Derivation and validation of clinical prediction rules for diagnosis of infectious mononucleosis: a prospective cohort study.

OBJECTIVES: Infectious mononucleosis (IM) is a clinical syndrome that is characterised by lymphadenopathy, fever and sore throat. Although generally not considered a serious illness, IM can lead to significant loss of time from school or work due to profound fatigue, or the development of chronic illness. This study aimed to derive and externally validate clinical prediction rules (CPRs) for IM caused by Epstein-Barr virus (EBV). DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: 328 participants were recruited prospectively for the derivation cohort, from seven university-affiliated student health centres in Ireland. Participants were young adults (17-39 years old, mean age 20.6 years) with sore throat and one other additional symptom suggestive of IM. The validation cohort was a retrospective cohort of 1498 participants from a student health centre at the University of Georgia, USA. MAIN OUTCOME MEASURES: Regression analyses were used to develop four CPR models, internally validated in the derivation cohort. External validation was carried out in the geographically separate validation cohort. RESULTS: In the derivation cohort, there were 328 participants, of whom 42 (12.8%) had a positive EBV serology test result. Of 1498 participants in the validation cohort, 243 (16.2%) had positive heterophile antibody tests for IM. Four alternative CPR models were developed and compared. There was moderate discrimination and good calibration for all models. The sparsest CPR included presence of enlarged/tender posterior cervical lymph nodes and presence of exudate on the pharynx. This model had moderate discrimination (area under the receiver operating characteristic curve (AUC): 0.70; 95% CI: 0.62-0.79) and good calibration. On external validation, this model demonstrated reasonable discrimination (AUC: 0.69; 95% CI: 0.67-0.72) and good calibration. CONCLUSIONS: The alternative CPRs proposed can provide quantitative probability estimates of IM. Used in conjunction with serological testing for atypical lymphocytosis and immunoglobulin testing for viral capsid antigen, CPRs can enhance diagnostic decision-making for IM in community settings.

Fever with atypical lymphocytosis: pearls and pitfalls in Epstein-Barr virus serology.

The heterophile antibody (also known as the Monospot) test is a useful screening tool for infectious mononucleosis (IM) resulting from primary Epstein-Barr virus (EBV) infection. However, up to 10% of patients with IM are heterophile negative. Heterophile-negative patients who have lymphocytosis or atypical lymphocytes on peripheral blood smear should be further tested for EBV serologies, which include testing for specific IgM and IgG antibodies against viral capsid antigens, early antigens and EBV nuclear antigen proteins. A diagnostic dilemma arises when the patient has clinical and laboratory features of IM, but is both heterophile negative and seronegative for IM, as illustrated in this case presentation. To avoid missed diagnoses of IM, misdiagnosis of mononucleosis-like illnesses and unnecessary testing, knowledge of test characteristics and the evolving course of EBV serologies is important to assure and inform both the physician and the patient.

[Epstein-Barr viral infection is a global epidemiological problem].

The number of studies devoted to Epstein-Barr viral infection (EBV infection) has been growing in recent years. However, they all relate to the clinical aspects of this problem. Epidemiology issues remain practically unexplored. A review of domestic and foreign publications has shown that at the present stage there is a high intensity of the epidemic process of EBV infection both in Russia and abroad. The main indicators of unfavorable epidemiological situation are the ubiquitous spread of the pathogen and the increase in the incidence of infectious mononucleosis in recent years. The deterioration of the epidemic situation of EBV infection is influenced by changes in the immunological reactivity of various population groups due to the spread of HIV, HBV, HCV, the causative agent of tuberculosis and SARS-CoV-2. The above makes it possible to classify the problem as a global one and determines the need for the rapid implementation of the system of epidemiological surveillance of EBV infection and optimization of the complex of preventive and anti-epidemic measures. Reducing the burden of EBV is possible only with the consolidated participation of specialists of various profiles.

Transient hypertriglyceridemia: a common finding during Epstein-Barr virus-induced infectious mononucleosis.

