Recurrence of infectious mononucleosis in adults after remission for 3 years: A case report

lNTRODUCTlON

Epstein–Barr virus (EBV) is a member of the herpesvirus family. It is one of the most common human viruses, affecting nearly 90% of the adult population worldwide. In the majority of individuals, EBV infection occurs during childhood. However, if an adult is infected with EBV, the viral genome remains latent and establishes lifelong persistence in a small portion of memory B cells[1]. EBV infections in children are usually asymptomatic or mild; whereas, primary EBV infections in adolescents or adults are commonly characterized by infectious mononucleosis (IM). Typical manifestations of adult IM are fatigue, fever, pharyngitis and lymphadenopathy. In addition, liver damage due to elevated transaminase, jaundice, and hepatomegaly may also be observed. In rare cases, hemolytic anemia, thrombocytopenia, aplastic anemia, myocarditis, and neurological complications are observed. EBV is treated with several antiviral drugs that aim to inhibit the replication of EBV; however, these drugs have limited clinical success. Thus far, no drug has been approved for the treatment of EBV infection[2].Supportive treatment is recommended for IM patients. EBV is known to be one of the main causes of nasopharyngeal cancer[3]. Usually, EBV is a harmless passenger residing in B cells. However, it may cause severe diseases, including hemophagocytic lymphohistiocytosis, and is associated with numerous human cancers. Most IM patients will attain remission without obvious sequelae and recover within 2 mo after disease onset. IM is a mild illness with better outcomes compared to other diseases related to adult EBV infections, such as hemophagocytic syndrome and malignancies[4].

腎開竅于耳：腎藏精，精生髓，髓聚于腦，精髓充盛，髓海得養，則聽覺才會靈敏，故稱腎開竅于耳，“耳為腎之外候”。臨床上常常把耳的聽覺變化，作為推斷腎氣盛衰的一個標志。人到老年，腎中精氣逐漸衰退，故聽力每多減退。

Informed written consent was obtained from the patients for the publication of this report and any accompanying images.

Here, we report a patient who showed IM-like symptoms with mild liver damage at 3 years after initial IM remission. Typical symptoms were fever and pharyngitis, accompanied by elevated transaminase levels. Results of routine blood tests and EBV viral capsid antigen (VCA) antibody test (positive for VCA IgM antibodies) confirmed the recurrence of IM. Only a few cases of adult IM have been reported to date. Our case demonstrates the possibility of IM recurrence in adults after remission of EBV-related diseases, even in well-controlled patients. In addition, symptoms is similar to the primary manifestations (liver damage in our case) may also recur.

CASE PRESENTATlON

Chief complaints

A 25-year-old male patient of Han nationality, who was admitted at the Department of Hematology,People’s Hospital of Quzhou, affiliated with the Zhejiang University School of Medicine on December 4,2015 (Figure 1).

History of present illness

The patient complained of sore throat lasting from November 23, 2015, accompanied with tenderness and enlargement of cervical lymph nodes. One week later, he had fever (39.2 °C) along with dizziness,weakness, and reduced appetite.

History of past illness

The patient conveyed that he did not have any other disease or was consuming other drugs.

Personal and family history

Routine blood test results revealed abnormal white blood cell (WBC) count, neutrophils, and atypical lymphocytes. Blood chemistry revealed highly elevated levels of alanine aminotransferase (ALT),aspartate aminotransferase (AST), -glutamyl transferase (GGT), alkaline phosphatase (AKP), lactate dehydrogenase (LDH) and moderately elevated values of total bilirubin and direct bilirubin. Elevated C-reactive protein (CRP) level was 4.5 mg/L. Positive results were obtained for EBV VCA IgM antibodies and negative results for EBV VCA IgG antibodies. Thyroid function [free triiodothyronine(T3), free thyroxine (T4), T3, T4, and thyroid-stimulating hormone] and tumor markers [carbohydrate antigen (CA) 724, -fetoprotein, carcinoembryonic antigen, total prostate-specific antigen (PSA), free PSA,CA199, and squamous cell carcinoma antigen] were normal.

Physical examination

Physical examination performed at admission demonstrated consciousness but with lassitude,pharyngeal hyperemia, swelling of the tonsils (Grade III, with yellow–white pus spots), and a palpable enlarged lymph node at the left submandibular region (1 cm × 1 cm in size, moderate hardness, smooth,and with satisfactory range of movement). Bilateral breath sounds in the lungs were coarse with the absence of dry or moist rales.

