A 40-year-old ethnic Han Chinese female, who used to be healthy and had no history of disorders related to the nervous system, respiratory system, circulatory system, digestive system, rheumatic immune system, and also had no history of mental disorders, from a family without history of genetic disorders, hypertension, coronary heart disease, diabetes, genetic inherited diseases, etc., forming a happy family with her beloved husband and two healthy daughters, initially presented with intractable nausea and dizziness for 9 weeks. She went to local hospital. Full blood count, serum biochemical tests, gastroscopy and head CT examination showed no obvious abnormalities. She felt that her nausea and dizziness did not improve after symptomatic therapy and even followed by dysphagia, limb weakness, blurred vision, ghosting in the right eye, and fatigue. Two weeks later, she went to another local hospital. A blood test was positive for AQP4 antibodies and brain MRI found high-signal lesions (Figures 1a-c). She was diagnosed with NMO and treated with high dose of intravenous methylprednisolone. Two days later, she felt shortness of breath, hard to swallow and difficulty in walking. She was transferred to the ICU and received a tracheotomy and mechanical ventilation due to severe breathing difficulties, and a nasogastric tube feeding due to difficulty swallowing. Her condition did not improve over 2 weeks despite treatment with high-dose intravenous methylprednisolone (0.5 g per day for 3 days, 0.25 g per day for 3 days, 0.12 g per day for 2 days) and immunoglobulin (20 g/day for 5 days) followed by 3 rounds of plasma exchange.
She was transferred to our hospital at midnight, and physical examination revealed a temperature and blood pressure of 37.1 C and 96/68 mmHg, respectively. She was conscious on mechanical ventilation, with blurred vision of the right eye, shallow right nasolabial fold, upper limb muscle strength level 1, and lower limb muscle strength level 0. Laboratory tests revealed a white blood cell (WBC) count of 28,240 cells/muL, serum albumin 32.3 g/L, prothrombin time 16 s, activate partial thrombin 38.6 s, and D-dimer 2.24 mug/mL. Rheumatoid, lupus, and vasculitis-related immune indicators, and biochemical indicators related to the heart, liver, and kidney function showed no obvious abnormalities. Tuberculosis-specific enzyme-linked immunospot assay (T-SPOT), hepatitis B virus, hepatitis C virus, HIV, CMV-DNA, CMV-IgM, and Epstein-Barr virus (EBV)-IgM were negative; however, the CMV-IgG antibody was positive. Alpha-fetoprotein, carcinoembryonic antigen, and carbohydrate antigen (CA) 19-9, 125, 153, 50, 724, and 242 were negative. Blood and CSF smears and cultures were negative.
On day 2 of admission, the patient developed 150 ml suspicious menstrual blood, accompanied by a high fever, and marked increase in C-reactive protein (CPR) and procalcitonin (PCT); however, WBC count, hemoglobin concentration (1, 3), -beta-D-glucan and galactomannan (GM) tests, and liver and kidney function were not significantly altered. Chest CT showed new glass-like lesions on both upper lungs. Multiple blood, sputum, and urine specimens were taken for pathogenic cultures (all final culture results were negative). Considering the hospital stay and administration of high doses of hormones in the external hospital, the patient was diagnosed with pulmonary infection and underwent an empirical broad-spectrum antibacterial and fungal treatment with meropenem, linezolid, and caspofungin. On day 3 of admission, the patient's body temperature peak began to decline; however, she suddenly passed 640 ml dark red bloody stool painlessly, resulting in shock. Blood transfusion and drug hemostasis treatment were administered to treat the shock. Meanwhile, bedside gastroscopy, colonoscopy, and full abdominal CTA scan were performed to identify the cause of bleeding. Abdominal CTA found a high-density shadow in the colon and rectum, which was considered an accumulation of blood; however, no bleeding vessels were found. Gastroscopy found no lesions in the upper digestive tract. However, colonoscopy revealed a large ulcer-like lesion at 10 cm above the anus and a large amount of feces and dark red bloody fluid (Figure 2a). Biopsy of ulcer-like lesions could not be performed due to coagulation dysfunction. On day 4 post-admission, the patient's body temperature returned to normal. On day 7 post-admission, the WBC count, CRP, PCT, and chest CT were normal; therefore, the anti-infective agents were removed; however, the daily excretion of 200-800 ml dark red bloody stool of this patient continued, and her muscle strength and vision loss did not improve.
Based on the patient's bleeding characteristics and lesions found via colonoscopy, it was speculated that the cause of the patient's acute lower gastrointestinal bleeding was most likely AHRU. The pathogenesis of AHRU remains largely unknown. Therefore, we speculated that the presence of AHRU in this patient may be linked with her NMO.
To assess this link, we reviewed literatures and only found one reported case of an acute NMO with rhabdomyolysis in an immune-competent patient following CMV infection. Infectious pathogens may trigger and exacerbate NMO by prompting AQP4-IgG production. AQP4-IgG+ NMO is refractory to glucocorticoid treatment. In this case, the patient did not respond to high-dose intravenous methylprednisolone and immunoglobulin followed by plasma exchange. Therefore, we speculated that NMO in this case was caused by the CMV infection.
Thereafter, we wondered whether CMV infection could induce AHRU. Enteritis caused by CMV in immune-competent individuals had been reported, although very rarely. Interestingly, no relevant literature about CMV-AHRU was found. However, ARHU may be caused by CMV infection from a monistic point of view. To verify this, on day 23 post-admission, CMV inclusions of pathology of a mucosal tissue specimen from the edge of the patient's rectal ulcer was carried out using routine HE staining and IHC. These results confirmed the presence of CMV infection (Figures 3a,b). In addition, CSF pathogen gene sequencing also detected CMV gene copies on day 25 post-admission (Figure 3c) and serum AQP4-IgG was still positive.
After 2 weeks of treatment with ganciclovir and sodium phosphinate, the patient's nausea, dizziness, visual impairment, and limb weakness gradually improved. After 3 weeks of antiviral therapy, her lower gastrointestinal bleeding stopped, and the CMV staining of rectal biopsies (Figures 3d,e), CSF CMV gene sequencing, and serum AQP4 all became negative. Further, high-signals on the brain MRI were significantly reduced (Figures 1d-f). After 4 weeks of antiviral therapy, the colonoscopy revealed a smooth intestinal wall at the original lesion (Figure 2b). In addition, her right eye visual acuity was resumed to counting fingers at 2 m, the muscle strength of her upper and lower limbs recovered to level 4 and 3, respectively. Following this, the antiviral drugs were stopped and the patient was discharged back to her local hospital for further rehabilitation.