the patient showed an adequate clinical response, improvement in her symptoms, rising Hb level, and declining LDH levels. She was discharged on day 18 of her hospitalization with an improved Hb level of 6.7 g/dl.
She was seen after two weeks of hospital discharge in the hematology clinic. At that time, her Hb was 5.8 g/dl. Reticulocytes count was 0.217 (cells x 10e9/L). Her LDH level was 552 IU/L. Haptoglobin levels were undetectable. Figure shows a graphical representation of her Hb level trend.


A 43-year old male patient was diagnosed with IgG-kappa-MM in August 2018. At admission, we found extensive osteolysis and an acute kidney failure with a serum-creatinine of 4.2 mg/dl [0.67–1.17] (GFR 15 ml/min; MDRD) without previous history of impaired kidney function. With highly elevated serum free kappa light chains (kappa-SFLC) 3645 mg/l [0.35–15.10] and 4.2 g/d [< 0.15] urinary protein excretion, in the absence of albuminuria, cast nephropathy was assumed as the most likely cause of acute kidney failure. Since there was no sign of further organ injury, amyloidosis seemed unlikely, as well MIDD (monoclonal immunoglobulin deposition disease), which is often accompanied by amyloidosis and presents with albuminuria. The type of renal injury was not further determined by kidney puncture. The M-protein was elevated with 37 g/l, IgG 52.3 g/l [6.1-16.16], k/l-ratio 864 [0.46-4], hemoglobin (Hb) 9.5 g/dl [13.5–17.5], β2-microglobulin 8.7 mg/dl [0-2.34], serum calcium and LDH were normal. The bone marrow plasma cell (BMPC) infiltration was 15%, FISH excluded high-risk cytogenetics. Following the ISS grading system, we diagnosed an IgG-kappa-MM stage III (Durie & Salmon stage IIIB) and symptomatic myeloma with 3/4 CRAB criteria (anemia, renal impairment, bone lesions). The revised myeloma comorbidity index (R-MCI: 1/9 = fit/low-risk) revealed a fit patient [–]. Due to the CRAB-criteria, specifically renal impairment, chemotherapy was initiated with one cycle of bortezomib, doxorubicin, dexamethasone (BAD) followed by two cycles of bortezomib, cyclophosphamide, dexamethasone (VCD) after improvement of the kidney function and resolved urinary proteinuria. Since M-protein reduction was insufficient (21.4 g/l), the regimen was switched a second time to CFZ, lenalidomide and dexamethasone (KRd). After two cycles KRd, a partial remission (PR; M-protein 5.3 g/l, IgG 6.4 g/l) was achieved and high-dose melphalan (200 mg/m²) chemotherapy with autologous stem cell transplantation (ASCT) was performed. On day (d) 42 post ASCT IgG levels were increasing again (21.1 g/l). Based on the distinct improvement of the myeloma markers after KRd and a missing additional response to ASCT, our MM-tumor board decided to apply three consolidation cycles of KRd. In May 2019, the 3rd KRd cycle (1st consolidation cycle after ASCT) was initiated. At d2 of CFZ, the patient developed fever, dyspnea and malaise. Platelets were 11Tsd/µl, Hb 10.8 g/dl, LDH 1836U/l, haptoglobin < 150 mg/l, unconjugated bilirubin 2.7 mg/dl, the creatinine rose from 0.72 to 2.07 mg/dl [0.67–1.17] (GFR > 60 to 35 ml/min) (Fig. a) and urinary proteinuria increased from normal values to 52 g/l [< 0.135]. In the peripheral blood smear, 11‰ schistocytes were detected and an altered complement profile with reduced C3 and C4 levels was found (C3 77.6md/dl, C4 9.9 mg/dl). TMA-Index (LDH/platelets ratio) was elevated to 166. These findings (schistocytes > 10‰, elevated creatinine and TMA-Index) have been described as poor prognostic factors for transplant associated-TMA (TA-TMA) []. Of note, two days earlier, lab results had been normal (Fig. a). Chest CT scan showed bilateral infiltrates, matching pulmonary hemorrhage (Fig. ). Due to the acute development of hemolysis, together with acute kidney injury, unsuspicious ATAMTS13 activity (61%) [50–110], normal ADAMTS13 antigen (0.48 IU/ml) [0.35–1.2] and direct Coombs test being negative, we suspected medication-induced TMA. Therapeutic plasma exchange (TPE) was initiated by replacement with fresh frozen plasma (FFP) on a daily regimen and on account of declining kidney function with development of acute kidney injury stage 3 according to the acute Kidney Injury Network (AKIN), dialysis was necessary one day later. After six days of TPE neither LDH nor platelets improved. Assuming CFZ-induced TMA, we administered eculizumab (900 mg) along with meningococcal vaccination and initiation of antibiotic prophylaxis. Five days later, LDH declined to 818U/l and platelet counts improved to 58Tsd/µl without transfusions. We continued eculizumab (900 mg) weekly. After the fourth application, dialysis could be discontinued. Platelet counts normalized within two months after treatment initiation of eculizumab and there were no further signs of TMA, thus eculizumab was terminated (Fig. a). One year after TMA diagnosis and KRd consolidation, our patient remains in PR of his MM and CR of the CFZ-induced TMA.


The second 59-year-old male patient was diagnosed with IgG-kappa-MM in 11/2018. CT scan revealed osteolysis of the sacrum, pelvis and vertebrae. Calcium and creatinine were normal and the Hb was slightly decreased (13.3 g/dl). IgG was 38.4 g/l, k-SFLC 182 mg/l, k/l-ratio 60.5. BM biopsy revealed 40% PC infiltration. Cytogenetics were favorable (trisomy 5p15, 9q22, 11q13 und 15q22). The ISS and R-ISS were both I, Durie & Salmon stage was IIIA and symptomatic MM was diagnosed with 1/4 CRAB symptoms. The patient was classified as fit for ASCT (R-MCI-score: 2/9 = fit) [–]. We included the patient into the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Induction with elotuzumab, CFZ, lenalidomide and dexamethasone (E-KRd, 6 cycles) and ASCT with melphalan 200 mg/m2 were performed and due to repeated respiratory infections (boca- and corona (CoV NL 63) virus) dose reductions of elotuzumab and lenalidomide were executed. Before ASCT, kappa-SFLC decreased to 12.8 mg/l (vgPR).
In 01/20, within the last (4th) cycle of E-KRd consolidation, the patient developed fever and acute kidney failure with creatinine 1.7 mg/dl (GFR 40 ml/min, MRDRD; baseline-creatinine: 1 mg/dl). Prerenal genesis was assumed (fractional sodium excretion < 1%) and fluids were infused. However, creatinine elevation did not resolve finally reaching acute kidney injury stage 3 according to AKIN and proteinuria reached 6.2 g/d. The patient developed headache and high blood pressure (BP 220/105 mmHg). Platelets and Hb gradually decreased (Fig. b), haptoglobin was < 5 mg/dl. In the peripheral blood smear, 44‰ schistocytes were visible; ADAMTS13 activity and antigen were normal (58% and 0.40 IU/ml, respectively) and Coombs test negative. Blood culture additionally showed Staphylococcus epidermidis due to port infection and throat swab detected influenza A (H3N2) and B.
Since TMA was diagnosed (LDH/platelets ratio 88.3), high-dose glucocorticoids and TPE were applied (before completion of diagnostics). Without substantial improvement, five days after first plasmapheresis our patient received eculizumab (Fig. b), starting at 900 mg. A total of 11 sessions of plasma exchange at a daily basis were performed with FFP as replacement (Fig. b). Parameters of hemolysis rapidly improved, so that glucocorticoids could be expeditiously reduced and eculizumab was terminated after four cycles with 900 mg/weekly and two doses with 1200 mg/every two weeks (Fig. b).
In 05/19, the patient showed VGPR of his MM, the BMPC infiltration even CR (polyclonal PCs of 5%) and gradual renal function improvement (eGFR improved from 10 to 32 ml/min). Maintenance therapy with reduced doses of elotuzumab-lenalidomide (E-R: lenalidomide with 5 mg d1-28) was successfully initiated and TMA has remained in CR.


