A 13-year-old male child was referred to local hospital due to 5 days of dizziness, and 2 days of fever and dyspnea. Except for a history of neurodermatitis cured by antihistamines, the patient had normal nutritional status without other previous underlying diseases, head injury and drug exposures. Additionally, routine childhood vaccines had been implemented in this patient. No local epidemiology of communicable diseases had been reported in the area where the patient resided. On physical examination, the children exhibited nasal flaring with respiratory rates of 31 breaths/minute, in absence of cyanosis, pallor, retractions, crackles, heart murmurs, hepatosplenomegaly, or extremity edema. The chest x-ray revealed streaky opacities in both lungs. Review of the rest documents suggested hypoalbuminemia (2.1 g/dl), along with normal results of cerebrospinal fluid (CSF) analysis, non-enhanced computed tomography (CT) scan of head, aminotransferase, and renal function. As being supposed to be secondary to acute infections, no further effort was directed toward defining the underlying causes of hypoalbuminemia. The patient was initially diagnosed as pneumonia, and antibiotic treatment (oxacillin, 100 mg/kg per day) was administered. His condition deteriorated within 2 days of hospitalization, presenting with a progressive course of breathlessness, lethargy, and hemodynamic instability, along with elevated levels of leukocyte. Thus, the patient was directly transferred to the pediatric intensive care unit (PICU) in our hospital in view of critical illness. On arrival, he exhibited altered mental status, sunken eyes, dehydrated skin, cold extremities, and photoreactive pupil with hypothermia (35.7 C), tachypnea (35 breaths/minute), tachycardia (127 beats/min), hypotension (82/60 mmHg), and percutaneous oxygen saturation of 95% via a nasal cannula. Other than rough respiratory sounds, the rest of his physical examinations were unremarkable.
Initial laboratory investigations performed on day 1 of hospitalization had revealed increased leukocyte (21,600/mul) with 84.3% neutrophils and 9.4% lymphocytes, red blood cell (RBC) count (4.14 x 106/mul), hemoglobin (11.3 g/dl), hematocrit (33.9%), procalcitonin (0.8 ng/ml), and C-reactive protein (CRP) (1.89 mg/dl) with normal platelets (39.4 x 104/mul). Results of renal function, electrolytes, and blood gas analysis were within normal ranges. Decreased antithrombin III level (44%) combined with elevation of fibrin degradation products (FDP, 45.8 mug/ml), D-dimer (DDI, 7.9 mug/ml) and fibrinogen (553 mg/dl), were identified. Moreover, Serum albumin was low at 2.4 g/dl (Table 1). Chlamydia/mycoplasma antibody, PPD test, myocardial troponin I, complement level, antistreptolysin O (ASO) titer, RT-PCR for SARS-CoV-2, blood culture, and echocardiography demonstrated normal findings. Urine examination was not performed because of anuria, while subsequent ultrasound did not revealed structural anatomic anomalies, hydronephrosis or obstructive uropathy. Repeat chest x-ray displayed bibasilar nodular opacities with consolidation. The patient was diagnosed as pneumonia combined with shock. Right internal jugular catheterization was placed under ultrasound guidance. The patient was then given intravenous resuscitation via 0.9% sodium chloride (20 ml/kg), and ceftriaxone (80 mg/kg per day). Notably, two samples of sputum cultures at 24 h both confirmed Streptococcus pneumoniae. Delayed urinalysis showed 4+ proteinuria by dipstick. Combined with hypoalbuminemia, an unexpected diagnosis of NS was brought to mind irrespective of its absence in symptoms. Despite being hemodynamically stable and absent from fever, his dyspnea and period of headache became progressively worsening. Respiratory distress with percutaneous oxygen saturation of 88% even via a face mask was noted on hospital day 3. Both meningeal irritation and pathological signs were negative. Based on a high degree of suspicion for NS and increased vigilance of consequent hypercoagulability, the possiblity of thromboembolism was taken into account, which might be attributable to dyspnea and headache. This speculation had been corroborated by subsequent amazing results of targeted tests for disclosing the nature of the pulmonary and neurological lesions. Specifically, a computed tomography angiography (CTA) of chest demonstrated multiple intraluminal filling defects in the branch pulmonary arteries of both lungs, suggestive of PE in bilateral pulmonary arteries (Figures 1A,C,E), whereas no evidence of DVT was identified in bilateral lower limb veins by ultrasound. Meanwhile, the head CT manifested high-density shadows in the tentorium cerebelli and venous sinus, with normal results of repeat CSF analysis. Based on the correlation between headache episode and possible intracranial clot, cranial magnetic resonance imaging (MRI) and MR venography (MRV) were subsequently performed. Notably, multiple signal abnormalities were found in superior sagittal sinus, inferior sagittal sinus, straight sinus, bilateral transversal sinuses, bilateral sigmoid sinuses, vein of Galen, and torcula (Figures 2A-D), consistent with the imaging features of CVST.