BACKGROUND: Hypertriglyceridemia can occur in lymphoproliferative disorders. Infectious mononucleosis is a self-limiting, benign lymphoproliferative disorder. This study aimed to investigate the serum triglyceride concentrations and their change over time in patients with infectious mononucleosis. METHODS: We evaluated an adult patient with severe hypertriglyceridemia (>1000 mg/dL) during infectious mononucleosis and reviewed the records of 360 patients admitted to our hospital because of infectious mononucleosis (median age, 19 years; range, 15-87 years; 51.4% male). We compared the serum triglyceride concentrations with those of a control sample from the general population (n=75). A second triglyceride measurement, obtained during convalescence (median of 30 days after the initial determination), was available for 160 patients. RESULTS: The triglyceride concentrations in the acute phase (median: 156 mg/dL) were significantly higher than those of the controls (median, 76 mg/dL; P<0.001). A total of 194 (53.9%) patients presented with hypertriglyceridemia (>150 mg/dL), which was more common in the patients older than 30 years than in the younger patients (78.6% vs. 50.6%; P<0.001). A significant correlation (P<0.005) was observed between the triglyceride levels and white blood cell counts, total cholesterol levels, and liver damage markers. The triglyceride concentrations decreased during convalescence (P<0.001) and were lower than the initial measurement in 83.7% of the cases. Conversely, the total cholesterol concentrations during the acute phase were lower than those of the controls and increased during convalescence (P<0.001). CONCLUSIONS: Patients with severe infectious mononucleosis frequently show mild, transient hypertriglyceridemia. Further studies are needed to elucidate the mechanisms underlying this finding.

A multicentre retrospective cohort study on COVID-19-related physical interventions and adult hospital admissions for ENT infections.

PURPOSE: To report changes in adult hospital admission rates for acute ENT infections following the introduction of COVID-19-related physical interventions such as hand washing, use of face masks and social distancing of 2-m in the United Kingdom. METHODS: Retrospective cohort study comparing adult admissions with acute tonsillitis, peritonsillar abscess, epiglottitis, glandular fever, peri-orbital cellulitis, acute otitis media, acute mastoiditis, retropharyngeal abscess and parapharyngeal abscess in the 1-year period after the introduction of COVID-related physical interventions (2020-2021) with a 1-year period before this (2019-2020) in three UK secondary care ENT departments. RESULTS: In total, there were significantly fewer admissions for ENT infections (n = 1073, 57.56%, p < 0.001; RR 2.36, 95% CI [2.17, 2.56]) in the 2020-2021 period than in the 2019-2020 period. There were significant reductions in admissions for tonsillitis (64.4%; p < 0.001), peritonsillar abscess (60.68%; p < 0.001), epiglottitis (66.67%; p < 0.001), glandular fever (38.79%; p = 0.001), acute otitis media (26.85%; p = 0.01) and retropharyngeal and/or parapharyngeal abscesses (45.45%; p = 0.04). CONCLUSION: Our study demonstrates a sizeable reduction in adult admissions for ENT infections since the introduction of COVID-19-related physical interventions. There is evidence to support the use of physical interventions in the prevention of viral transmission of respiratory disease. Preventing ENT infections requiring admission through simple physical interventions could be of great benefit to the quality of life of patients and economical benefit to healthcare systems.

A Multicentre Retrospective Cohort Study on Covid-19-related Physical Interventions and Adult Hospital Admissions for ENT Infections (preprint)