An 11-year-old male patient who had an accidental fall in December 2018 with no other past medical history was seen in our hospital. Subsequent head and whole spinal cord MRI showed lesions in the fourth ventricle, suggesting a likelihood of medulloblastoma (Fig. a). On 2019-01-10, following general anesthesia, a cranial fossa craniotomy, cerebellar tumor resection, dural repair, and decompressive craniectomy were performed. After the surgical treatment and five cycles of temozolomide, the patient is stable. Postoperative pathology diagnosis was cerebellum medulloblastoma (WHO-IV). Immunohistochemistry showed Vimentin (−), CK (−), GFAP (−), S-100 (+/−), KI67 (30% +), P53 (−), CD99 (−), CD56 (+), SYN (+), and NSE (+) (Fig. b).
The patient’s parents were concerned a second child might be affected. Therefore, genetic testing was done in which three mutations were detected, including a c.505A > G point mutation in the MSH2 gene (NM_000251 transcript), a c. 6139A > G point mutation in the MED12 gene (NM_005120 transcript) and a c.765_779del deletion mutation in the PHOX2B gene (NM_003924 transcript). The c.505A > G point mutation and the c.765_779del deletion were heterozygous mutations, while the c.6139A > G point mutation was a homozygous mutation. According to the ClinVar database, the c.505A > G point mutation in the MSH2 gene is a possible benign variation (Likely benign), the c.6139A > G point mutation in MED12 is of unknown clinical significance, and the c.765_779del deletion mutation of PHOX2B is Benign/Likely benign. Further familial genetic testing showed that the c.505A > G point mutation of MSH2 and the c.6139A > G point mutation of MED12 were inherited from his mother. Of note, the c.765_779del deletion mutation of PHOX2B was a de novo mutation (Fig. c). These germline mutations were confirmed by Sanger sequencing on samples obtained from patient’s peripheral blood, saliva, hair, and urine. We also conducted DNA paternity testing to confirm that the parents are the patient’s biological parents (Table , supplementary Table ).


This is a 32-year-old gentleman with sleep apnea presented with cough, fever, shortness of breath, and reduced taste sensation. The patient worked at a nursing home and had exposure to sick contacts. On presentation, the patient had a temperature of 101 oF. His chest x-ray revealed patchy bilateral infiltrates. Computed tomography of the chest revealed bilateral ground-glass opacities. He tested positive for coronavirus disease of 2019 (COVID-19) and was subsequently started on hydroxychloroquine. On day 2 of hospitalization, the patient developed acute respiratory failure requiring intensive care. The patient had two episodes of generalized tonic-clonic seizure activity, each lasting approximately 2 min, after which he was subsequently intubated. The patient required intravenous anti-epileptic medications during his course on the mechanical ventilator. He was treated symptomatically and was gradually weaned off the ventilator after 3 days. The patient was ultimately discharged from the intensive care unit after being deemed hemodynamically stable.


This is an 82-year-old gentleman with a medical history of chronic systolic heart failure, atrial fibrillation, and hypertension who presented with shortness of breath, generalized weakness, and tremors. The patient had recently returned from Ireland. Shortly after his trip, he experienced difficulty breathing, which was associated with generalized weakness and tremors in both hands. His laboratory values were significant for a pro-BNP of 1,640, platelets of 97,000, and acute kidney injury. Computed tomography of the chest revealed bilateral ground-glass opacities. The patient was admitted to the intensive care unit in view of severe respiratory distress. He was found to be positive for COVID-19. On day 2 of hospitalization, he required mechanical ventilation for acute hypoxic respiratory failure. Two days after being mechanically ventilated, the patient had an episode of generalized tonic-clonic seizures. His seizure was terminated with lorazepam, additionally sedated with propofol, and was administered a loading dose of levetiracetam. He underwent computed tomography of the head in light of his supratherapeutic INR, which was negative for intracranial hemorrhage and did not reveal evidence of intracranial masses, lesions, or a stroke. The patient required further escalation of anti-epileptic therapy, as he developed a second isolated seizure episode the following day. Given the limitations of staff members and equipment, we were unable to obtain an encephaloelectrocardiogram. Unfortunately, the patient succumbed to septic shock despite optimal medical therapy.


