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A Jaundiced Eye
John K. Amory, M.D., Henry Rosen, M.D., Chadd Sukut, M.A., Findlay Wallace, M.D., and Sanjay Saint, M.D., M.P.H.
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors commentary follows.

From the Department of Internal Medicine, University of Washington, Seattle ( J.K.A., H.R., F.W.); the University of Washington School of Medicine, Seattle (C.S.); the Ann Arbor Veterans Affairs Health Services Research and Development Center of Excellence, Ann Arbor, Mich. (S.S.); and the University of Michigan Medical School, Ann Arbor (S.S.). Address reprint requests to Dr. Amory at the Division of General Internal Medicine, University of Washington, Box 356429, 1959 NE Pacific St., Seattle, WA 98195, or at jamory@ u.washington.edu. N Engl J Med 2006;354:1516-20.
Copyright 2006 Massachusetts Medical Society.

A previously healthy 27-year-old man presented to his primary care physician six days after the onset of a nonproductive cough, sore throat, and a feeling of being run down. During the preceding week, he had also noted fever and diffuse abdominal pain that was mild to moderate in intensity. Two days before presentation, he noticed dark-colored urine and that his eyes were red and itchy, with a clear, thick discharge. He did not have chest pain, dyspnea, palpitations, headache, nausea, vomiting, diarrhea, dysphagia, urinary frequency or urgency, decreased appetite, or weight loss. The patients initial presentation is consistent with the presence of a viral syndrome such as infection with one of the hepatitis viruses; a member of the herpes group such as cytomegalovirus (CMV), EpsteinBarr virus (EBV), adenovirus, or herpes simplex virus (HSV); or possibly, human immunodeficiency virus (HIV). Hepatotoxic reactions to herbal remedies or drugs also merit consideration. Although the dark urine may simply reflect dehydration, it could also reflect bilirubinuria or hemoglobinuria. Further questions about the patients history should focus on the location, timing, and intensity of the abdominal pain. In addition, information regarding contact with ill persons, sexual history, contact with animals, and recent travel would be useful. The patient denied having any risk factors for HIV infection, including a history of unprotected intercourse, injection-drug use, or receipt of blood transfusions. His medical history was unremarkable. He was not taking any prescription medications but was taking Fat Burner II, an over-the-counter weight-loss supplement that contained milk thistle and N-acetylcysteine for liver health. He had not traveled recently, except for a brief trip to British Columbia, Canada, two months previously. He drank approximately 1080 ml (36 oz) of beer per week and smoked cigarettes rarely. He lived in the Pacific Northwest with his wife and three small children, all of whom were well. He was employed as a trucking manager. His family history was negative for diseases of the liver; he did not use acetaminophen and had not ingested wild mushrooms. The patient received a diagnosis of a viral syndrome and was sent home to rest. On the basis of this patients history, HIV and other sexually transmitted infections, zoonoses, and alcoholic hepatitis are unlikely diagnoses. Milk thistle has no major hepatotoxic effects, and N-acetylcysteine, an agent used to attenuate acetaminophen-mediated hepatotoxicity, is also unlikely to be a factor in his illness. A viral syndrome remains a likely cause of his presentation. At this point, a physical