高分方案數代表來自外部評價指標的設計師產出質量(本實驗采用外部專家組評價每一款方案)，被引用次數則代表設計師的作品在團隊內部的認可度。內外兩個指標結合起來可以作為設計師產出質量的一個較全面的表征。

Laboratory examinations

He denied a family history of disease.

Imaging examinations

After 2 wk of treatment, on December 22, 2015, the patient’s temperature returned to normal with improvement in clinical symptoms. No abnormal values were observed in blood test results except for the low level of neutrophils. However, slightly elevated levels were seen in liver function of ALT, AST,AKP and GGT. Abdominal ultrasound indicated a slightly enlarged spleen (Figure 2C). The patient was discharged on December 24, 2015. One week later, follow-up routine blood and liver function tests were performed with no abnormal results. In addition, ultrasound of the abdomen indicated no obvious abnormality (Figure 2D). In November 2016 and November 2017, the patient underwent follow-up routine examinations, which indicated normal results.

FlNAL DlAGNOSlS

In November 2018, the patient visited the outpatient department (1 wk prior to readmission) and his physical examination showed swelling of the tonsils (Grade II, with pus spots). Routine blood tests revealed normal findings. Serological tests indicated negative result for EBV VCA IgM antibodies and positive result for EBV VCA IgG antibodies. Tests for adenovirus,, respiratory syncytial virus, influenza virus, coxsackievirus, and norovirus were negative. Therefore, the outpatient department confirmed the diagnosis of acute suppurative tonsillitis and administered levofloxacin (500 mg, q24h) for 5 d; however, no signs of improvement were observed. On November 26, 2018, he was readmitted to the Department of Hematology of Medicine with recurrent fever (highest body temperature 39.9 °C) for 10 d, accompanied with pharyngalgia, fatigue, and systemic muscle pain. The patient was conscious at admission. Physical examinations revealed absence of yellowing of the skin or sclera; conjunctival congestion; enlarged lymph nodes that were palpable at the right neck with tenderness (size of a soybean, hard, with satisfactory range of movement); and enlarged tonsils (Grade III, with pus spots). Routine blood tests revealed slightly elevated WBC count (12.5 × 10/L) and atypical lymphocytes (10%) and the absolute lymphocyte count was 5.86 × 10/L and reduced neutrophils (16.9%). Liver function tests indicated elevated ALT (104.8 U/L), AST (66.6 U/L), and GGT(65.5 U/L) and normal levels of AKP (92.7 U/L). Serological tests were positive for both EBV VCA IgM and EBV VCA IgG antibodies. His EBV-DNA titer was ＜ 1000 copies/mL and VCA-IgG was not detected, which were both lower than the lowest value that could be detected in the laboratory. Procalcitonin level was 0.22 g/L. Cellular immunophenotyping indicated elevated levels of CD3and CD8T cells, and decreased levels of CD4/CD8T cells. Autoimmune-related antibody tests were also negative.Ultrasound of the abdomen indicated that the spleen was approximately 11.4 × 3.6 cmin size, with a homogeneous echogenic pattern (Figure 2E). Biopsy of bone marrow (Figure 2F) was sent to the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine for examination. Results indicated active proliferative myeloid series with granulocytes at all stages of development (predominately myelocytes,metamyelocytes, band cells, and polymorphonuclear granulocytes); active proliferative erythroid series with discretely distributed nucleated cells; visible clusters of immature erythroid cells (with an irregular nucleus in some of the immature erythroid cells); and active proliferative megakaryocytes (no abnormality in counts or distribution). However, no abnormalities were observed in immunophenotyping and chromosomal analysis. As the patient had IM-like symptoms again after 3 years, we considered the possibility of chronic active EBV infection and recurrent IM in our diagnosis. His EBVDNA titer and titers of VCA-IgG were both lower than the lowest value that could be detected in the laboratory, and there were no clinical symptoms that IM or other chronic diseases could not explain.Under the current medical conditions of our hospital and the guidelines[5], we considered that all the recent clinical evidence was insufficient for the diagnosis of chronic active EBV infection. Therefore,

TREATMENT

We administered ganciclovir (5 mg/kg q12h for 14 d) for antiviral treatment, as well as glycyrrhizin (50 mg, bid) and reduced glutathione (2.4 g, qd) for liver protection and enzyme-lowering on December 7,2015.