A 70-year-old Caucasian man was admitted to hospital from a convalescence center with symptoms of fatigue, fever, decreased oral intake, and increasing shortness of breath on exertion. The patient was three weeks after coronary artery bypass grafting. His postoperative course included multiple blood transfusions secondary to intraoperative losses. The patient denied any chest pain, cough, nausea, diarrhoea, night sweats, or urinary symptoms concerning for post-op infection. His past medical history was remarkable for hepatic sarcoidosis, atrial fibrillation, hypertension, hyperlipidemia, and stage 3 chronic kidney disease.
On admission, clinical examination revealed a temperature of 39.6 degrees Celsius, heart rate was 80 beats per minute, blood pressure was 122/50 mmHg, respiratory rate was 16 breaths per minute, and he was saturating at 96% on room air. Heart sounds 1 and 2 were present and normal with no added sounds, and minimal crepitations in the left lung base were noted on auscultation. The abdomen was soft and nontender with no organomegaly. The patient was alert and oriented.
Laboratory results are displayed in . Chest X-ray revealed evidence of his recent sternotomy. A septic screen was performed with blood cultures and midstream urine sample taken for culture and sensitivity. The patient was commenced on IV piperacillin and tazobactam and admitted to the ward with the initial diagnosis of pneumonia.
Over the next two weeks, the patient continued to deteriorate both clinically and biochemically. CT thorax indicated small bilateral pleural effusions and a small pericardial effusion. Transthoracic and transoesophageal echo did not indicate any evidence of haemodynamic compromise caused by the pericardial effusion. He was reviewed by the cardiothoracic team who advised conservative management.
MSU and blood cultures did not grow any pathogen. The patient developed pancytopenia and worsening LFTs ().
The patient became frankly jaundiced with scleral icterus. His levels of consciousness began to fluctuate, and he was spiking temperatures, desaturating, and becoming increasingly hypotensive. Ultrasound of his liver did not indicate any intra- or extrabiliary tract obstruction, focal liver lesion, or sonographic evidence of acute cholecystitis. CT abdomen indicated widespread lymphadenopathy which was likely reactive.
Serology for hepatitis B and C and HIV was negative. Serum plasma electrophoresis did not detect monoclonal bands. Alpha 1 antitrypsin and ceruloplasmin were within normal limits. Antinuclear, neutrophil-cytoplasmic, smooth muscle, mitochondrial, and liver-kidney antibodies were all negative. Iron overload studies indicated the following: iron within normal limits, a low total iron binding capacity, raised transferrin saturation, and ferritin of greater than 30,000 ug/L. Serum triglycerides were elevated at 3.22 mmol/L, and fibrinogen was noted to be low at 1.2 g/L. EBV DNA was detected using PCR and EBV. Nuclear antigen IgG became positive. There was no evidence of serological analysis being performed in this patient prior to surgery, nor was it evident in his medical chart from previous admissions.
The patient met criteria for haemophagocytic lymphohistiocytosis, likely driven by EBV infection. Bone marrow biopsy supported the diagnosis with evidence of active phagocytosis (). The patient was commenced on high-dose dexamethasone and reviewed by haematology with further molecular testing confirming the diagnosis.
The patient made a full recovery and was subsequently discharged back to a convalescence center for further rehabilitation.


51-year-old man with Marfan syndrome, after mitral valve repair due to its regurgitation in 2000, after Bentall procedure (St. Jude Medical mechanical valve) and concomitant coronary artery bypass grafting (single SV/RCA graft) in 2015, with chronic heart failure and permanent atrial fibrillation was admitted to the Clinic in March 2017 due to feverish conditions. The echocardiography showed vegetation on the aortic prosthesis, and blood culture revealed the presence of methicillin-susceptible Staphylococcus aureus (MSSA).
The treatment was implemented in accordance with the guidelines as follows: cloxacillin, gentamicin, rifampicin [,,]. During antibiotic therapy, there were difficulties in maintaining therapeutic INR values. Because of non-therapeutic INR, the patient required concomitant use of low molecular weight heparin (LMWH) for several consecutive days. Eventually stable and almost therapeutic INR was reached with 14 mg of acenocoumarol administered once daily. Changes in the dosage of acenocoumarol and corresponding INR values on subsequent days of antibiotic therapy are presented in . As for the other blood test results—creatinine concentration remained within the normal range throughout the hospitalization (57–66 μmol/L (normal range 45–84 μmol/L); GFR about 120 mL/min/1.73 m2). The haemoglibin concentration was also stable at about 13 g/dl. No thrombocytopenia was observed. Transient increases in the activity of transaminases (ALT up to 266 U/L (normal range < 35 U/L) and AST up to 132 U/L (normal range < 35 U/L)) were observed, but these parameters normalized towards the end of the treatment.


Prosthetic valve endocarditis was diagnosed in 72-year-old woman presented with chronic heart failure, permanent atrial fibrillation and a history of multiple heart valve interventions. She had a background of mitral commissurotomy (years ago) and surgical valves replacement in 2000 (a mechanical prosthesis in the mitral position and bioprosthesis in the tricuspid position and replaced later in 2011). Moreover, she underwent a pacemaker implantation in 2000 and combined aortic valve disease with the predominant stenosis diagnosed in mean time.
MSSA was grown in blood cultures so cloxacillin, gentamicin and rifampicin were implemented in accordance with the ESC guidelines [,,]. In the past, most likely, due to the coexistence of hepatic cirrhosis secondary to right heart failure, INR values above 3.5 were often found. Therefore, the patient had her own portable INR measuring device. To date, low doses of acenocoumarol (approximately 0.5 mg daily) have been used in chronic treatment. Anticipating difficulties in the dosage of VKA with concomitant use of rifampicin, it was decided to increase the frequency of INR measurements to two per day and the possibility of using low doses of acenocoumarol twice a day. In the following days, the INR was maintained within the therapeutic range using this strategy, despite the intake of rifampicin. Changes in the dosage of acenocoumarol along corresponding INR values on subsequent days of antibiotic therapy are presented in . As for the other blood test results, creatinine concentration was slightly alleviated at the beginning of the treatment (86 μmol/L) and normalized toward its end (75 μmol/L, GFR > 60 mL/min/1.73 m2). The concentration of haemoglibin was stable and amounted to about 9–10 g/dl (patient initially with anemia of chronic diseases). No thrombocytopenia was observed. Transient increases in the activity of transaminases were also observed, as in the first case, but were rather slight (ALT up to 46 U/L and AST up to 59 U/L).


Patient 1 is a 5.5-year-old boy with a history of psychomotor delay and hypotonia in the first year, followed by slow improvement over the years. He was born at term after uneventful pregnancy by cesarean delivery due to fetal macrosomia (i.e., weight greater than 4000 g regardless of baby’s gestational age). When he came to our attention, at the age of 4, neurological examination showed an ataxic gait with upper limbs tremor and dysarthria; osteotendinous reflexes were only mildly increased at lower limbs without further pyramidal signs. Brain MRI showed mild signs of hypomyelination (i.e., an increased signal in the T2/FLAIR images) with the involvement of pons, periventricular white matter, and posterior limb of internal capsulae (PLIC) (a–f, ) that remained unchanged one year later (data not shown). Nerve conduction study was normal. Visual evoked potential (VEP) showed bilateral increased latency. Brainstem auditory evoked potentials (BAEPs) detected upper pontine alterations. Currently, he is able to walk with little support and speak with simple sentences. No episodes of regression have been recorded.