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examination, an assessment of liver function, a more than 50 percent of the total suggests that determination of blood counts and electrolyte lev- the liver cells can conjugate the pigment, but that els, and a urinalysis should be undertaken. excretion pathways are blocked or dysfunctional. Atypically, there is only a slight increase in the Three days after the initial clinic visit, the patient level of alkaline phosphatase. The ultrasound exbegan to have nausea and vomiting, jaundice, and amination did not show mechanical extrahepatic worsening cough. He returned to the clinic, with obstruction; however, intrahepatic cholestasis rea temperature of 39C, a heart rate of 100 beats per mains a possibility. Ascending cholangitis is a minute, and a blood pressure of 117/85 mm Hg. concern. I would recommend hospitalization, volHis conjunctivae were injected, and his sclerae ume resuscitation, and blood cultures, followed by were markedly icteric. His anterior cervical lymph the administration of antimicrobial therapy directnodes were moderately enlarged. His lungs were ed against the enteric flora associated with asclear on auscultation, with no murmur or addi- cending cholangitis. I am uncomfortable with the tional heart sounds. His abdomen was mildly ten- decision to treat this man empirically with azithroder in the right upper quadrant, but neither hepa- mycin as an outpatient. Diagnostically, analysis of tomegaly nor splenomegaly was found; the rest of blood and urine cultures; serologic testing; polythe examination was normal. Laboratory analysis merase-chain-reaction (PCR) assays of nucleic revealed a white-cell count of 12,400 per cubic acid for CMV, EBV, HSV type 1 (HSV-1) and HIV; millimeter, of which 79 percent were neutrophils, and testing of the peripheral blood for CMV anti15 percent lymphocytes, 3 percent monocytes, gen are in order. 1 percent eosinophils, and 1 percent basophils. The aspartate aminotransferase level was 40 U per Two days later, the patient returned to his primaliter (normal range, 10 to 44), the alanine amino- ry care physician with dyspnea, worsening cough, transferase level 164 U per liter (normal range, 12 and a pruritic rash on both arms. Radiography to 79), the alkaline phosphatase level 155 U per of the chest was repeated and revealed bilateral liter (normal range, 35 to 109), the total bilirubin pulmonary infiltrates. He was referred to the hoslevel 7.1 mg per deciliter (140 mol per liter; nor- pital for further evaluation. On arrival at the mal range, 0.2 to 1.3 mg per deciliter [3.4 to 22.2 hospital, the patient was in mild distress owing mol per liter]), and the conjugated bilirubin to dyspnea. The temperature was 36.7C, the level 4.1 mg per deciliter (70 g per liter; normal pulse 98 beats per minute, the blood pressure range, 0.0 to 0.3 mg per deciliter [0.0 to 5.1 g 106/73 mm Hg, and the respiratory rate 22 breaths per liter]). Serologic tests for hepatitis A, B, and per minute, with an oxygen saturation of 91 perC viruses were negative. Abdominal ultrasonog- cent while he was breathing room air. He had raphy revealed hepatosplenomegaly and possible scleral icterus with mild conjunctivitis. In addition, thickening of the gallbladder wall, but no dilata- shotty anterior cervical lymphadenopathy was tion or obstruction of the biliary ducts. A chest noted. Examination of the lungs revealed faint radiograph was interpreted as normal. A medica- crackles bilaterally. Abdominal examination retion for nausea and an empirical five-day course of vealed mild tenderness in the right upper quadazithromycin were prescribed, and the patient rant. Cutaneous examination revealed a diffuse, was discharged home. macular, erythematous rash that involved the back, arms, and legs but spared the hands and feet. The patient has a fever, with a pulse rate that is There was no asterixis or encephalopathy; the reonly slightly elevated. This pulsetemperature dis- mainder of the examination was normal. sociation, in which the pulse rate is slow relative The results of laboratory studies performed on to the degree of fever, is sometimes observed in admission revealed an elevated white-cell count infections with intracellular pathogens, includ- of 18,200 per cubic millimeter, with 76 percent neuing viruses and certain bacteria. The patient also trophils, 9 percent lymphocytes, 11 percent monohas cholestatic jaundice, but the slight elevations cytes, 3 percent eosinophils, and 1 percent basophils. in the aminotransferase levels do not suggest the The hematocrit was 43 percent, and the platelet count presence of extensive hepatocellular necrosis, as was 253,000 per cubic millimeter. The aspartate may be seen with acute hepatitis A, B, or C. The aminotransferase level was 62 U per liter, the alaobservation that conjugated bilirubin made up nine aminotransferase level 152 U per liter, and

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the alkaline phosphatase level 152 U per liter, and the total bilirubin level had increased to 11.8 mg per deciliter (202 mol per liter). The partial-thromboplastin time was elevated, at 16.6 seconds (normal range, 10.7 to 15.6), and the serum albumin level was 2.9 g per deciliter (normal range, 3.5 to 5.2). Serum levels of amylase, lipase, and electrolytes, and plasma levels of ammonia were normal. A repeated chest radiograph (Fig. 1) revealed bilateral patchy infiltrates. Repeated ultrasound examination revealed mild hepatosplenomegaly and enlarged peripancreatic lymph nodes. A diffuse rash that spares the palms and soles is consistent with the presence of a viral eruption, although a drug-induced eruption should also be considered. The two possible explanations are not mutually exclusive, since viral illnesses sometimes result in diffuse activation of immune responses and may increase the likelihood of drughypersensitivity reactions. A classic example is the measles-like eruption that may occur in patients with mononucleosis in response to ampicillin preparations. Although this patients rash is consistent with measles, his presentation is not typical. However, it would be worth inquiring about his vaccination history. Given the clinical worsening of his condition and the absence of hepatic obstruction on imaging, a liver biopsy may be warranted. If his condition continues to deteriorate, empirical antiviral therapy for HSV-1 with acyclovir should also be considered. The chest radiograph shows diffuse bilateral infiltrates without cavitation, pleural effusion, or mediastinal lymphadenopathy, consistent with the presence of an atypical pneumonia. Infectious causes include many viruses and atypical bacterial pathogens, such as coxiella, chlamydia, legionella, and mycoplasma, although a bacterial infection is unlikely to explain all the extrapulmonary manifestations of the disease in this case. In addition, infection with Pneumocystis carinii should be considered, although the patient has no known risk factors for HIV infection. Blood and urine cultures were obtained. Grams staining of the sputum revealed numerous neutrophils but no microorganisms. Empirical treatment with intravenous levofloxacin and metronidazole was started because of the possibility of cholangitis. Intravenous fluids were also initiated. During the next two days, the rash resolved and