OUTCOME AND FOLLOW-UP

B-type ultrasound of the abdomen indicated splenomegaly (Figure 2A) and that of cervical lymph nodes indicated bilateral cervical lymphadenopathy (Figure 2B).

We considered a diagnosis of IM.

結果顯示，在親密關系喪失組被試中，高自尊者在職業認同及其職業行為、職業期望、職業情感維度上均顯著高于低自尊者，而在職業承諾、職業價值觀及職業認知方面無顯著差異，詳見表 8。

based on the clinical manifestations of the patient (lymphadenopathy and pharyngitis) and the laboratory test results (atypical lymphocytes ≥ 10% and positive EBV VCA antibodies), we confirmed the diagnosis of recurrent IM in the patient. We administered ganciclovir (5 mg/kg, q12h) for antiviral treatment, diammonium glycyrrhizinate (50 mg, bid) and reduced glutathione (2.4 g, qd) for liver protection, ceftriaxone (2 g, q24h) for anti-infection, and vitamin C (250 mg, bid) and vitamin B6 (100 mg, qd) for vitamin supplementation. From December 10, 2018 onwards, the patient’s temperature did not exceed 38°C. Results of laboratory tests indicated normal coagulation function, and normal levels of total bilirubin, AST and ALT. WBC and lymphocyte proportions were also normal. The patient’s condition improved and he was discharged on December 11. After discharge, the patient underwent routine blood tests, liver function tests, and B-mode ultrasound at 1, 3, 6, 12, and 24 mo. The test results indicated no abnormalities during these follow-ups.

DlSCUSSlON

IM is a rare disease in adults and has complex and nonspecific clinical manifestations; hence, it can be easily misdiagnosed. Therefore, detailed examinations are necessary for accurate diagnosis[6]. In this case report too, the patient was misdiagnosed with AST during IM recurrence. Previously, the patient was diagnosed with IM and received successful treatment. The follow-up tests also showed no abnormalities. However, 3 years later, he showed symptoms of enlarged tonsils, fever, pharyngalgia,fatigue, and muscle pain, along with mild liver damage. Laboratory test results indicated positive EBV VCA antibodies, which confirmed recurrence of IM. Once diagnosed, the patient was successfully treated with no further complications. This finding confirms the possibility of recurrence of IM in patients who are infected with EBV previously.

At present, most clinicians believe that the common symptoms of IM in adults are fever, sore throat,and muscle pain. The majority of patients aged ＜ 20 years present these classic symptoms; however, the prevalence of nonspecific clinical features of abnormal liver function increases with age[7]. Prognosis of IM may be associated with age, body temperature at onset, and baseline disease. Age above 30 years may be a risk factor for onset of severe IM[8]. We reviewed relevant studies extracted from the Web of Science using “infectious mononucleosis” and “adult” as keywords and found eight case reports(Table 1). From these case reports, we observed that liver damage is the most frequently found complication in adults with IM. Our patient also had liver dysfunction mainly manifested as increased levels of aminotransferase. This finding was consistent with most of the cases that have been reported.In one case that mentioned recurrence[9], the patient was a 54-year-old middle-aged man with a history of recurrent IM-like symptoms for at least 1 year. However, in our case, the patient had his initial IM attack at the age of 25 (＜ 30 years), and he had been healthy without any baseline disease or immune system diseases. The patient was cured and discharged after 2 wk of treatment for the initial attack.Follow-up after discharge indicated no abnormalities in blood tests (atypical lymphocytes) or B-mode ultrasound. In addition, the patient did not have persistent or recurrent IM-like symptoms during the follow-up period. IM is usually associated with mild transaminitis and may induce acute hepatitis.However, liver damage is often mild and is characterized by a mild increase in transferase levels but not jaundice. For such patients, symptomatic treatments are administered. Older patients with IM have higher risks of liver dysfunction. The incidence rate of liver dysfunction is about 10% in younger patients; whereas, it could be as high as 30% in older patients, with clinical symptoms often being more severe[10]. EBV infections may induce hepatitis in susceptible individuals but are seldom associated with acute fulminant liver failure unless patients are undergoing transplantation or have immunodeficiency[11]. In addition, IM-induced liver damage may be associated with gene expression or mutations,resulting in a more severe clinical course[12]. The pathogenesis and immune mechanism of IM in the presence of acute or chronic hepatitis are unknown. However, infiltration of CD3and CD8T lymphocytes may be involved. With regard to IM hepatitis, CD8T cells or cytotoxic T lymphocytes infected with EBV may be present in the liver to release interferon β and tumor necrosis factor α to induce liver cell damage[13]. In summary, EBV-related liver damage is often self-limiting and resolves unnoticed. Hence, mildly elevated transferase levels during the early stages may be the only clinical manifestation.