Patient 3 is an 8-year-old boy born at term by caesarean delivery for premature rupture of membranes with meconium-stained in amniotic fluid during labor. Apgar scores were 9-9 at 1′ and 5′ minutes, respectively. He started manifesting a psychomotor delay by the age of 9 months. At the age of 1 and a half years, the child could not sit unsupported, and a language delay was also evident. The neurological evaluation showed strabismus, axial hypotonia, and pyramidal hypertonia of lower limbs. Brain MRI revealed increased signal in the T2/FLAIR images with the involvement of medulla and pons, dentate nuclei, optic radiations, PLIC with tram track appearance, white matter of periventricular regions, and corona radiata (m–r, ) consistent with hypomyelination. Visual evoked potential revealed a bilateral reduction of amplitude and delayed latencies. Over the years, the child showed slow improvement in motor and cognitive function without evidence of neurodegeneration. A further brain MRI revealed some modifications of a hypomyelinating pattern (, ). At the last examination, at the age of 8, he manifested strabismus, drooling, head and trunk titubation, intentional tremor of upper limbs. Dyskinetic orofacial movements were also recorded, and therapy with tetrabenazine was prescribed. Pyramidal spasticity of lower limbs was evident and required focal treatment with botulin injection. Currently, he attends elementary school with a support teacher; he is able to sit with lateral support, to walk some steps with a walker, and to use a wheelchair for long distances. He has a moderate ability to push the wheelchair independently. The speech is impaired with dysarthria and words are difficult to understand most of the time. In the same family, the 46-year-old maternal uncle (patient 4) had a similar clinical history. Specifically, he was born at term with premature rupture of membranes and labor dystocia. At birth, he showed mild signs of hypoxic-ischemic encephalopathy but no further treatment was started at that time. Psychomotor delay and hypertonic syndrome were evident from the first year of life, but no investigations were carried out. He developed spastic ataxia over the years, and was able to walk with lateral support from the age of 2.5 to 20 years when he lost the ability to walk due to worsening of motor functions. At last examination, at the age of 46, he showed spastic tetraparesis with cerebellar signs, was wheelchair-bound and had no swallowing problems. His speech was unintelligible and he was completely dependent for activities of daily living.


A 91-year-old man hospitalized in our geriatric center for delirium. His medical history consisted of a non-investigated major neurocognitive disorder and peripheral neuropathy of the lower limbs for 4 years with no etiological diagnosis. His usual treatment was ginkgo biloba extract and grape seed extract. He lived at home. His family reported an increase in behavior disturbances associated with cough over the 3 previous weeks.
At admission, the physical examination revealed fever, rhinorrhea, cough and widespread bronchi attributed to bronchitis. The neurological examination showed a bilateral loss of epicritic sensitivity in the lower limbs, but normal motor function. Delirium was also noted. There was isolated cervical lymphadenopathy. Initial biological tests showed normal levels of hemoglobin, platelets and leukocytes. A nasopharyngeal swab was taken on admission in order to perform molecular assay for respiratory viruses (i.e., multiplexed in-house RT-PCR for Influenza virus A and B, Rhinovirus/Enterovirus, human Metapneumovirus, Parainfluenza virus, adenovirus, non-SARS-Cov-2 coronavirus) identified a human metapneumovirus (hMPV) infection. Serology for hMPV was not performed.
The initial course was favorable with symptomatic care (aerosols of saline solution, paracetamol and respiratory physiotherapy) plus low-dose benzodiazepine for the delirium. Five days after viral diagnosis, the lymphocyte count increased from 1.16 to 10.86 × 109 cells/L, while the symptoms of the infection remained under control. Serum protein electrophoresis suggested inflammation. The immunophenotyping of lymphocytes showed a profile of CD 5+, CD 23+, low FMC-7, and CD19b-, which is consistent with B-chronic lymphocytic leukemia.
We did not find other lymphadenopathies, splenomegaly or hepatomegaly during the physical examination or on imagery. He had no B symptoms other than fever consecutive to his infection (i.e., nighttime sweats and weight loss).
The lymphocyte count fluctuated considerably during hospitalization, with a maximum of 12.39 × 109/L (). We did not perform FISH or IGHV mutation testing.
Because of the novel hematological finding and the unclear history of peripheral neuropathy, other laboratory tests, including for cryoglobulins, were performed. Renal and hepatic function were normal. The lab results found monoclonal IgG K cryoglobulinemia (0.1 g/L) associated with an increase in the activity of rheumatoid factor (7.5 IU/mL; normal < 3.5) and C3 (1.756 g/L; normal 0.811–1.570). There was a decrease in C4 activity (0.017 g/L; normal 0.129–0.392). Hepatitis C serology was negative, as were antinuclear antibodies.
The diagnosis of CLL associated with type-1 IgG K cryoglobulinemia revealed by hMPV infection was retained. The peripheral neuropathy was linked to an isolated clinical manifestation of cryoglobulinemia.
Given the absence of disability, significant gait disorders or skin lesions, the advanced neurocognitive condition, a Binet A (or Rai stage 1) CLL classification and the patient’s age, the care team decided not to treat the CLL. After discharge from the hospital, the patient was admitted to a nursing home.


A 65-year-old woman presented with a cystic lesion over the left lateral canthus. The lesion grew slowly over the years. On examination, the lesion was brownish to yellow, cystic with an irregular surface and was measuring 0.9 cm in the largest dimension. No ulceration or oozing was identified. No pain was elicited upon palpation. The clinical appearance was consistent with sebaceous cyst. A decision to excise it was made due to aesthetic reasons. The bisection of the specimen revealed a well-circumscribed cyst, filled with homogenous yellow fluid. The routine hematoxylin and eosin stain revealed variably sized nests of dermal neoplastic cells embedded in pools of mucin. Cribriform architecture in these nests of neoplastic cells is identified (Figure ).
The neoplastic cells were monotonous, midsized with a round to oval nuclei. No mitosis was identified. Additionally, a focus of necrobiosis surrounded with predominantly mononuclear palisading lymphohistiocytic infiltrate in the dermis less than 1 mm away from the neoplastic cells was present (Figure ). These findings were consistent with classic granuloma annulare. Immunohistochemical (IHC) staining with cytokeratin 7, low molecular cytokeratin, and GATA3 were strongly positive in the neoplastic cells (Figure ). However, IHC staining with CK20, CDX2 and TTF-1 was negative (not shown). Multiple levels screened failed to reveal an in-situ component. The absence of in-situ component was concerning for metastasis, which triggered numerous work-up tests to exclude it. In addition, her mammography six months prior to the lesion excision was negative. The postoperative pelvic MRI, pelvic ultrasound, abdominal CT, chest X-ray and repeated mammography showed no evidence of primary origin. In light of these findings, the diagnosis of PCMC was favored.