Figure 1. Radiograph of the Chest Revealing a Diffuse Interstitial Process in the Axial and Peripheral Upper and Inferior Lung Zones.

the abdominal pain began to decrease. In addition, the serum bilirubin level began to decrease and the partial-thromboplastin time returned to normal. The results of numerous additional tests were negative, including serologic tests for acute EBV (positive for IgG and nuclear antigen and negative for IgM), HIV, hepatitis A, B, and C viruses, and Mycoplasma pneumoniae; immunostaining for CMV antigen; PCR tests of nucleic acid for HIV, adenovirus, and enteroviruses; direct fluorescent antibody tests for chlamydia and influenza; staining of urine samples, serologic tests, and culture for leptospirosis; viral culture for respiratory syncytial virus; and urinary antigen testing and sputum culture for legionella. In addition, tests for serum ceruloplasmin and antinuclear, anti smooth-muscle, and antimitochondrial antibodies were negative. The patients oxygen saturation decreased, and he required supplemental oxygen to maintain the level above 90 percent. Computed tomography (CT) of the chest revealed bilateral interstitial infiltrates and a small, right-sided pleural effusion. Prednisone (40 mg orally daily) was initiated. The possibility of EBV infection, initially a strong consideration, has nearly been eliminated by results of serologic tests consistent with a history of an old, but not acute, EBV infection. Other viral infections seem less likely, but CMV infection has not been ruled out. Although the antigen test for CMV infection is sensitive and specific in immu-

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nocompromised patients, it has limited sensitivity in an immunocompetent host. Conjunctivitis, lymphadenopathy, hepatitis, and a nonproductive cough can be features of leptospirosis, and the sensitivity of serologic testing varies greatly depending on the point in the infection at which the specimens are obtained, potentially leading to a false negative result early in the infection. The serologic test for legionella infection is species-specific and focuses on Legionella pneumophila, not on other species, which remain possible, if unlikely, culprits. Chlamydia and influenza are less likely, in part, because of their low probability before testing. Negative results of tests for ceruloplasmin, antinuclear antibodies, and antimitochondrial antibodies do not definitively rule out Wilsons disease, autoimmune hepatitis, or primary biliary cirrhosis, respectively; however, these diseases do not adequately explain the other features of this patients presentation. Since pneumonia is associated with inflammatory features in the sputum but no Grams staining of microorganisms, the differential diagnosis should focus on a viral, chlamydial, or mycoplasmal infection, although this patients prior exposure to antibiotics may reduce the likelihood of finding another pathogen on Grams staining. In rare instances, patients with legionella, mycobacteria, fungi, pneumocystis or Coxiella burnetii can present in this way. If the patients respiratory function continued to worsen, I would undertake bronchoscopy, with bronchoalveolar lavage and transbronchial biopsy. The prednisone is unlikely to be harmful when given for a short period, but I am concerned about its use in the absence of a diagnosis. Lastly, the addition of trimethoprim sulfamethoxazole to his regimen to treat a possible infection with pneumocystis should be considered, pending the results of further studies. The patient continued to receive levofloxacin and metronidazole. His bilirubin level had decreased to 5.3 mg per deciliter (91 mol per liter) four days after admission. He was eating normally and was comfortable while breathing room air. Tests for IgM and IgG antibody against CMV in serum samples that had been obtained at admission were reported as positive. Quantitative PCR testing of CMV DNA was also positive, at 100 copies per milliliter. This is a dramatic case of CMV infection. Although

this infection is commonly subclinical or associated with mild manifestations in immunocompetent patients such as this one, it readily explains most of the features of this patients illness, including the lymphadenopathy, hepatic dysfunction, and diffuse pneumonia. On the other hand, conjunctivitis has not been prominent in descriptions of this disorder. The neutrophilic leukocytosis is consistent with the presence of CMV infection, although the absence of atypical lymphocytes is less typical. Fortunately, this patients condition is improving, and he will probably recover fully. As with many herpesvirus infections, CMV becomes latent and usually persists for life, with the potential for reactivation if the patient were to become immunocompromised. One month after discharge, the patients health was greatly improved and he had returned to fulltime employment. Laboratory assessment revealed complete normalization of liver-function abnormalities (bilirubin, 1.5 mg per deciliter [27 mol per liter]; aspartate aminotransferase, 19 U per liter; and alanine aminotransferase, 13 U per liter) and a white-cell count of 7400 per cubic millimeter, with 51 percent lymphocytes and a few atypical lymphocytes on microscopical examination.

