74-Year-Old Woman With Dyspnea, Fever, and Cough

Residents' Clinic 74-Year-Old Woman With Dyspnea, Fever, and Cough CHARLES

F. THOMAS, JR., M.D.,* THOMAS K. JONES, M.D.,* AND RANDALL S. EDSON, M.D.t

A 74-year-old white woman from Arizona sought medical assistance because of progressive dyspnea, cough, and fever of 3 weeks' duration. Her medical history included biopsyproven polymyositis of 1 year's duration, which had been treated with prednisone (55 mg/day) and azathioprine (50 mg/day). In addition, she had hypertension, atrial fibrillation, and a recent embolism of the right brachial artery. One month before admission, a chest roentgenogram had shown normal findings as part of a general medical examination. One week later, she was admitted to her local hospital; cough productive of white sputum, fever (temperatures to 37.g°C), bibasilar crackles, and a leukocyte count of 22 X 109/L with 10% bands were noted. A chest roentgenogram revealed patchy bilateral alveolar infiltrates. She was treated with clindamycin and ceftazidime intravenously, and fluconazole was administered orally for thrush. On dismissal from the hospital, she received a 7-day regimen of clarithromycin. Ten days later, she was readmitted to the hospital because of dyspnea, cough productive of white sputum, fever, and weakness. Physical examination disclosed a temperature of 36.3°C, a white exudate in the oropharynx, and coarse bilateral crackles. Initial laboratory tests revealed a leukocyte count of 20 X 109/L with 27% bands, hemoglobin concentration of 11.2 g/dL, platelet count of 177 X l09/L, serum creatinine of 1.2 mg/dL, erythrocyte sedimentation rate of 114 mm in 1 hour, and arterial blood gas values as follows: pH, 7.46; carbon dioxide tension, 34 torr; oxygen tension, 54 torr; and bicarbonate, 25 mEq/L. Results of the following initial investigations were normal or negative: sputum and blood cultures; serologic tests for blastomycosis, histoplasmosis, cryptococcosis, coccidioidomycosis, and aspergillosis; Legionella direct fluorescent antibody assay; smears for acid-fast bacilli, Pneumocystis carin ii, and fungi; purified protein derivative skin test; human immunodeficiency virus (HIV) antibody test; urinalysis; and liver func-

tion tests. A chest roentgenogram (Fig. 1) showed extensive bilateral nodular, patchy, irregular infiltrates with a "cannonball" appearance. On echocardiography, left ventricular size and function were normal, and no vegetations were detected.

1. Which one of the following diagnoses is most likeIv in this patient? a. b. c. d. e.

Carcinoma Wegener's granulomatosis Rheumatoid nodules Septic emboli Infection

The rapid appearance of the nodules would not correspond to the time course of either bronchogenic carcinoma or pulmonary metastatic involvement. Among the metastatic carcinomas that can be associated with multiple pulmonary nodules, the most common primary lesions are melanoma and lung, breast, thyroid, gastrointestinal, or renal cell carcinoma . Although patients with polymyositis may have an increased frequency of occurrence of cancer (usually of the foregoing types), this relationship is not entirely clear. I Our patient had no history of a malignant tumor or other features suggestive

*Resident in Internal Medicine, Mayo Graduate School of Medicine, Mayo Clinic Rochester, Rochester, Minnesota. tResidents' adviser and Consultant in Infectious Diseases and Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota. See end of article for correct answers to questions. Address reprint requests to Dr. R. S. Edson, Division of Infectious Diseases, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo Clin Proc 1995; 70:397-400

Fig. 1. Chest roentgenogram at time of admission, showing nodular, patchy, irregular infiltrates bilaterally. 397

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of a malignant lesion. Wegener's granulomatosis manifests with rounded opacities and cavity formation in 50% of patients. Usually, affected patients have evidence of upper airway disease and a rapidly progressive glomerulonephritis, neither of which was present in the current patient. The presence of necrobiotic lesions histologically similar to those found in subcutaneous nodules is one of several pulmonary manifestations of rheumatoid arthritis.' Such lesions tend to be present only in advanced rheumatoid arthritis and are asymptomatic unless the patient has a superinfection. Septic pulmonary emboli in association with Staphylococcus aureus bacteremia or right-sided endocarditis would be unlikely in the absence of intravenous drug use, an indwelling central venous catheter, and positive blood cultures. The state of this patient's compromised cellmediated immunity and the clinical course are most consistent with an acute infection. 2. Which one of the following procedures should be performed to establish the diagnosis? a. Computed tomography ofthe chest b. Computed tomography-guided biopsy of a lung nodule c. Bronchoscopy and hronchoalveolar lavage (BAL) d. Sputum examination and culture e. Thoracentesis Computed tomography of the chest would offer better definition of the multiple pulmonary nodules (in comparison with roentgenography) and would identify associated