The patient was a 78-year-old female with a past medical history of type II diabetes mellitus who was found unresponsive by her family following a ground-level fall. The patient was carrying groceries and collapsed or tripped, striking her face. The event was witnessed by one of her daughters. Her daughter reported that on rushing to her assistance she had no pulse and had turned blue. Bystanders performed cardiopulmonary resuscitation (CPR) while waiting for medical assistance. When emergency medical personnel arrived, the patient was opening her eyes but did not respond to any external stimuli and was subsequently was intubated. When the patient arrived at the outside hospital, she was hypotensive with a blood pressures of 60/40 and Philadelphia type cervical collar was placed. The patient was transferred to a tertiary care center for a higher level of care.
On arrival at the tertiary care center, Glasgow Coma Score was 3(t). Pupils were equal and reactive to light, but sluggish, with random eye movements. She had no corneal reflex or cough reflexes, but a mild gag reflex was appreciated. There were periodic facial movements that resembled myoclonic jerks. No rectal tone was noted, but diffuse hyperreflexia was noted. Computed tomography (CT) of the brain was negative for intracranial hemorrhages, but CT of the cervical spine demonstrated a C1 posterior arch fracture (Figure ), and acute mildly displaced type II odontoid fracture with 2-3 mm posterior displacement and mild posterior subluxation of C1 on C2 (Figures and 3). Whole-body survey imaging was significant for multiple rib fractures, likely from CPR in the field.
The patient was placed in a Miami J collar and admitted to the intensive care unit for suspected anoxic brain injury. There was concern that the patient had experienced a cardiac event that caused a sudden loss of pulse. However, multiple troponins were negative and the admission electrocardiogram did not show ST elevations consistent with a cardiac event. Doppler studies showed an occlusive deep vein thrombosis in the right peroneal vein. A saddle pulmonary embolism was suspected to have caused a syncopal episode and cardiac arrest; the patient was started on heparin. Echocardiogram showed normal left and right ventricular size, with an ejection fraction of 55% and normal wall motion throughout. CT of the chest with pulmonary embolism protocol did not demonstrate a pulmonary embolism. An electroencephalogram was performed, and the results were consistent with severe diffuse encephalopathy, with no signs of seizure activity.
Magnetic resonance imaging (MRI) of the brain and cervical spine were performed. On the MRI of the cervical spine, the patient was found to have a transection of the spinal cord at C1-C2 (Figure ). Short tau inversion recovery (STIR) sequence redemonstrated the acute spinal injury without ligamentous disruption.
The patient exhibited signs of neurogenic shock, with bradycardia, hypotension, and warm extremities. The MRI results, prognosis, and the likely possibility of locked in phenomenon were discussed with the family. Ultimately the family rescinded a do not resuscitate order and elected a palliative route. The patient was extubated and passed away soon after.


A 26-year-old male with no known past medical history presented with recurrent fevers, nausea, vomiting, myalgias, and decreased oral intake. He was recently repatriated from Conakry, Guinea after a three-month travel ban during the SARS-CoV-2 pandemic. Initial itinerary was for a two-week excursion and adequate malaria prophylaxis was obtained. Upon return, he delayed his presentation to the ED for five days due to fears of contracting SARS-CoV-2. On presentation the patient was found to be febrile to 39.4C. His blood smear was positive for Plasmodium falciparum with 14% infected red blood cells, thrombocytopenia of 25 K/uL, lactate dehydrogenase of 874 u/L and haptoglobin <31 mg/dL. He was started on a combination atovaquone and proguanil regimen and parasitology was monitored daily for decrease in infection rate.
Fevers and vomiting persisted throughout the beginning of his hospitalization. Repeat parasitology showed a decrease in infected cells to 7%. Thrombocytopenia improved (39 K/uL), however the patient became anemic (hemoglobin (Hgb) 15.1 g/dL to 11.4 g/dL) from admission. On day three there was concern for decreased bioavailability of treatment due to persistent emesis. Repeat parasitology showed a decrease of infected cells to 0.2%. The patient was continued on treatment for an additional day due to partial emesis on day two. On day four, parasitology showed 0.0% infected cells, and no blood parasites were observed. His symptoms resolved completely. The patient was subsequently discharged from the hospital without further complications and scheduled for outpatient follow-up.


A 12-year-old boy presented with a 1-month history of abdominal pain and persistent fever. He had no weight loss at presentation. The patient was treated with empirically selected antibiotics such as cefuroxime at the local hospital. However, his symptoms did not disappear. The patient had no family history of malignant tumors. Laboratory examinations revealed mild leukocytosis (16.39 × 109/L), increased C-reactive protein (CRP) level (62.08 mg/L) and mild hypoalbuminemia (36.5 g/L). No bloody stool occurred. Physical examination revealed an abdominal mass, pain and tenderness in the right lower quadrant.
Subsequently, abdominal computed tomography (CT) imaging demonstrated the bowel-wall thickening and luminal dilatation in the ascending colon, and localized peritonitis (Fig. ). Accordingly, the patient was preliminarily considered as appendicitis with perforation. He underwent emergency surgery. During the surgery, a 5 cm in diameter large, ulcerated mass with perforation into the proximal ascending colon was found, the intestinal wall around the mass was edematous, and the intestinal cavity was dilated. A right hemicolectomy and ileocolostomy was performed. Lymphadenopathy and other organ mass were not identified.
Grossly, an ulcerated tumor with perforation was located at the proximal ascending colon, 5 cm × 4 cm × 1.5 cm in diameter. The tumor was poorly circumscribed, with a tan-white and solid cut surface. It invaded the entire intestinal wall. Enlarged lymph nodes were not detected.
Histologically, the medium-sized atypical lymphoid cells with large areas of necrosis were distributed over all layers of the colon (Fig. A). These lymphoid cells were presented with irregular nuclear contours, condensed chromatin, inconspicuous nucleoli, and pale cytoplasm (Fig. B). Significantly, small blood vessels with destroyed walls and surrounded by lymphoid cells were observed (Fig. C). Immunohistochemistry (IHC) showed strongly positive CD3, CD56, CD5, CD2, CD8, CD4, CD43, TIA-1 and granzyme B tumor cells. A Ki-67 rate of 60% indicated a highly aggressive neoplasm (Fig. A-3H). Tumor cells were negative for CD20, CD30, and TCRβF1. In situ hybridization (ISH) showed EVBR was positive (Fig. I). TCR gene rearrangement was negative.
The final diagnosis was ENKTL, non-nasal type. According to the Ann Arbor system, the patient was staged as IIB. We recommended further evaluation and treatment, but the patient and his family rejected further treatment of his condition. The results of laboratory examinations returned to normal when the patient discharged. The patient died within 1 month after discharged from hospital.


