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Miss Chan was a 22 years old lady, a clinic clerk who was admitted to the Medical Unit of Queen Elizabeth Hospital on 15th May, 2010 with one week history of fever, sore throat, fatigue and epigastric discomfort. There was no cough, runny nose, chest pain or shortness of breath. Other abdominal and urinary symptoms were absent. There was no yellow discoloration of skin, dark urine or pale stool. She also complained of yellow vaginal discharge for 2 days.
She enjoyed unremarkable past health with no regular medications but had history of intake of seven doses of herbal medicine for general health in late April, 2010. Last dose was received on 23rd April, 2010. She did not smoke or drink and lived alone with no pet adopted. Hepatitis status was unknown. Suspicious food intake was absent. There was no piercing, tattooing, injection drug use or needle sharing. She had history of unprotected sexual intercourse before the onset of her illness with the same stable partner. Last menstrual period was 24th April, 2010 with normal menses. There was no history of recent travel or contact with sick persons.
On physical examination, she was hemodynamically stable with satisfactory oxygen saturation and low-grade pyrexia (37.6oC). There was no jaundice or pallor. The throat was mildly congested with no palatal petechaie or oral ulcer. Bilateral shotty tender cervical lympadenopathy was detected without enlarged axillary or groin lymph nodes. Chest, cardiovascular and neurological examinations were unremarkable. Abdomen was soft and non-tender with no peritoneal sign or hepatosplenomegaly. Per rectal examination showed no mass or melena. There was no skin rash or joint swelling. Gynecological assessment indicated an uncomplicated vaginal discharge with no ano-genital lesion or ulcer. Bedside pregnancy test was negative.
Laboratory investigations showed leucocytosis (12.7 x 109/L) with an absolute lymphocytosis (6.6 x 109/L) (52% of the total white cell count) and 17% atypical lymphocytosis and mild thrombocytopenia (103 x 109/L). Liver function test showed anicteric hepatitic pattern of deranged liver function (total bilirubin 9 umol/L, ALP 191 IU/L, ALT 461 IU/L, AST 444 IU/L, GGT 246 IU/L) with normal clotting profile. Chest X-ray showed no definite consolidation and abdominal X-ray was unremarkable. Nasopharyngeal aspirate grew no respiratory virus and blood culture yielded no growth. HAV IgM, HBsAg, anti-HCV, monospot test were all negative. Abdominal ultrasound revealed normal liver with no splenomegaly. The herbal formula was sent to Hong Kong Poison Information Center for interpretation commented that one of the drug was a well-known hepatotoxic herb and the dosage used was within the therapeutic range and urine toxicology detected no herbal markers in the urine sample.
The clinical picture was compatible with heterophile negative infectious mononucleosis-like syndrome supported by laboratory findings. She was assessed by infectious disease team and managed with supportive treatment with adequate fluid, anti-pyretic and throat lozenges. Special serology tests suggested showed positive EBV (Epstein-Barr virus) VCA (Viral Capsid Antigen) IgM and negative EBV VCA IgG [with negative CMV (cytomegalovirus) IgM and anti-HIV (human immunodeficiency virus)] which confirmed the diagnosis of heterophile negative infectious mononucleosis caused by EBV. Symptoms improved with defervescence of fever and improvement of liver functions upon discharge.
During follow-up in Medical Specialist Out-Patient Clinic, her symptoms completely subsided with resolution of cervical lymphadenopathy and normalization of liver function. Repeated EBV serology showed negative EBV VCA IgM and positive EBV VCA IgG with negative repeated anti-HIV serology.
In summary, Miss Chan was a 22 years old young lady who presented with classical triad of fever, pharygnitis and lymphadenopathy of infectious mononucleosis supported by atypical lymphocytosis and positive EBV VCA IgM serology.
Infectious mononucleosis is a clinical syndrome associated with primary EBV infection. EBV is a herpes virus with a double-stranded DNA genome. Natural EBV infection occurs only in humans and results in life-long infection. Over 95% of adults worldwide will eventually acquire EBV developing latent infection of B-lymphocytes. Mononucleosis-like illnesses are similar presentations caused by other processes.
Our patient illustrates a common presentation of primary infection of infectious mononucleosis in young adults. Although flu-like symptoms are common in adults, infectious mononucleosis should be suspected in adolescents and young adults (10 to 30 years of age) who present with fever, pharyngitis and lymphadenopathy. It is because in developed countries like Hong Kong and higher socio-economic groups, primary EBV infection is shifted to later ages. Due to improvement in economic and sanitary conditions over past decades, EBV infection in early childhood become less common and more children are susceptible as they reach adolescence and early adulthood. 50-74% develop symptoms consistent with infectious mononucleosis in adolescence and early adulthood. On the contrary, in developing countries and lower socioeconomic groups, most EBV infections occur in early childhood (1 to 5 years of age). Primary infections in young children are often asymptomatic and typical symptoms of infectious mononucleosis are uncommon. The risk of developing symptomatic infection drops 100 fold by age 35 or older.
