A Young Woman with Fever, Headache, and Lymphadenopathy

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A SELF-TEST IM BOARD REVIEW DAVID L. LONGWORTH, MD, JAMES K. STOLLER, MD, EDITORS ON A CLINICAL ROY F. CHEMALY, MD SUSAN J. REHM, MD Department of Infectious Disease, Department of Infectious Disease, CASE Cleveland Clinic Cleveland Clinic

A young woman with fever, headache, and lymphadenopathy

33-YEAR-OLD Hispanic woman was no sexual contact in the preceding 8 A admitted from the emergency depart- months. She had not traveled recently and ment with a 5-day history of headache, fever, had no history of intravenous drug use. She rash, and neck pain. Her symptoms started was a student who recently began a part- when she woke up with severe retro-orbital time job as a nurse assistant in a nursing headache, photophobia, and a fever (temper- home. ature 40˚C, 104˚F). She was seen in an emergency department the following day, where a Physical examination lumbar puncture and a computed tomogra- On admission, physical examination revealed phy (CT) scan of the head were performed an ill-appearing woman in mild acute distress. and were reportedly normal. The next day Her temperature was 37.2˚C (98.9˚F), blood she noticed a generalized maculopapular rash pressure 113/66 mm Hg, heart rate 111 beats and pain on the right side of her neck. On per minute, and respirations 20 per minute. A the 5th day, she was admitted through the generalized maculopapular rash was present, emergency department because her symp- and right-sided anterior and posterior cervical toms persisted. lymph nodes were large and tender on palpa- Her past medical history was significant tion. Smaller, tender left anterior cervical for migraine headache, depression, and an lymph nodes were also noted. There was no abnormal Papanicolaou smear. She had meningismus. The remainder of the physical undergone a cone biopsy of the cervix a few examination was normal. months earlier. She denied any history of sexually transmitted diseases and had had Additional testing Additional test results were as follows: • White blood cell count 2.02 × 109/L (normal range 4.0–11.0) with 70% granulo- cytes, 15% lymphocytes, 10% monocytes, 4% eosinophils, and occasional reactive lymphocytes • Hemoglobin concentration 11.6 g/dL (normal range 12.0–16.0) • Platelet count 105 × 109/L (normal range 150–400) • Bone marrow biopsy revealed hypocellu- larity and no neoplastic cells • Alkaline phosphatase 93 U/L (normal range 20–120) • Aspartate aminotransferase 183 U/L (nor- FIGURE 1. CT scan of the neck showing an increased number mal range 7–40) of lymph nodes with central necrosis in the right posterior • Total bilirubin 0.6 mg/dL (normal range triangle (arrow). 0–1.5).

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T ABLE 1 ■ THE DIFFERENTIAL DIAGNOSIS

Differential diagnosis of Which condition or conditions should be infectious mononucleosis- 1 included in the differential diagnosis of like syndrome this patient’s illness? Infectious causes ❑ Infectious mononucleosis Viral ❑ Epstein-Barr virus Toxoplasmosis Human immunodeficiency virus ❑ Cytomegalovirus infection Cytomegalovirus ❑ Acute retroviral syndrome Human herpesvirus 6 ❑ All of the above Bacterial Meningococcemia This case illustrates many of the important Salmonella bacteremia features of the infectious mononucleosis-like Streptococcal tonsillopharyngitis syndrome (IMLS) in an adult, which can be Bartonellosis (cat-scratch disease) caused by all of the above. The constellation Brucellosis of symptoms includes fever, rash, headache, Yersiniosis and lymphadenopathy. Rash and pharyngitis Tuberculosis are frequent. Severe cases may be associated Tularemia with meningitis, hepatitis, or transverse Spirochetal myelitis. IMLS is typically caused by acute Syphilis Epstein-Barr virus infection, but other herpes- Leptospirosis viruses and a variety of other infectious and Lyme disease noninfectious processes may present with the Parasitic same symptoms (TABLE 1). Toxoplasmosis Acute Epstein-Barr virus syndrome (infec- Malaria tious mononucleosis) most commonly affects Exudative Trichinosis young adults from 15 to 35 years of age. The diagnosis is established by accurate assessment tonsillitis with Noninfectious causes Rheumatic diseases of clinical, hematologic, and serologic mani- posterior Systemic lupus erythematosus festations of the illness. The presence of cervical Kawasaki syndrome exudative tonsillitis with posterior cervical Kikuchi disease adenopathy suggests Epstein-Barr virus infec- adenopathy Juvenile rheumatoid arthritis tion. suggests Neoplastic and paraneoplastic diseases Lymphoma The most valuable test to diagnose infec- EB virus Angioimmunoblastic lymphadenopathy 2 tious mononucleosis at presentation is: Castleman lymphadenopathy ❑ Immunoglobulin G (IgG) antibody Drugs against Epstein-Barr viral capsid antigen Phenytoin ❑ Antibodies against Epstein-Barr virus Sulfonamides Dapsone early antigen ❑ Antibodies against Epstein-Barr virus Other nuclear antigen Sarcoidosis ❑ Heterophile antibodies