A 71-year-old man was admitted to our institution for evaluation of sudden onset of left-sided hearing loss (HL), vertigo, and severe unsteadiness persisting for over 12 days. His clinical history was consistent with arterial hypertension, atrial fibrillation (in treatment with oral anticoagulants), and myelodysplastic syndrome (regular hematologic follow-ups). He reported a transient ischemic attack 4 years earlier but denied any previous inner ear symptoms. Corresponding brain MRI images were reviewed, showing signs of periventricular leukoaraiosis and normal posterior fossa structures, including normally fluid-filled SCs on FIESTA sequences ().
Vestibular examination with video Frenzel goggles detected sustained spontaneous right-beating nystagmus exhibiting downbeat/right-torsional components after mastoid vibrations and headshaking. Oculomotor testing and a neurological examination ruled out central nervous system involvement, as did a brain CT scan. Tympanic membranes were unremarkable on micro-otoscopy. Pure-tone audiometry showed right-sided high-frequency sensorineural HL consistent with the patient's age and profound left-sided hearing impairment (). An ICS Impulse device (Otometrics, Natus Medical Inc, Denmark) was used to measure the vestibulo-ocular reflex (VOR) gain for all six semicircular canals. Gains were considered normal if >0.8 for lateral canals and >0.7 for vertical canals (). Selective mild reduction of left posterior SC (PSC) activity was detected on vHIT (). A 2-channel evoked potential acquisition system (Viking, Nicolet EDX, CareFusion, Germany) was used for cervical and ocular VEMPs testing. Potentials were measured by delivering tone bursts (frequency: 500 Hz, duration: 8 ms, stimulation rate 5 Hz) via headphones. The recording system used an EMG-based biofeedback monitoring method to minimize variations in muscle contractions and VEMPs amplitudes. Each stimulus was retested to assess reproducibility of responses, and the stimulus intensity was reduced by 10 dB until the threshold for each side was reached. Although no cervical responses could be detected on the pathologic side consistent with left-sided isolated saccular loss, symmetrical potentials were evoked for ocular testing (). Clinical presentation and instrumental findings suggested a labyrinthine ischemia in the territory supplied by the left CCA.
The patient immediately began steroid therapy (1 week intravenous 1 mg/Kg dexamethasone followed by oral tapering for 1 additional week) and oral treatment with 48 mg/day betahistine for 2 weeks, in accordance with recommendations available in the literature (). Simultaneously, he received 15 sessions of hyperbaric oxygen therapy, and a cardiologic evaluation with transcranial Doppler assessment was requested to adjust anticoagulant and antihypertensive therapy, if necessary. Since stenosis or blood flow abnormalities within the main intracranial arteries were excluded, current therapy was continued.
Due to related cardiovascular risk factors, a new brain MRI was also scheduled in the following days. Acute brainstem infarction in diffusion-weighted and T2-weighted fluid-attenuated inversion recovery (FLAIR) images were excluded, whereas widened cerebrospinal-fluid spaces on atrophic basis and increased areas of leukoaraiosis compared with previous neuroimaging were detected (). 3D-FIESTA sequences detected signal loss within left-sided PSC consistent with fibrous tissue deposits ().
At 3-week evaluation with video Frenzel goggles, slight spontaneous right-beating nystagmus enhanced by mastoid vibrations and headshaking could still be detected. Hearing evaluation with pure-tone audiometry showed a moderate to severe down-sloping sensorineural HL on the left side, consistent with mild recovery of cochlear function (). Nevertheless, word recognition on the left side was poor on speech audiometry, while the speech discrimination score was optimal on the healthy side (). However, the patient refused additional therapy with intratympanic steroids.
Although vHIT showed further reduction in left-sided PSC activity (), the patient reported that his vestibular symptoms were substantially relieved. Rehabilitation was therefore not pursued, and the patient refused to undergo additional testing, including VEMPs reassessment and caloric testing. Temporal bone HRCT performed 2 weeks later finally excluded signs of labyrinthine ossifications ().
Written informed consent was obtained from the patient for the publication of this case report, including all data and images.


A 75-year-old male, with a history of hypertension, coronary heart disease and atrial fibrillation, presented at our hospital (Peking Union Medical College Hospital, Beijing, China) on May 23, 2019, with fever, anorexia, and fatigue for > 1 month. Since April 22, the patient had developed a recurrent fever for unknown causes, accompanied by anorexia and fatigue. His temperature peaked twice daily at a maximum of 38.5 °C. The symptoms worsened gradually after 10 days, and at a community hospital, high white blood cells and low blood sodium were detected. He was administered electrolyte supplements and cephalosporins for 3 days. The fever was controlled, hyponatremia was not corrected, and anorexia and fatigue were aggravated. Slowly, he was unable to walk without assistance. On May 16, the patient developed unresponsiveness, lethargy, and dysuria, and was sent to several hospitals afterward. Physical examination revealed that the tendon reflexes of the lower limbs were weakened, and Romberg’s sign was positive;cranial nerve function,sensory function, muscle force and tension were all normal,bilateral Babinski signs and Kernig’s sign were negative. Laboratory tests showed that the white blood cell count fluctuated between 8.49 and 14.85 × 109/L (predominantly neutrophils), and serum electrolyte levels were 128 mmol/L for sodium (Na+), 86 mmol/L for chloride (Cl−), and 3.2 mmol/L for potassium (K+). Other liver and kidney indexes, ESR, CRP, immunoglobulin, complement, myocardial enzymes, and BNP were unremarkable. The 24-h Holter test revealed sustained atrial fibrillation. Lung computed tomography (CT) showed bronchiectasis with slight inflammatory exudation and emphysema. Brain MRI revealed multiple abnormal signals in the brain stem, the bilateral basal ganglia, the thalamus, the corpus callosum, the left frontal lobe, and the left semi-oval center, leading to a preliminary diagnosis of pulmonary infection with cerebral lacunar infarction. The patient was then catheterized and given sodium supplements and ceftazidime for 7 days, followed by levofloxacin for 3 days and low molecular weight heparin 5000 U once daily. Consequently, there was no visible improvement, and the patient was transferred to our hospital for further investigation and treatment on May 27. The patient had been in a feeble condition during the disease course. He had poor sleep and reduced appetite and had lost 15 kg in weight. During hospitalization at other hospitals, he had a history of nausea and vomiting. He also had experienced diarrhea but defecated only once or twice a day. Nonetheless, his urine volume and color were normal. On admission, the patient was afebrile but still unconscious. He had a blood pressure of 114/86 mmHg and a heart rate of 103 beats/minute. His body mass index (BMI) was 19.4 kg/m2. The superficial lymph nodes were not palpable. No rales or rhonchi were heard. Arrhythmia, short pulse, and cardiac auscultation were generally normal. The liver and spleen were not palpable below the ribs. Also, no limb edema was detected. Ataxia and suspicious neck resistance were noted. He had normal muscle tension, knee reflexes were elicited, and negative Babinski signs were observed. The patient was unable to cooperate for further examination.
The patient’s blood electrolytes test documented that the Na+ was 129 mmol/L, and K+ was 3.1 mmol/L; therefore, sodium and potassium were supplemented. Blood and urine osmotic pressure was normal. Thyroid and adrenal functions were also normal. Therefore, the SIADH was suspected and potential causes were investigated. The following tests were either normal or negative: anti-HCV, anti-HIV, and anti-syphilis antibodies; Legionella pneumophila antibodies; blood Cryptococcus antigen (qualitative) test, and Brucella agglutination test; T-spot. TB test; inflammatory markers; anti-nuclear antibodies; Lupus anticoagulant; antiphospholipid antibodies, anti-neutrophil cytoplasmic antibodies; blood tumor biomarkers and serum immunofixation electrophoresis; positron emission tomography/computed tomography (PET/CT).
Lumbar puncture revealed normal opening pressure. The total white blood cell count of the CSF was 34 × 106/L, consisting of all mononuclear cells (LY% 90, MONO% 10). Total protein was 1.58 g/L, and glucose was not decreased. IL-6 and TNF-α were elevated, while IL-8 and IL-10 were normal. Epstein–Barr virus (EBV)-DNA was 500 copies/mL, and Cytomegalovirus (CMV)-DNA and next-generation sequencing (NGS) were unremarkable. Anti-LGI1, anti-CASPR2, anti-NMDA and Hu.Yo.Ri antibodies in the blood and the CSF were negative. Brain contrast-enhanced MRI + diffusion-weighted MRI (DWI) + fluid-attenuated inversion recovery (FLAIR) + SWI displayed multiple abnormal signals in both thalami, the basal ganglia, the left cerebellum, the pons, and the white matter of the bilateral cerebrum (Fig. a1-a4, b1-b4).
After excluding the potential infections or malignancies, multiple autoimmune leukodystrophy of the nervous system was considered, and since June 18, after explaining the current condition to the patient, he agreed to be on intravenous infusion of immunoglobulin (IVIG) 20 g daily for 5 days and intravenous methylprednisolone 40 mg daily. The patient began to gain strength in the legs on day 3 and could stand with assistance. On June 25, using the tissue based indirect immune-fluorescence test, we detected that anti-GFAP antibody was positive for CSF, while anti-GFAP and anti-MOG antibodies for serum were negative, thereby leading to the diagnosis of autoimmune GFAP astrocytopathy. The patient was given intravenous methylprednisolone 1 g daily for 3 days, followed by an oral taper with prednisolone 50 mg daily. After the first 3 days, his blood sodium was maintained with oral supplements. The patient was conscious and had good orientation, and thus, was therefore discharged on June 28.
The patient’s symptoms improved gradually, and hence, the use of prednisolone was reduced. The patient was on 40 mg daily prednisolone during the subsequent follow-up and no sodium supplements; his blood electrolytes were within the normal range (K+ 4.2 mmol/L and Na+ 141 mmol/L). CSF analysis revealed that white cell count dropped to 22 × 106/L, and the protein level was lowered to 0.67 g/L. Nonetheless, on August 9, anti-GFAP antibody in CSF and serum were both positive on a repeat testing, and head contrast-enhanced MRI + SWI showed a wide afflicted region (Fig. c1-c4, d1-d4). Given that the disease was not well-controlled, 20 g daily intravenous immunoglobulin was administered for 5 days along with 0.5 g MMF twice daily. Consequently, the patient reported improved strength of the upper and lower limbs and could walk for 2 km on plain ground. In the subsequent follow-ups, he was on a continual gradual reduction in prednisone that was finally maintained at a 5 mg daily dosage plus 0.5 g MMF twice/day.