Classical clinical features of infectious mononucleosis include fever, sore throat, lymphadenopathy, which typically begin after a 4- to 7-week incubation and often heralded by a 3- to 5- day prodrome of non-specific symptoms. Common symptoms and signs include lymphadenopathy (anterior and posterior cervical, auricular or generalized) (94%), pharygnitis (84%), malaise (82%), fever (76%) and splenomegaly (52%). Less common symptoms and signs include myalgia (20%), hepatomegaly (12), rash (macular, petechial, scarlatiniform, urticarial, erythema multiforme) (10%), jaundice (9%), arthralgia (2%).
Laboratory evidence shows atypical lymphocytosis (>10% total leucocytes) (90%), mild transaminitis (2-3x normal) (90%), heterophile positive (85-90%), lymphocytosis (70%) and mild thrombocytopenia (25-50%).
In infectious mononucleosis, liver involvement is usually mild and resolves spontaneously. Typically, mild transaminitis is noted consistent with parenchymal injury rather than cholestatic liver disease due to decreased bile flow. Hyperbilirubinemia and jaundice are uncommon. In our patient, the anicteric hepatitic pattern of impaired liver function is more likely to be contributed by infectious mononucleosis than herbs-induced hepatitis because of the classical presentation of infectious mononucleosis and prolonged period between last dose of herbs and clinical presentation.
Hoaglandâ€™s criteria are the most widely cited diagnostic criteria for infectious mononucleosis: at least 50% lymphocytes and at least 10% atypical lymphocytes in the presence of fever, pharyngitis and lymphadenopathy and confirmed by a positive serological test. In patients with clinically suspected infectious mononucleosis, >50 lymphocytosis and >10% atypical lymphocytosis has 61% sensitivity and 95% specificity whereas heterophile antibody test has 71-95% sensitivity and 82-99% specificity and antibodies to VCA and EBNA (Epstein-Barr nuclear antigen) have 95-99% sensitivity and 89-99% specificity.
The differential diagnoses of infectious mononucleosis (primary EBV infection) include mononucleosis-like illnesses caused by non-EBV viral etiologies [primary infection with CMV, human herpes virus 6 (HHV-6), HIV], bacterial infections (Streptococcus pyogenes) and protozoal causes (Toxoplasma gondii). A systemic approach is essential to detect the etiological cause. Besides comprehensive history and physical examination, an algorithm is suggested to guide laboratory diagnosis. Patients with clinical picture compatible with infectious mononucleosis should first include heterophile antibody test. If positive, it is highly suggestive of infectious mononucleosis caused by EBV but does not exclude the possibility of other infections such as HIV. If negative, a complete blood picture with automated differential is helpful. Marked lymphocytosis (more than 50% of total leucocytes) with atypical lymphocytosis at least 10% in Hoaglandâ€™s criteria suggests heterophile-negative infectious mononucleosis caused by EBV. Specific serology for EBV VCA antibodies or repeated heterophile antibody test should be sent for confirmation. If negative, serological tests for CMV and HHV-6 should be checked for two other main viral etiologies. Negative results should prompt a reassessment of patientâ€™s history and symptoms for other less common diagnosis (such as toxoplasmosis, other viral pharyngitis and non-infectious causes) and appropriate testing.
Like in our patient, she presented with classical features of infectious mononucleosis. However, the heterophile antibody test (monospot test) is negative. Complete blood picture with differential shows marked lymphocytosis and atypical lymphocytosis. So, specific serological tests are done to determine the etiological agent which show positive EBV VCA IgM and negative CMV IgM. As a result, the diagnosis of heterophile-negative infectious mononucleosis caused by EBV is made. Moreover, in view of risk factors of acute HIV infection (sexually active and history of unprotected sexual intercourse), she is also screened for anti-HIV tests which are negative.
Infectious mononucleosis is usually self-limited. The mainstay of treatment is supportive care including adequate hydration and nutrition, acetaminophen, non-steroidal anti-inflammatory agents for fever and myalgia; throat lozenges or sprays or gargling with a 2% lidocaine solution to relieve sore throat.
Specific treatment has a limited role and is not recommended for routine treatment of infectious mononucleosis. Anti-viral therapy is not recommended. Randomized controlled trials showed that acyclovir had a transient reduction in oropharyngeal shedding at the end of therapy but provided no significant or consistent clinical benefit. Corticosteroids are not indicated for uncomplicated infectious mononucleosis because of insufficient evidence but may be helpful in the management of severe complications like severe pharyngeal edema with respiratory compromise, hemolytic anemia and thrombocytopenia.
Serious complications of infectious mononucleosis are rare and usually come after the onset of the illness. Complications include
Fatigue, mylagia and need for sleep may persist for several months after the acute infection has resolved. But the majority of patients will recover without sequelae and return to normal activities within two months after the onset of symptoms. Splenic rupture is the widely feared complication of infectious mononucleosis but the risk is estimated at 0.1% only and most splenic ruptures reported have occurred three weeks after diagnosis. These data suggest that atheletes with infectious mononucleosis are advised not to participate in contact or collision sports for a minimum of three to four weeks after the onset of symptoms and until they are asymptomatic. The above information and advice can be given to our patient before discharge.