Heterophile antibodies may be demonstrable Because of significant cervical adenopathy at the onset of illness or may appear later in on admission, a CT scan of her neck was done the course of the illness, and therefore are the and showed multiple small reactive and most valuable test to diagnose infectious necrotic lymph nodes on the right side of the mononucleosis. Commercial spot tests are neck (FIGURE 1). generally sensitive and specific for the

586 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 7 JULY 2001 Downloaded from www.ccjm.org on October 2, 2021. For personal use only. All other uses require permission. demonstration of heterophile antibodies. phadenopathy and other features, including False-positive infectious mononucleosis slide atypical lymphocytes. Chorioretinitis is a dis- tests have been reported in patients with lym- tinguishing feature of toxoplasmosis, since it phoma or hepatitis. A determination of does not occur in IMLS. Epstein-Barr virus-specific antibodies is rarely Malaria. Clinical manifestations of malar- necessary for the diagnosis, because 90% of ia include many symptoms that also occur in the cases are heterophile-positive. For the IMLS, such as fever, shaking chills, headache, heterophile-negative cases and for the diag- myalgia, and arthralgia. The lack of lym- nosis in atypical cases, a determination of phadenopathy, pharyngitis, and atypical lym- Epstein-Barr virus antibodies may help to phocytes on a peripheral blood smear in establish a cause. The most valuable serolog- patients with malaria distinguishes it from ic finding is the presence of IgM antibody to IMLS. Epstein-Barr viral capsid antigen, which is Bacterial infections. A number of bacteri- found during acute primary Epstein-Barr virus al infections can present with symptoms resem- infection. Serum antibodies to Epstein-Barr bling IMLS. Streptococcal tonsillopharyngitis, virus early antigen and nuclear antigen peak mainly with group A streptococcus, can mimic 3 to 4 weeks after onset of infection. This IMLS in its clinical features. However, syndrome is considered a self-limited illness, splenomegaly and generalized adenopathy are but it may result in serious complications, absent in streptococcal tonsillopharyngitis. A such as splenic rupture. direct throat antigen test that is specific for Cytomegalovirus infection is the most group A streptococcus has proven to be useful common identifiable cause of heterophile- in diagnosing this infection. negative IMLS. One distinguishing feature of Enteric fever (most often caused by cytomegalovirus infection is the absence of Salmonella typhi) is worth mentioning, because tonsillopharyngeal exudate, which is com- some of its common features were seen in our monly seen in patients with Epstein-Barr patient—ie, pancytopenia, maculopapular virus-related pharyngitis. The diagnosis of rash on the trunk, and cervical adenopathy. cytomegalovirus mononucleosis-like syn- The diagnosis usually is made by blood cul- Several drome is established by identification of an ture, stool culture, or both. Furthermore, pan- bacterial IgM-specific antibody or demonstration of a cytopenia is sometimes seen with any over- fourfold increase in cytomegalovirus-IgG anti- whelming bacterial infection but is also seen infections have body. with viral infection. symptoms Up to 90% of patients with primary Cat-scratch disease (bartonellosis) usually human immunodeficiency virus (HIV) causes regional adenopathy without pharyngi- resembling infection may experience IMLS as they sero- tis, but the oculoglandular form (Parinaud infectious convert. The prognosis may be worse if the oculoglandular syndrome) may resemble symptoms persist longer or are more severe IMLS. mononucleosis- or if the HIV viral load is higher at the time Other bacterial infections (ie, brucellosis, like syndrome of seroconversion. The diagnosis of HIV meningococcemia, chlamydial and spiro- should be considered in any patient who chetal infection) can mimic IMLS and the experiences an acute infectious illness that diagnosis is usually established by serology or cannot be explained by common infectious cultures. causes, regardless of the patient’s HIV risk factors. Noninfectious conditions that mimic IMLS Noninfectious disorders such as autoimmune ■ CONDITIONS THAT MIMIC IMLS disorders and lymphoreticular neoplasms can also cause signs and symptoms mimicking Infections IMLS. However, systemic lupus erythemato- Toxoplasmosis. Infection by certain para- sus, lymphoma, and other vasculitides have a sites can mimic IMLS. Only 15% of patients longer duration of symptoms and a subacute with primary infection with Toxoplasma gondii onset, which help distinguish them from have symptoms, often with cervical lym- infection.