The patient was a 61-day-old girl. She was born at a gestational age of 37 weeks and had a birth weight of 2.41 kg. She had a slightly high galactose concentration on mass screening for congenital metabolic abnormalities at 4 days of age. She was examined at another hospital at 13 days of age, when she exhibited white feces and a high circulating direct bilirubin concentration. Her gallbladder could not be identified by abdominal ultrasonography; therefore, biliary atresia was suspected. At the age of 39 days, bile excretion was not observed on hepatobiliary scintigraphy, and hepatobiliary scintigraphy at the previous hospital had not confirmed excretion into the intestinal tract. Due to the novel coronavirus pandemic and the circumstances of the family, her referral to our hospital was slightly delayed. The patient was admitted to our department at the age of 57 days and underwent exploratory laparotomy at the age of 61 days, when she was diagnosed with type III biliary atresia (the type of extrahepatic biliary obstruction was determined using the Japanese Society of Pediatric Surgeons Classification
) using intraoperative cholangiography (
) and underwent open KPE using the 8K UHD television system.
A right subcostal laparotomy was performed and intraoperative cholangiography was performed via the atrophied gallbladder. Only the gallbladder could be detected, and the contrast agent leaked from the lateral aspect under compression. A diagnosis of type III biliary atresia was made on the basis of the cholangiographic and gross findings, and open KPE was performed.
The connective tissue in the portal region was dissected using Metzenbaum scissors at the level of the hepatic capsule, from the medial side of the left portal vein toward the medial side of the right portal vein, while applying gauze saturated with warm physiological saline to aid hemostasis.
At that time, the site of dissection was confirmed by examining the portal region using the camera of the 8K UHD laparoscopic system, and the biliary outflow site was examined after dissection. Bile outflow near the right hepatic artery was observed in 8K UHD mode (
,
and
), but was not visible in high-definition mode (
).
The jejunum was separated at a point 30 cm from the ligament of Treitz, an ascending limb of 40 cm in length was elevated in front of the colon, and portoenterostomy was performed. The jejunum was anastomosed to the
porta hepatis
using 5–0 PDS II, which sufficiently covered the biliary outflow site (
).
The biliary tract was reconstructed using the Roux-en-Y procedure, with the creation of a Nakajo-type enteric antireflux valve at a point 10 cm toward the liver from the Roux-en-Y limb and the Roux-en-Y limb was secured at an acute angle by suturing the seromuscular layer, to prevent food reflux. We performed an antireflux plasty using the intussuscepted valve Roux-en-Y procedure, according to the technique performed at Tohoku University Hospital.
The postoperative course was uneventful. Oral feeding was initiated on postoperative day (POD) 3, and the drain was removed on POD 6. Steroid administration was started, according to the protocol of the Japanese Biliary Atresia Society, on POD 7, and the patient was discharged on POD 17 with a total bilirubin concentration of 2.4 mg/dL. Thereafter, the patient was followed up on an outpatient basis, involving weekly attendance at the clinic during the immediate period following discharge, and once monthly visits when her blood parameters had normalized. She was initially followed up by both a pediatric surgeon and a pediatrician, but in the longer term she is being monitored principally by a pediatric surgeon. At the time of writing (POD 115), no cholangitis has been noted and her total bilirubin concentration is 0.5 mg/dL (
).


