Today we'll be following the thought process of a primary care physician as she works her way through the list of possible diagnoses for a prolonged unexplained fever. When this 19 year old college athlete and pre med student fell ill and developed a fever soon after his first sexual encounter, he began to fear the worst. Joel came into the university health care center with a three-week history of elevated temperature, swollen lymph nodes, and fatigue. The nurse who recorded his vital signs measured a temperature of 102.9 degrees Fahrenheit, 39.4 degrees Celsius. And as he waited for the physician to enter the examining room, his mind raced with the results of his recent searches. He had read that prolonged fever and swollen lymph nodes could be caused by infections like HIV. Four weeks ago Joe had sexual intercourse, for the first time with a student he'd met at an athletes' social. He'd been increasingly worried that he'd contracted HIV, and this concern finally brought him into the clinic. When the physician entered the room, she came in with her own set of ideas about what was most likely causing Joel's fever. Many of the college students she saw with this presentation were suffering from an infection with Epstein-Barr virus. The virus often causes infectious mononucleosis, or mono for short in young adults. Infection with EBV usually occurs via the oral transfer of saliva. If the virus is able to avoid clearance by the mucosal barriers, it can then colonize the epithelium over the tonsils where it replicates before infecting the B cells in the tonsils. The virus preferentially replicates inside B cells, which can then leave the tonsils, enter the lymphatic circulation, and spread the virus to other lymphoid tissues. The virus silently spreads until antigen presenting cells stimulate CD8 positive T cells which find and kill infected B cells. The resulting proliferation of these CD8 positive T cells along with the release of cytokines leads to the systemic signs and symptoms of EDV infection, including the fever and swollen lymph nodes. Other non-infected B cells also respond to the infection and differentiate into plasma cells that produce antibodies to the virus. So EBV was at the top of the physician's preliminary differential diagnosis when she entered the examination room to meet Joel. Although she knew she needed to keep in mind the other major ideologies associated with fever of unexplained origin or FUO. Other infections can cause these symptoms and so can cancer and autoimmune conditions. So her task during the history taking was to look for clues for other etiologies. She discovered that Joel had been healthy up until the last three weeks, when he began to have a mild sore throat, headache, and fevers. She also asked him if he'd noticed any skin rashes, because she knew that many viral infections can cause rashes and that hematological malignancies can present with petechiae. He remembered seeing a few unusual red spots on his trunk and upper extremities, but they had since disappeared. The differential diagnosis would be different if he'd recently returned from travel abroad, so she also asked about travel. But Joel hadn't traveled anywhere recently, or been around any sick friends or relatives. He also wasn't taking any medications or recreational drugs. The physician knew that with chronic illnesses like cancer, tuberculosis, and autoimmune diseases, he may have other signs like weight loss but Joel's weight had remained stable and he had no family history of autoimmune disorders. During the sexual history Joel reluctantly revealed to the doctor his recent, first sexual encounter. And his fears about having contracted HIV. She needed to get more explicit information to consider high risk situations for HIV. So she took a thorough sexual history. During this part of the history, Joel told her that this had been his first and only sexual partner, a female student whom he'd recently met and he hadn't used a condom or any other form of protection during intercourse. He denied any symptoms that are commonly associated with sexually transmitted infections, including painful urination or discharge. On examination, the physician found multiple bilateral tender mobile lymph Lymph nodes in the cervical and axillary regions. Joe's throat was also slightly red or arsempatis. In the abdominal exam she could feel the type of Joe's spleen consistent with splenomegaly although his liver felt normal. She examined Joe's skin for pallor, petechia, or other rashes and saw none. Joel's joints didn't appear to be painful or swollen and his genital exam was normal. Given Joel's age and the history of sore throat, rash, headache, and fatigue as well as his lymphadenopathy and splenomegaly, the physician decided to conduct several investigations including a complete blood count with differential in platelets. This will let her look for abnormality from the blood and platelet counts that could reflect a malignancy and the CBC might also reveal atypical lymphocytes which are the deactivated CDA positive T cells that respond to EVV. She ordered a mono spot test, also called a heterophile antibody test, which would be consistent with EBV infection. But since she was also considering other viral infections and the mono spot test is non specific, she also ordered EBV serology. Because the symptoms of HIV mimic certain viral infections, she decided to order an HIV antibody test and an HIV PCR test as well. The physician told Joel that these tests would help her figure out what was causing his fevers. Although HIV was possible, there were other relatively benign illnesses that could explain his symptoms for example, EBV infection. She didn't want to alarm him with the possibility of cancer, so she didn't mention a malignancy as a possible diagnosis. Instead she advised Jule to take antipyretic medications to control his fever as necessary, to remain well hydrated by drinking plenty of fluids, and to refrain from doing any gymnastics until a diagnosis had been confirmed. The spleen is an encapsulated lymphoid organ that when enlarged is at risk for rupture if exposed to blunt trauma, including the trauma that can occur during sporting events. Two days later Joel's test results returned and the physician called him to schedule a follow up appointment with her as soon as possible. He returned the following morning to receive his diagnosis.