Objectives: To report changes in adult hospital admission rates for acute ENT infections following the introduction of Covid-19-related physical interventions such as hand washing, use of face mask and social distancing of 2-metres in the United Kingdom. Design: Retrospective cohort study comparing a one-year period after the introduction of Covid-related physical interventions (2020-21) with a one-year period before this (2019-20). Settings: 3 UK secondary care ENT departments Participants: Adult patients admitted with acute tonsillitis, peritonsillar abscess, epiglottitis, glandular fever, peri-orbital cellulitis, acute otitis media, acute mastoiditis, retropharyngeal abscess and parapharyngeal abscess. Main outcome measures: Number of adult hospital admissions Results: In total there were significantly fewer admissions for ENT infections (n=1073, 57.56%, p<0.001; RR 2.36, 95% CI [2.17, 2.56]) in the 2020-2021 period than in the 2019-2020 period. There were significant reductions in admissions for tonsillitis (64.4%; p<0.001), peritonsillar abscess (60.68%; p<0.001), epiglottitis (66.67%; p<0.001), glandular fever (38.79%; p=0.001), acute otitis media (26.85%; p=0.01) and retropharyngeal and/or parapharyngeal abscesses (45.45%; p=0.04) Conclusion: Our study demonstrates a sizeable reduction in adult admissions for ENT infections since the introduction of Covid-19-related physical interventions. There is evidence to support the use of physical interventions in the prevention of viral transmission of respiratory disease. Preventing ENT infections requiring admission through simple physical interventions could be of great benefit to the quality of life of patients and economical benefit to healthcare systems.

Concomitant nephrotic syndrome and tubulointerstitial nephritis in a child with Epstein-Barr virus mononucleosis.

Acute kidney injury (AKI) and nephrotic syndrome (NS) are uncommon manifestations of Epstein-Barr virus (EBV) mononucleosis. We report a 4-year-old boy with Infectious mononucleosis (IM) who presented with dialysis-requiring AKI and NS. Renal biopsy showed severe acute tubular necrosis, mild chronic interstitial nephritis and focal podocyte foot processes effacement. EBV early RNA was not detected in the renal tissue. However, immunophenotyping of peripheral lymphocytes showed increased cytotoxic T cell activity and increased memory B cells. Treatment with steroid led to rapid resolution of NS within 3 weeks. Renal function stabilised. EBV viral capsid antigen (VCA) IgM remained elevated until 4 months before starting to decline when VCA IgG and nuclear antigen started appearing. B lymphocytes are the predominant target cells in EBV infection and additionally may also act as antigen presenting cells to T lymphocytes, thereby eliciting the strong immune response and leading to podocyte and tubulointerstitial injury.

Development of infectious mononucleosis as an unusual manifestation of COVID-19.

It has generally been reported that patients with COVID-19 show a fever, cough, and/or respiratory failure as the most common clinical symptoms but some have unusual symptoms, such as anosmia, diarrhea, and throat pain. We herein report a 26-year-old woman with chief complaints of lymphadenopathy and a fever. First, she underwent a laboratory examination, which showed a high proportion of atypical lymphocytes (19%) and an increase in hepatic enzyme activities, and was then hospitalized with a diagnosis of infectious mononucleosis (IM). However, the blood examination did not show any increase in anti-Epstein-Barr virus VCM-IgM. Subsequently, she developed tonsillar hypertrophy with purulent plugs. An additional examination for infection of other pathogens revealed positivity only for SARS-CoV-2 in a loop-mediated isothermal amplification (LAMP) test. The patient was transferred to the COVID-19-specific isolation ward, and none of the ward staff, patients, or either of the two otolaryngologists who had directly examined this patient showed positive signs for SARS-CoV-2 in a LAMP test. Consequently, this case suggests that even if patients show clinical symptoms and signs of common diseases for otolaryngologists, such as IM, we should keep in mind the possibility of COVID-19 without arbitrarily assuming that IM is caused by Epstein-Barr virus.

Case of haemophagocytic lymphohistiocytosis following Epstein-Barr virus infection.