Physical examination on admission: Obese 61-year-old woman (BMI 30.1 kg/m2), pulse 60/min, blood pressure 120/80 mmHg, temperature 36 °C, O2 saturation 94% under mechanical ventilation. Heart, lungs, and abdomen unremarkable. Laboratory studies: Complete blood count: unremarkable. Plasma coagulation study: normal, D-dimers within normal limits, Clinical chemistry: C-reactive protein 6 mg/L (normal 5 mg/L), all other values within normal limits. ECG: Sinus rhythm, HF 60, no AV-Block, no QT time prolongation, inverted T-waves in the inferior leads (III, aVF) (Fig. b). Fast echocardiography: Normal systolic right and left ventricular systolic function, severe mitral regurgitation, no pericardial effusion. Chest x-ray: Normal cardiac size with evidence of pulmonary venous congestion.
Intensive care therapy achieved stabilization of the patient’s general condition. Controlled ventilation was stopped on the fourth day. Except for a hypoactive delirium, which was adequately controlled by administration of a neuroleptikum, no neurological deficits were manifested.
Evaluation of the 12-lead ECG did not reveal any evidence of ECG changes, which are normally associated with canalopathies (Brugada, ARVC, long-, short QT syndromes etc.).
However, we have registered recurrent ventricular salves during monitoring (Fig. c). In addition, we registered a short-lasting atrial fibrillation with spontaneous termination (Fig. d). Therefore, oral anticoagulation was initiated.
Follow-up echocardiography showed a significant mitral valve insufficiency with preserved left ventricular pump function. The left ventricle demonstrated mild endsystolic and enddiastolic dilatation. A severe dilatation of the left atrium (LA area 45 cm2) was noticed (Fig. a). The lateral mitral annular velocities was quantified with Doppler tissue imaging. The peak systolic lateral mitral annulus velocity was 18 cm/s (Fig. b).
Transesophageal echocardiography was performed to evaluate the mitral valve more precisely. A high-grade eccentric mitral valve insufficiency due to a pronounced PML and a mild AML prolapse could be demonstrated (Fig. c). Especially the PML showed thickening and myxomatous changes (Fig. d). The tendinous chordae appeared to be intact.
For further clarification of the arrhythmogenic event, we ordered a CMR. This exploration has shown a discreet mid-wall LGE in the LV inferobasal region (Fig. a). Additionally, LGE of the PM was visible on mid short-axis view (Fig. b). The right ventricle showed no pathology by echocardiography and CMR. A significant mitral annulus disjunction (MAD) measuring 11,2 mm was identified. (Fig. c).
Regarding the severe mitral valvular insufficiency due to the MVP, the case was discussed in the heart team. It was decided to provide the patient with an internal automatic cardioverter defibrillator (ICD) first and to repair the mitral valve by mini invasive surgery in 3 months.
The patient showed regression of the delirium and an increasing mobility. After implantation of an ICD device (Fig. a), the patient was discharged in good general condition and without significant neurological deficits. A cardio-neurological rehabilitation was organized. The first ICD follow-up analysis after 3 Weeks did not show any arrhythmogenic events. At the 3 months ICD follow up, few days after the mitral valve reconstruction, we detected a VT, which has been successfully electrocardioverted (Fig. b).


A 30-year-old male visited our outpatient clinic in March 2019, presented with irregular fever and newly-onset proteinuria. He was from Shanxi province in the northwestern part of China. His fever started in April 2018, with the highest body temperature reaching 40 °C. Meanwhile, he only experienced a slight cough. Doctors in local hospitals found an enlarged spleen by physical examination, while the routine tests were mostly normal, including complete blood count (CBC), urinalysis, and tests for liver functions. His serum creatinine (SCr) was 72.5 μmol/L, and total serum protein level was 102.65 g/L, dominated with immunoglobulin (Ig) G (51.2 g/L). The inflammatory markers were elevated (C reactive protein 31.93 mg/L, erythrocyte sedimentation rate 68 mm/h). Abdominal ultrasound revealed enlarged spleen and kidneys. Empirical antibiotic and antiviral treatments were administered without significant effect. The patient reported a weight loss of 25 kg within 3 months. In October 2018, a positron emission tomography-computed tomography scanning showed an enlarged spleen with a longitudinal diameter of 30 cm and a standardized uptake value (SUV) of 5.92. The max SUV of his bone marrow also reached 4.66. Malignant diseases were suspected, and he underwent bone marrow biopsy and splenectomy. Pathology of bone marrow indicated scattered infiltration of the plasma cell, and necrosis with reactive hyperplasia was seen in the spleen. Further tests for fusion genes, chromosomes, and fluorescence in situ hybridization (FISH) were not remarkable. His fever and increased serum IgG remained after the splenectomy, while SCr increased to 100 μmol/L. Repeated urinalysis indicated moderate protein and blood. His past medical history was generally nonremarkable.
In March 2019, his tests in our outpatient clinic showed proteinuria (24-h urine protein 6.88 g) and hypoalbuminemia (serum albumin 23 g/L). His SCr was 93 μmol/L, and serum IgG level was higher than the normal upper range (99 g/L), dominated with IgG1 (106 g/L). None monoclonal protein was found after performing serum protein electrophoresis, immunofixation electrophoresis, and urine free light chain test. Finally, we repeated bone marrow biopsy and found Leishmania inside and outside the phagocytes (Fig. ). A diagnosis of Leishmaniasis was established, but inquiries of travel history or contact history were nonremarkable. From March 2019 to October 2019, the patient underwent treatments of sodium antimony gluconate (Table ), after which a repeated bone marrow biopsy proved the clearance of Leishmania. However, the elevation of his serum IgG level and urine protein persisted.
In November 2019, he was admitted to our nephrology department. Physical examination was mostly normal, without palpable lymph nodes or extremity edema. His SCr and proteinuria improved (SCr 58 μmol/L, 24-h urine protein 3.71 g, serum albumin 33 g/L). His urine protein was composed of albumin (45.6%), IgG (39.6%), transferrin (9.8%), free light chain (1.0%), and unknown proteins (4.0%), as shown by the electrophoresis. The flow cytometry of peripheral blood mononuclear cells revealed elevated count B cells (894/μL) and normal counts of T cells and natural killer cells. The urinary transferrin, β2-MG, and α1-MG were also above the normal upper range. The longitudinal diameters of kidneys, measured by ultrasound, were l5.6cm and 14.7 cm, respectively. A renal biopsy was performed. Light microscopy showed mild segmental mesangial proliferation and glomerular hypertrophy, without tubulointerstitial lesions (Fig. a, b). The immunofluorescent stainings of immunoglobulin and complements were negative. Electron microscope showed the increased lysosomes in proximal tubules, but immune complex deposits were not found in the mesangial area (Fig. c, d).
Based on renal biopsy findings, we did not recommend immune-suppressive therapies but administrated Valsartan to decrease urinary protein. The urine protein gradually dropped to 1.59 g during the following 3 months, and the serum IgG level decreased to 45 g/L. His serum albumin and SCr levels remained stable (Fig. ).