Pharyngitis, Splenomegaly, and Hilar and Peripheral Adenopathy in a 29-Year-Old Man With Acute Hypoxic Respiratory Failure - )
From CHEST, 5/1/01 by Kristin B. Highland

(CHEST 2001; 119:1586-1589)

A 29-year-old white man was seen in a local emergency department with complaints of fatigue, night sweats, cervical and inguinal lymphadenopathy, nausea, and right-upper-quadrant pain. His illness began when he developed a sore throat and weakness. He was treated with amoxicillin and had some improvement in symptoms over the next 2 days.

This patient had no significant medical or surgical history, was receiving no long-term medications, and had no known drug allergies. He never smoked and had no history of illicit drug use.

Physical Examination

On presentation to the emergency department, the patient appeared dyspneic and jaundiced. He had a pulse rate of 104 beats/min; BP, 90/40 mm Hg; and temperature, 39.4 [degrees] C. Oxygen saturation on room air was 91%. He had marked cervical and inguinal adenopathy, an erythematous oropharynx, bronchial breath sounds bilaterally, and splenomegaly.

Laboratory Findings

WBC count was 9,500 cells/L, with 31% polymorphonuclear cells, 57% lymphocytes with 21% atypical lymphocytes, and 12% monocytes. Total bilirubin level was 7.6 mg/dL; direct bilirubin, 6.1 mg/dL; aspartate aminotransferase, 280 IU/L; alanine aminotransferase, 566 IU/L; and alkaline phosphatase, 463 IU/L. Coagulation studies, electrolyte measurements, and renal function results were normal. A chest radiograph showed bilateral hilar adenopathy and bilateral alveolar and interstitial infiltrates (Fig 1).

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Clinical Course

He was started on IV levofloxacin and admitted to a hospital On hospital day (HD) 2, the patient's liver function tests improved, but he developed worsening dyspnea and hypoxemia. Arterial blood gas analysis on 2 L/min of oxygen by nasal cannula showed a pH of 7.48; [PCO.sub.2], 31 mm Hg; and [PO.sub.2], 60 mm Hg. An abdominal ultrasound revealed no obvious pathologic condition. A CT scan of the chest (Fig 2) showed hilar adenopathy and bilateral parenchymal infiltrates. CT of the abdomen and pelvis showed diffuse adenopathy with splenomegaly. Results of a sputum Gram's stain were negative. Ampicillin/sulbactam and fluconazole treatment was started.

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An inguinal lymph node biopsy obtained on HD 3 revealed a reactive lymph node with paracortical hyperplasia. The patient continued to be febrile. Imipenem was added to his antibiotic regimen. On HD 4, the patient developed worsening dyspnea, was intubated, and was transferred to our institution.

Physical examination in our ICU was essentially unchanged, except that the patient was intubated and sedated, and had developed a nonblanching macular rash on his torso and eyelids. Arterial blood gas analysis on 100% oxygen and 10-cm [H.sub.2]O positive end-expiratory pressure was pH of 7.37; [PCO.sub.2], 42 mm Hg; and [PO.sub.2], 106 mm Hg.

What diagnostic test would you order?

What is the etiology of this man's hypoxic respiratory failure?

Answer: Heterophile antibody screen; Epstein-Barr virus pneumonia

Infectious mononucleosis (IM) is an acute febrile illness of children and young adults with an incidence of 38/100,000. It is generally a benign, self-limited multisystem lymphoproliferative disease caused by the Epstein-Barr virus (EBV). The EBV is a ubiquitous DNA virus of the herpesvirus group. The respiratory tract is a major reservoir for EBV, and the epidemiology of IM suggests a respiratory mode of transmission. It has also been suggested that the disease is likely spread by intimate oral contact in young adults, and therefore is known as the "kissing disease."

Typically, patients present between the ages of 15 years and 25 years, with the classic triad of fever, pharyngitis, and lymphadenopathy. Periorbital edema and splenomegaly are usually found on physical examination. Older patients with IM may present a diagnostic dilemma, as they often do not have typical features. Up to 80% of patients with IM develop a rash when they are given ampicillin.

Laboratory studies usually reveal an increase in mononuclear cells of [is greater than] 50%, with at least 10% atypical lymphocytes and a positive heterophile antibody test result. In addition, findings of liver function tests are commonly abnormal. The serologic basis for the diagnosis of IM is a positive heterophile test result and tests specific for EBV antibodies. However, up to 22% of patients with IM may have a negative heterophile test result. The EBV antibody test is highly sensitive for IM, and the lack of any EBV antibodies excludes the disease.