C om men ta r y
In this case, the discussant correctly focused on ruling out an infectious cause for this acute, multisystem presentation of a disease in an otherwise healthy young man. Ultimately, this patient was found to have an uncommonly severe illness caused by a common organism, CMV. In making the diagnosis, the discussant placed weight on the most important features of the patients presentation, such as the fever and lymphadenopathy, and was not overly distracted by anomalous findings such as the conjunctivitis, which is infrequently associated with CMV infection. Infection with CMV can be manifested in various ways. In immunocompromised patients, especially transplant recipients and those infected with HIV, CMV can cause substantial rates of complications and death. Acute infection in the immunocompetent host is usually asymptomatic or produces only mild symptoms.1 Between 40 and 90 percent of the adult general population has had prior infection with CMV. When a pa-

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tient with CMV infection comes to medical attention, the presentation is usually similar to that of infectious mononucleosis. In a small number of patients, manifestations of acute CMV infection are severe and associated with organ dysfunction and even death in some instances.2,3 Although in immunocompetent adults, CMV infection is often confused with EBV infection, there are some notable differences. The typical patient with symptomatic CMV infection is older than 30 years of age, whereas the peak incidence for EBV infection occurs between 15 and 20 years of age.4 In addition, the usual duration of fever with CMV infection is much longer than with EBV-related mononucleosis.5 Sore throat is a frequent symptom in patients with either type of infection, but pharyngeal exudates and lymphadenopathy are less common in adults with CMV infection than in those with EBV infection.4 Elevations of the peripheral white-cell count are uncommon in patients with CMV infection. Although atypical lymphocytes are often present in cases of either CMV or EBV infection, the appearance of atypical lymphocytes in CMV infection may be delayed for several weeks, as appeared to happen in this case, and may persist for months.2 During the course of CMV infection in many patients, a rash develops that has been described variably as macular, papular, morbilliform, and scarlatiniform. Exposure to ampicillin or ampicillin-related beta-lactam antibiotics has been associated with the development of a rash in patients with CMV mononucleosis,6 just
References 1. Gandhi MK, Khanna R. Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments. Lancet Infect Dis 2004;4:725-38. 2. Cohen JI, Corey GR. Cytomegalovirus infection in the normal host. Medicine (Baltimore) 1985;64:100-14. 3. Horwitz CA, Henle W, Henle G, et al. Clinical and laboratory evaluation of cytomegalovirus-induced mononucleosis in previously healthy individuals: report of 82 cases. Medicine (Baltimore) 1986;65: 124-34.

as in those with EBV mononucleosis.7 Liver-function abnormalities are often found in patients with symptomatic CMV infection; mild transaminitis is the most common. In this case, some atypical features of CMV infection may have increased the difficulty of finding the correct diagnosis. Frank jaundice is seen in only about 10 percent of patients with acute CMV infection,2 and CMV pneumonia is also uncommon. Whereas CMV retinitis is well described in patients with advanced HIV infection, other ocular symptoms associated with CMV infection are uncommon. In contrast to the high sensitivity of testing for CMV antigen in immunocompromised patients, the sensitivity of the CMV antigen test in immunocompetent patients with such an infection is only about 50 percent. In addition, the number of viral copies in immunocompetent patients is typically low. Absolute levels of CMV DNA do not correlate with the severity of the clinical disease.8 This case vividly illustrates the presentation of CMV infection as a severe multisystem disorder in a previously healthy host. This case demonstrates that to make the correct diagnosis, the experienced clinician must occasionally view uncharacteristic findings with suspicion or through a jaundiced eye to avoid erroneously ruling out the correct diagnosis.
Dr. Amory reports having received research funding from Schering and GlaxoSmithKline and consulting fees from GlaxoSmithKline. No other potential conflict of interest relevant to this article was reported.

4. Evans AS. Infectious mononucleosis

and related syndromes. Am J Med Sci 1978; 276:325-39. 5. Porath A, Schlaeffer F, Sarov I, Keynan A. Cytomegalovirus mononucleosis: a report of 70 patients in a community hospital. Isr J Med Sci 1987;23:268-73. 6. Kano Y, Shiohara T. Current understanding of cytomegalovirus infection in immunocompetent individuals. J Dermatol Sci 2000;22:196-204. 7. Pullen H, Wright N, Murdoch JM. Hypersensitivity reactions to antibacterial

drugs in infectious mononucleosis. Lancet 1967;2:1176-8. 8. Revello MG, Zavattoni M, Sarasini A, Percivalle E, Simoncini L, Gerna G. Human cytomegalovirus in blood of immunocompetent persons during primary infection: prognostic implications for pregnancy. J Infect Dis 1998;177:1170-5.
Copyright 2006 Massachusetts Medical Society.

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