Haemophagocytic lymphohistiocytosis (HLH) is a rare diagnosis that carries a high degree of mortality. We present this case of a previously healthy 22-year-old woman, who was admitted acutely ill to the hospital. One week prior, she had been seen by her primary care physician for fatigue and malaise. At that time, she was noted to have anterior and posterior cervical lymphadenopathy. She was referred to the emergency room and was diagnosed with acute Epstein-Barr virus (EBV) mononucleosis based on her clinical symptoms and positive heterophile antibody test. She was discharged after an uneventful 48-hour stay on the wards. She represented 7 days after discharge with cough, fatigue, nausea, vomiting, epigastric abdominal pain, diarrhoea, weight loss and subjective fevers. She had also reported haematemesis, epistaxis and melaena. Vital signs included temperature 36.9°C, blood pressure 90/50 mm Hg, heart rate 130 beats per minute and respiratory rate 32 breaths per minute. Physical examination was notable for an acutely ill appearing woman with scleral icterus, hepatosplenomegaly and palpable cervical and axillary lymphadenopathy. Complete blood count showed pancytopaenia with haemoglobin 59 g/L (normal 120-160 g/L), white blood cell count 2.7×109/L (normal 4-10.5×109/L) and platelet count 50×109/L (normal 150-450×109/L). The white blood cell count differential included 58% neutrophils (normal 38%-77%) with immature neutrophils in band form elevated at 45% (normal <14%), 16% lymphocytes (normal 20%-48%), 7% monocytes (normal <12%) and no eosinophils (normal <6%). Blood smear revealed anisocytosis, poikilocytosis and hypochromia. Coagulation panel showed elevated levels of d-dimer level at 1.39 µg/mL (normal <0.45 µg/mL), prolonged prothrombin time at 34.4 s (normal 11-15 s), prolonged activated partial thromboplastin time of 55.6 s (normal 25-34 s), prolonged international normalised ratio at 3.31 (normal <1.1) and low fibrinogen 60 mg/dL (normal >200 mg/dL). Lipid panel showed cholesterol at 114 mg/dL (normal 125-200 mg/dL), triglycerides 207 mg/dL (normal 30-150 mg/dL), high-density lipoprotein cholesterol 10 mg/dL (normal 40-60 mg/dL) and low-density lipoprotein cholesterol 63 mg/dL (normal <100 mg/dL). Other lab abnormalities included elevated ferritin of 6513 ng/mL (normal 10-150 ng/mL) and elevated lactate dehydrogenase of 1071 unit/L (normal 95-240 unit/L). Soluble interleukin-2 receptor alpha level was elevated at 60 727 units/mL (normal 223-710 units/mL). Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed abnormal tracer localisation within the paratracheal, hilar, pelvic, abdominal and subcarinal lymph nodes, along with FDG-PET positive hepatosplenomegaly. A bone marrow biopsy showed hypercellular marrow (95% cellularity) with trilineage haematopoiesis, haemophagocytic cells, polytypic plasmacytosis and T-cell lymphocytosis, along with positive latent membrane protein-1 immunohistochemical staining for EBV. EBV quantitative DNA PCR showed >1 million copies. These findings were consistent with a diagnosis of HLH secondary to EBV infection. Despite intense therapy with the HLH-94 protocol, the patient expired from her illness after a prolonged hospital course.

Effects of chloroquine or hydroxychloroquine treatment on non-SARS-CoV2 viral infections: A systematic review of clinical studies.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used as antiviral agents for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. We performed a systematic review to examine whether prior clinical studies that compared the effects of CQ and HCQ to a control for the treatment of non-SARS-CoV2 infection supported the use of these agents in the present SARS-CoV2 outbreak. PubMed, EMBASE, Scopus and Web of Science (PROSPERO CRD42020183429) were searched from inception through 2 April 2020 without language restrictions. Of 1766 retrieved reports, 18 studies met our inclusion criteria, including 17 prospective controlled studies and one retrospective study. CQ or HCQ were compared to control for the treatment of infectious mononucleosis (EBV, n = 4), warts (human papillomavirus, n = 2), chronic HIV infection (n = 6), acute chikungunya infection (n = 1), acute dengue virus infection (n = 2), chronic HCV (n = 2), and as preventive measures for influenza infection (n = 1). Survival was not evaluated in any study. For HIV, the virus that was most investigated, while two early studies suggested HCQ reduced viral levels, four subsequent ones did not, and in two of these CQ or HCQ increased viral levels and reduced CD4 counts. Overall, three studies concluded CQ or HCQ were effective; four concluded further research was needed to assess the treatments' effectiveness; and 11 concluded that treatment was ineffective or potentially harmful. Prior controlled clinical trials with CQ and HCQ for non-SARS-CoV2 viral infections do not support these agents' use for the SARS-CoV2 outbreak.