大功率參量陣定向揚聲器聲學空間覆蓋特性如圖5所示。由圖5可知，大功率參量陣定向揚聲器區別于普通揚聲器的特性在于它有著極強的指向性，聲音發散角度達到±15°，在其指向區間范圍外幾乎無聲音；且定向揚聲器的發聲強度超過100 dB，該指標非常先進，目前國內外類似產品均未達到該水平。當定向場聲器安裝于室內空間通道內時，沒有了致命的強近場聲音反射，僅僅產生遠端反射(見圖6)。遠端反射通常比直接傳播到聽者的聲強要低2個dB左右，而人耳的定向能力則在0.1 dB范圍內即可明確方向，因此在封閉的室內空間，大功率參量陣定向揚聲器有著極強的音源方向性。

CONCLUSlON

The possibility of IM should be considered when patients aged 15–30 years show symptoms of persistent fever and sore throat. Moreover, for an accurate diagnosis, EBV VCA IgM antibody tests should be used to determine primary EBV infection. Our case report demonstrates the possibility of IM recurrence in cured adults after infection with EBV. Because of the association between EBV infections and malignant diseases, long-term follow-up and monitoring are necessary.

FOOTNOTES

Zhang ΧY contributed to study design, data collection and analysis, statistical analysis, and manuscript drafting; Teng QB revised the manuscript; all authors have read and approved the manuscript.

隨著社會生產力的進步，土陶時代、青銅時代、鐵器石代、機械時代及電子時代的到來，石器在漫長的歲月長河中，大浪淘沙，逐漸退出了人類第一生產工具的歷史舞臺。但是，人類并沒有忘記石頭在人類進化過程中的歷史作用和功績，將其作為一種圖騰而世代流傳。

Recurrent IM after remission in adults has rarely been reported. The cause of IM recurrence in our patient was unknown. It is known that almost all individuals are infected with EBV at least once in their lifetime, which persists in a latent form throughout their life. EBV reactivation occurs mostly in immunocompromised individuals[14]. However, our patient reported no history of autoimmune disorder. During recurrence, laboratory tests indicated the absence of other pathogenic infections. The main clinical manifestations observed in our patient were mild liver dysfunction in addition to the classic symptoms of fever, fatigue, pharyngitis, and lymphadenopathy. Uncontrolled EBV infection can initiate autoimmune diseases in susceptible individuals, causing different symptoms and disease flareups that could lead to misdiagnosis[15]. Therefore, association of EBV with autoimmune disorders and malignancies confirms the importance of long-term monitoring in susceptible individuals.

The authors declare that they have no conflict of interest.

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

基于統計的巖石密度數據可知，偏基性的安山巖、玄武巖密度較高，超過2.50×103kg/m3，因此，可推測高密度巖石中偏基性的火山巖占有較大比例，而低密度巖石中偏酸性的火山巖所占比例較高。由此可得出冀北地區火山巖在空間上的分布呈現以下規律：偏酸性的火山巖圍繞著偏基性的火山巖以環狀形式分布。

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China

價格折扣是生鮮農產品行業中供應商通常采取的加大對生鮮農產品銷售的手段，一般對大批量采購會存在相應的價格折扣，而對小批量訂貨則有可能會收取其他費用，從而產生企業的價格折扣成本。

Χin-Yue Zhang 0000-0001-9934-1566; Qi-Bei Teng 0000-0003-3826-8822.

(一)互聯網時代下的大數據發展是一個漫長的過程，即便數據已滲透于各個行業中，但人們還未能正確的認識到新事物的發展狀態。以致于數據并不能充分的實現其價值。總而言之，人們對大數據現有的認知還存在一些誤區，專業知識還較匱乏，認識過于碎片化，還無法使其適應新時期的種種要求。

Chen YL

Kerr C

Chen YL