Life-threatening complications rarely occur, with an estimated mortality rate between 0.3% and 1%. The most common of these complications include upper-airway obstruction, splenic rupture, autoimmune hemolytic anemia, thrombocytopenia, hepatitis, myocarditis, and meningoencephalitis.

A clinical syndrome of "atypical pneumonia" has been described in 3 to 5% of patients with IM and is characterized by mild respiratory complaints, such as a paroxysmal nonproductive cough, which may or may not be associated with radiographic abnormalities. Pulmonary infiltrates with IM have an incidence ranging from 3 to 5% to as high as 10%. Other chest radiographic findings with IM include splenomegaly (47%), hilar adenopathy (1.5 to 13.6%), and cardiac enlargement with pulmonary venous hypertension (2%). Other pulmonary manifestations of IM include superimposed bacterial pneumonia, atelectasis, pleuritic pain, and pleural effusions.

Respiratory failure due to IM may result from neuromuscular paralysis, upper-airway obstruction, or CNS disease. Significant hypoxemia secondary to pulmonary involvement by IM has been previously described in the literature on only six occasions, and respiratory failure requiring mechanical ventilation secondary to severe hypoxemia from diffuse pneumonia has been reported only three times. There has only been one reported death due to severe pneumonia from IM.

It is unclear whether pulmonary manifestations in EBV infections are the result of direct viral invasion of the lung tissue or whether they represent an immunologic reaction. It is likely secondary to both. Histopathology of the lung in patients with pulmonary involvement by IM usually reveals a mononuclear cell infiltration of the perivascular and peribronchial tissue as well as the intra-alveolar septa. The inflammatory infiltrate is composed mainly of mature plasma cells mixed with small lymphocytes and large transformed lymphocytes. Consolidation with both mononuclear and polymorphonuclear exudates, as well as eosinophilic fibrinous material, has also been described. Using both polymerase chain reaction and in situ hybridization, EBV has been demonstrated in lymphocytic infiltrates of the lung. In addition to lymphocytic infiltration, secondary immunologic responses are thought to play an important role in complicated courses of IM. There have also been several case reports of simultaneous Mycoplasma pneumoniae infection, which raises the possibility that IM may predispose patients to other infections. In fact, transient suppression of immunity, especially cellular immunity, has been well documented.

The treatment of IM is mainly supportive, and 95% of patients recover fully without specific therapy. Controlled studies using corticosteroids in patients with uncomplicated IM have shown no clinical benefit. In patients with severe IM, corticosteroids traditionally have been used to treat severe secondary immunopathologic manifestations, including impending airway obstruction, hemolytic anemia, severe thrombocytopenia, neurologic involvement, and myocarditis. Treatment with prednisone in dosages of 60 to 80 mg/d is suggested, with taper over 1 to 2 weeks. Based on these recommendations, one could extrapolate that severe pulmonary manifestations of IM, including respiratory failure, should be treated with corticosteroids. Anecdotal reports suggest a benefit from the use of steroids in the treatment of severe EBV-related pneumonia.

Infectious mononucleosis was confirmed in our patient by a positive heterophile screen and a markedly positive EBV viral capsid antigen IgM. On HD 6, the patient was successfully extubated. Other pathogens were excluded during his hospital stay. BAL findings showed 353 cells/[micro]L RBCs, 552 cells/[micro]L nucleated cells with 76% macrophages, 14% polymorphonuclear cells, and 10% lymphocytes. BAL was negative for cytology, fungi, acid-fast bacilli, pneumocystis, and legionella. Serologies for hepatitis A, B, and C, Ehrlichia, Leptospira, cytomegalovirus, and toxoplasmosis were all negative. HIV antibodies were negative. On HD 8, the patient's oxygenation continued to improve, all antibiotics were stopped, and the patient was transferred to the floor for further observation. Since the patient was improving clinically, corticosteroids were not administered. On HD 11, the patient was discharged home in stable condition.

CLINICAL PEARLS

1. IM should be included in the differential diagnosis of acute respiratory failure in children and young adults.

2. Clues suggesting IM-induced respiratory failure include peripheral adenopathy, splenomegaly, elevated liver function test results, jaundice, hepatomegaly, and hilar adenopathy on chest radiograph.

3. Heterophile antibody-negative mononucleosis occurs in up to 22% of patients with clinical IM. EBV antibodies are highly sensitive for the diagnosis of IM.

4. Steroids may benefit patients with respiratory failure secondary to severe EBV-related pneumonia.