The patient immediately received treatment with high flow nasal oxygen (HFNO) therapy, subcutaneous injection of low molecular weight heparin calcium (150 U/kg per day), and continuous dripping intravenous infusion of urokinase (an initial bolus of 4 x 103 U/kg for 15 min followed by a maintenance dose of 100 x 103 U/kg per day). Of great concern, it was crucial to further confirm the underlying disease contributing to the pathogenesis of CVST and concurrent PE. It was noteworthy that multiple urinalysis had uniformly displayed massive proteinuria without hematuria. 1+ hyaline casts along with granular casts were detected in the sediment under a microscope at low power field (x10). Increase levels of urine beta2-microglobulin were found with values between 1.64 and 2.20 mug/ml (normal value <0.25 mug/ml). Furthermore, a 24-h urine examination revealed 12.5 g proteinuria with a proteinuria to serum albumin (2.0 g/dl) ratio of 6.25. Meanwhile, dyslipidemia (elevated total cholesterol of 11.3 mmol/L and low density lipoprotein of 9.0 mmol/L), and progressive abnormalities in the coagulation-fibrinolysis system (antithrombin III of 37%, FDP of 57.1 mug/ml and DDI of 19.2 mug/ml), were identified. Given negative history of Henoch-Schonlein purpura along with unremarkable findings of human immunodeficiency virus, hepatitis B surface antigen, hepatitis C virus, autoimmune antibody and abdominal CT scan, the diagnosis of primary NS was ultimately confirmed.
Given negative findings of T-spot assay, serum glucan/galactomannan tests, and radiographic evaluation suggestive of tuberculosis or fungal infections, additional therapy of oral prednisone (2 mg/kg per day) was administered for the treatment of NS. Despite this, screening for a comprehensive prothrombotic workup was also performed in order to exclude multiple additional risk factors for CVST and PE, including protein C/S, homocysteine, Leiden factor V, antineutrophil cytoplasmic antibodies (ANCA), anticardiolipin antibody, anti-Ro/SSA, anti-La/SSB, antiglomerular basement membrane (GBM) antibody, tumor marker concentrations, and bone marrow biopsy. All the results were within normal limits. Encouragingly, his headache and breathlessness gradually resolved. Radiographic recanalization of the infarcted pulmonary and cerebral vessels was identified on the 6th day (Figures 1B,D,F) and 20th day (Figures 2E-H) of antithrombotic therapy, respectively. Moreover, renal remission was achieved on the 13th day of steroid treatment, associated with complete resolution of the coagulation profile. The patient was discharged on oral prednisone, aspirin and dipyridamole after spending 28 days in hospital. Apart from normal renal function without proteinuria, no thromboembolic complications, neurological sequelae and side effects of drugs developed during follow-up for 6 months. Figure 3 summarized the Timeline with relevant data from the episode of care in this case.