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adenopathy, but it would not provide a clear diagnosis unless coupled with biopsy. The increased risk associated with such a procedure was clinically deemed unnecessary in this patient. Bronchoscopy in conjunction with BAL is useful for diagnosing infection in the immunocompromised host; however, in this patient a less invasive, inexpensive alternative might yield the diagnosis. A Gram-stained sputum specimen (Fig. 2) revealed characteristic gram-positive branching, beaded, filamentous organisms and was the basis for treatment. Thoracentesis would not have been helpful in the absence of pleural fluid. 3. Which one of the following is the most likely diagnosis for this slow-growing, beaded, filamentous organism in an immunocompromised host? a. Aspergillus species b. Coccidioides immitis c. Pneumocystis carinii d. Actinomyces species e. Nocardia species Aspergillus is a ubiquitous fungus acquired by inhalation of spores by patients with either prolonged neutropenia or impaired cell-mediated immunity (for example, associated with corticosteroid therapy). In immunocompromised hosts, Aspergillus infection manifests as a rapidly invasive necrotizing bronchopneumonia in conjunction with hemorrhagic infarcts. Microscopically, it appears as septate branching hyphae, best seen on methenamine silver stain. C.

Fig. 2. Gram-stained sputum specimen, demonstrating branching, beaded, filamentous organisms.

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immitis is endemic to Arizona and is acquired by inhaling arthroconidia. In immunocompromised hosts with coccidioidomycosis, disseminated disease that involves the lungs, skin, or meninges can develop. Morphologically, C. immitis organisms appear as thick-walled spherules in tissue specimens. P. carinii can manifest as a fulminant or subacute infection associated with dry cough, shortness of breath, and hypoxia. On microscopic examination, these organisms appear as clusters of cysts on silver, Giemsa, or Wright's stain.' Actinomyces is a gram-positive anaerobic bacterium that can inhabit the oral cavity as a commensal agent. Pulmonary infections are usually due to aspiration, tend to be chronic, and are associated with sinus tract formation. Sulfur granules are a helpful diagnostic finding, but they occur only rarely and are a manifestation of this organism's filamentous growth. Nocardia organisms are gram-positive, partially acid-fast bacilli that appear as beaded, branching filaments and are acquired by inhalation. Patients with altered cell-mediated immunity are at risk for Nocardia infection, as are patients with lymphoreticular malignant lesions, the acquired immunodeficiency syndrome (AIDS), or bronchiectasis and those who have undergone organ transplantation.' Examination of a sputum specimen is diagnostic in a third of the cases, and although subclinical infection and oropharyngeal colonization can occur, isolation of Nocardia from the sputum of an immunocompromised host should be considered diagnostically significant and regarded as a true infection.' In the current case, sputum and blood cultures became positive for N. asteroides after 4 days.

4. Which one of the following treatment strategies is the most appropriate for this patient? a. Discontinue the immunosuppressive therapy and treat with chloramphenicol b. Taper the doses of the immunosuppressive agents and treat with trimethoprim-sulJamethoxazole c. Continue the immunosuppressive therapy and treat with trimethoprim-sulJamethoxazole d. Simply taper the doses of the immunosuppressive agents e. Taper the doses of the immunosuppressants and treat with amikacin and imipenem Corticosteroids and azathioprine alter cell-mediated immunity and are important factors in the pathogenesis of Nocardia infection. Although corticosteroids do not contribute to an increase in disseminated Nocardia infection, the mortality is higher among patients who receive corticosteroid therapy. The dose of prednisone should be carefully tapered, and azathioprine therapy should be discontinued, if possible. Chloramphenicol may inhibit the organism in vitro but has poor or unpredictable in vivo activity. Trimethoprim-sulfamethoxazole is the drug of choice for treating

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Nocardia infections; the combination of amikacin and imipenem is better reserved for resistant strains or for patients allergic to sulfa drugs." Minocycline and amoxicillinclavulanate potassium are alternative medications that seem to be efficacious in patients who cannot tolerate sulfa drugs. Antituberculous and antifungal agents have no role in the treatment of Nocardia. 5. Which two of the following statements are true about pulmonary nocardiosis? a. An association exists with pulmonary alveolar proteinosis b. Extrapulmonary disease (particularly brain abscess) should be sought in patients with neurologic symptoms c. Infections are easily cured with appropriate antibiotic therapy d. Once the diagnosis has been made, respiratory isolation is necessary to prevent spread of this disease e. The chest roentgenographic findings are diagnostic of Nocardia infection Nocardia infections frequently occur in immunocompromised patients, patients with chronic lung disease, and those with the rare condition of pulmonary alveolar proteinosis. In approximately a third of affected patients, extrapulmonary spread occurs, usually to the central nervous system, and disseminated disease should be sought in patients with neurologic symptoms. Even with treatment, the mortality rate is high in immunocompromised patients. No evidence of person-to-person spread has been reported," and no specific chest roentgenographic features have been consistently noted. The most common pulmonary abnormalities are localized consolidation with or without cavitation, multiple or single nodules, and pleural effusion (in a third of the affected patients)." Our patient had a fulminant infection at the time of initial assessment and died after a rapidly deteriorating course, despite appropriate intravenous treatment with trimethoprim-sulfamethoxazole. DISCUSSION In immunocompromised patients with pneumonia, the clinician should identify whether the major defect is with B-cell, T-cell, or granulocyte number and function. This information is important in understanding the pathogens that commonly cause infection in a patient with immunodeficiency. Patients with B-cell abnormalities are susceptible to Streptococcus pneumoniae, Haemophilus injluenzae, Pseudomonas aeruginosa, and gram-negative bacilli. Patients with altered cell-mediated immunity (attributable to corticosteroid therapy, organ transplantation, a lymphoreticular malignant lesion, or HIV infection) are susceptible to P. carinii, Mycobacterium, Nocardia, Legionella, herpesviruses, Cryptococcus, and the pathogenic fungi. Patients with granulo-