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 7 JULY 2001 587 Downloaded from www.ccjm.org on October 2, 2021. For personal use only. All other uses require permission. T ABLE 2 The patient’s serologic tests on admission

SEROLOGIC TEST RESULTS INTERPRETATION

Human immunodeficiency virus (HIV) Negative ELISA* Negative screening test for HIV Cytomegalovirus titers IgG positive, IgM negative Previous exposure Infectious mononucleosis slide test Negative No heterophile antibodies detected Epstein-Barr virus titers (viral capsid antigen, nuclear antigen) IgG positive, IgM negative Previous exposure Parvovirus titers IgG positive, IgM negative Previous exposure Toxoplasma titers IgG negative, IgM negative No acute or prior infection Human herpesvirus 6 titers† (total IgG/ IgM antibodies) 1:80 Positive titers Hepatitis B, C (remote and acute panel) Negative‡ No acute infection Bartonella henselae titers IgG positive, IgM negative Previous exposure Rapid plasma reagin Nonreactive Negative screening test for syphilis

*Enzyme-linked immunosorbent assay †To document an acute viral infection, a fourfold increase in titers should be observed; convalescent titers of HHV-6 were 1:320 ‡Hepatitis B surface antibody was positive, consistent with immunity to hepatitis B

The mode of HHV-6 Kawasaki syndrome can also mimic IMLS. departments for febrile illness in children It presents with prolonged fever and a poly- between 6 and 12 months of age, and it is the transmission is morphic exanthem. Although Kawasaki syn- commonest cause of fever-induced seizures in not yet known drome has been reported in a few adults, it is children under 2 years of age.2 HHV-6 has overwhelmingly a disease of children, particu- been identified as the etiologic agent of larly children of Asian ancestry. exanthem subitum (6th disease, roseola Finally, drugs such as phenytoin, sulfon- infantum) in infants. amides, and dapsone can produce a syndrome The clinical syndrome is fever followed by that mimics IMLS. a maculopapular rash after the temperature Multiple serologic tests were obtained and normalizes. In addition to nonspecific febrile the results are shown in TABLE 2. The results illness and otitis, the most frequent clinical indicated prior exposure to a number of virus- symptoms are upper respiratory tract or gas- es and current infection with human herpes- trointestinal involvement.3 virus 6 (HHV-6). Modes of transmission ■ HUMAN HERPES VIRUS 6 The exact mode of transmission has not yet INFECTION IN ADULTS been determined. Because HHV-6 is shed in saliva and urine, some postulate that these are Our patient illustrates the course of primary the likely sources of transmission.4 HHV-6 HHV-6 infection in an adult. HHV-6 was actively replicates in the salivary glands, stays first isolated in 1986 by Salahuddin et al.1 latent in at least lymphocytes and monocytes, HHV-6 infection is often asymptomatic or and persists in various tissues.5 Complications minimally symptomatic, but it accounts for of primary HHV-6 infection in children are approximately 20% of visits to emergency uncommon.