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cytopenia are at risk for infections with Staphylococcus, gram-negative bacilli, enteric bacilli, Candida, Aspergillus, and other opportunistic fungi. A chest roentgenogram may be helpful in narrowing the differential diagnosis. Diffuse pulmonary involvement will be evident in patients with P. carinii, herpesvirus, Legionella, or Mycoplasma pneumoniae infection as well as those with pulmonary edema, drug reactions, or carcinomatosis. A nodular or cavitary pattern may be detected in patients who have an infection with Nocardia, Actinomyces, atypical mycobacteria, Cryptococcus, or Aspergillus or who have a bacterial lung abscess. Focal infiltrates are common with bacteria (including Nocardia), mycobacteria, Cryptococcus, or Aspergillus. The assessment of immunocompromised patients with pneumonia necessitates, in addition to a thorough history and physical examination, a comprehension of the potential pathogens associated with the immunodeficiency, an appreciation of the tempo at which the pneumonia evolved, a summary of the chest roentgenographic findings, and the understanding that standard laboratory tests (stains and cultures of sputum and blood) may not be helpful. The use of empiric broad-spectrum antibiotics or bronchoscopy with BAL, protected specimen brush, or biopsy depends on the clinical situation> Our patient had an acute pneumonia as a consequence of altered T-cell function attributable to corticosteroid and azathioprine therapy; N. asteroides infection was identified. In 1888, Nocard described aerobic actinomycetes in a disease of cattle (a type offarcy) characterized by pulmonary lesions, multiple cutaneous abscesses, and draining sinuses. N. asteroides, N. brasiliensis, and N. caviae (N. otitidiscaviarum) are the major pathogenic species in humans. N. asteroides is a gram-positive, partially acid-fast bacillus that appears as beaded, branching filaments and is acquired by inhalation. No evidence of person-to-person spread has been found. Nocardia infection has commonly occurred in patients with altered cell-mediated immunity, chronic lung disease, pulmonary alveolar proteinosis, lymphoreticular malignant lesions, organ transplants, corticosteroid therapy, or AIDS, although patients without underlying conditions can be infected as well. Diagnostic findings on sputum

examination are noted in a third of the cases and should be regarded as evidence of infection in immunocompromised hosts.' Chest roentgenographic findings are nonspecific.' A search for extrapulmonary spread (especially brain abscess) is imperative in all patients with pulmonary infection who have neurologic symptoms. Trimethoprim-sulfamethoxazole is the drug of choice for treatment. Other potentially useful medications include the combination of amikacin and imipenem, minocycline, and amoxicillin-clavulanate. Because the relapse rates are high, treatment should be given parenterally for 4 to 8 weeks, followed by oral therapy for 6 to 12 months. The HIVinfected patient likely requires continuous treatment. Antituberculous and antifungal agents have no role in the treatment of Nocardia. The prognosis is poor in immunosuppressed patients and is worse in patients with disease of the central nervous system." REFERENCES 1. Plotz PH, Dalakas M, Leff RL, Love LA, Miller FW, Cronin ME. Current concepts in the idiopathic inflammatory myopathies: polymyositis, dermatomyositis, and related disorders. AnnInternMed 1989; 111:143-157 2. Viggiano RW, Swensen SJ, Rosenow EC III. Evaluation and management of solitary and multiple pulmonary nodules. Clin Chest Med 1992 Mar; 13:83-95 3. Koneman EW, Allen SD, Dowell VR Jr, Sommers HM. Color Atlas and Textbook of Diagnostic Microbiology. 2nd ed. Philadelphia: Lippincott, 1983: 507-566 4. Conant EF, Wechsler RJ. Actinomycosis and nocardiosis of the lung. J Thorac Imaging 1992; 7:75-84 5. Rivera MP, Jules-Elysee KM, Stover DE. Immunocompromised patients. In: Niederman MS, Sarosi GA, Glassroth J, editors. Respiratory Infections: A Scientific Basis for Management. Philadelphia: Saunders, 1994: 163-181 6. Lerner PI. Nocardia species. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and Practice of Infectious Diseases. Vol 2. 4th ed. New York: Churchill Livingstone, 1995: 2273-2280 7. Feigin DS. Nocardiosis of the lung: chest radiographic findings in 21 cases. Radiology 1986; 159:9-14

Correct answers:

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