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Rare in adults cence testing. This technique has a reported Primary HHV-6 infection is rare in adults sensitivity and specificity of 86% and 100%, because more than 90% of people seroconvert respectively, for specimens from solid organ during childhood. In immunocompetent transplant recipients, but it is not routinely per- adults who are seronegative, HHV-6 infection formed in clinical laboratories. may present as a mononucleosis-like illness Serologic testing is helpful in diagnosing with negative tests for Epstein-Barr virus and HHV-6 infection if a seroconversion can be cytomegalovirus. These patients present with demonstrated for IgG from negative to posi- fever, lymphadenopathy, and hepatitis or tive. Clinicians should be aware that a single encephalitis. Furthermore, HHV-6 has been high IgG antibody titer represents previous implicated as a cause of other diseases such as exposure and that at least 90% of adults are Kikuchi lymphadenitis, a type of necrotizing seropositive. A fourfold increase in IgG anti- lymphadenitis,6 or associated with other dis- body detected by immunofluorescence sug- eases such as multiple sclerosis. gests infection, but the distinction between The findings on CT scan of the neck in primary infection and reactivation may be dif- our patient were described as “small reactive ficult. lymph nodes with necrotic center,” which led Qualitative polymerase chain reaction to concern about possible suppurative lym- testing for HHV-6 is probably the most sensi- phadenitis on admission. Sumiyoshi et al7 tive and specific means of documenting pri- found HHV-6 DNA in the lymphocytes of a mary infection. Ideally, to distinguish primary young woman with acute HHV-6 infection. infection from reactivation, a quantitative technique (viral load) should be used, but Immunocompromised patients at risk these techniques are still investigational. In contrast, HHV-6 infection or reactivation has been recognized as a cause of severe illness Which of the following would be the in immunocompromised adults, namely bone 3 appropriate therapy for HHV-6 in this marrow or solid organ transplant recipients patient? Diagnosis and HIV-infected patients. In these patients, ❑ of HHV-6 HHV-6 infection or reactivation may result in Start oral acyclovir bone marrow suppression, pneumonitis, ❑ Start oral ganciclovir infection is encephalitis, hepatitis, fever, skin rash, and ❑ Start intravenous acyclovir ❑ based on viral possible reactivation of other herpesviruses, Start intravenous ganciclovir especially cytomegalovirus. It may also com- ❑ None of the above culture, plicate engraftment of the transplanted organ serology, and and lead to rejection and death.5 In HIV- The in vitro susceptibility data for HHV-6 infected patients, HHV-6 infection or reacti- show that acyclovir is inactive against the polymerase vation has indirect effects on HIV replication. virus and that the response to ganciclovir is chain reaction It has been speculated that HHV-6 acts as a variable. The effectiveness of these antivirals cofactor in the progression of AIDS. in treating selected patients with severe testing HHV-6 infection (eg, those with encephalitis ■ TESTING FOR HHV-6 or post-transplant pneumonia) has not been established. The diagnosis of HHV-6 infection is based on There is no specific treatment for HHV-6 viral culture, serology, and polymerase chain itself. Symptomatic therapies for fever, reaction. headache, and other symptoms are appropri- Viral culture is the gold standard method ate. for detecting HHV-6 in peripheral blood mononuclear cells. Inoculated cell cultures are ■ CLINICAL COURSE AND FOLLOW-UP examined 5 to 7 days after infection, looking for specific cytopathic effects, and immunolog- For 2 days, the patient received broad-spec- ic confirmation is carried out by immunofluo- trum antibiotics for possible suppurative lym- rescence or anticomplement immunofluores- phadenitis. Her fever persisted during the

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antibiotic therapy but slowly subsided on the 5th day after admission. The rash disappeared and the cervical lymph nodes became smaller and less tender. The headache and photophobia persisted for a week; she was discharged after these symptoms resolved. At the time of her follow-up appoint- ment in the outpatient department 3 weeks later, the patient’s symptoms and signs had completely resolved. Viral titers were repeated, revealing a fourfold increase in the serum HHV-6 IgG titer, from 1:80 to 1:320. The presence of HHV-6 was con- firmed by polymerase chain reaction on a serum specimen taken from the patient on admission.

■ LESSONS LEARNED

HHV-6, a herpesvirus first described 14 years ago, is a rare but important cause of IMLS in non-immunocompromised adults. IMLS in adults is a frequent cause of visits to physician’s offices and emergency departments; patients with severe manifestations of disease may be hospitalized for evalu- ation and therapy. The differential diagnosis of IMLS is broad, encompassing a variety of infections, neoplasms, and immunologic disorders.

■ REFERENCES

1. Salahuddin SZ, Albashi DV, Markham PD, et al. Isolation of a new virus, HBLV, in patients with lym- phoproliferative disorders. Science 1986; 234:596–601. 2. Hall CB, Long CE, Schnabel KC, et al. Human herpesvirus-6 infection in children. A prospective study of complications and reactivation. N Engl J Med 1994; 331:432–438. 3. Dockrell DH, Smith TF, Paya CV, et al. Human herpesvirus 6. Mayo Clin Proc 1999; 74:163–170. 4. Levy JA, Ferro F, Greenspan D, et al. Frequent isolation of HHV-6 from saliva and high seroprevalence of the virus in the population. Lancet 1990; 335:1047–1050. 5. Campadelli-Fiume G, Mirandola P, Menotti L. Human herpesvirus 6: an emerging pathogen. Emerging Infect Dis 1999; 5:353–366. 6. Bhat NA, Hock YL, Turner NO, et al. Kikuchi’s disease of the neck (histiocytic necrotizing lymphadenitis). J Laryngol Otol 1998; 112:898–900. 7. Sumiyoshi Y, Kikuchi M, Ohshima K, et al. A case of human herpesvirus-6 lymphadenitis with infectious mononucleosis-like syndrome. Pathol Int 1995; 45:947–951.

ADDRESS: Susan J. Rehm, MD, Department of Infectious Disease, S32, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: [email protected].

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