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Geoffrey A. Jackman, MD
From Emory University School of Medicine, Egleston Children's Hospital, Atlanta, Ga.

Arch Pediatr Adolesc Med. 1999;153:887-888.

A 9-MONTH-OLD previously healthy infant presented with a history of a fever (temperature to 39.5°C) daily for 32 days. At the onset of the fever, she had several small bumps around her mouth and cold symptoms consisting of a nonproductive cough and rhinorrhea. Her primary care physician diagnosed a viral illness. The physician reevaluated her persistent fever 2 weeks later, diagnosed otitis media, and started treatment with an antibiotic. After completion of the antibiotic course, she was still febrile and was given a second antibiotic with no improvement of her condition. The parents reported she was weaker and her activity level had decreased. She no longer pulled herself to a standing position. She had no noticeable decrease in appetite or weight and no change in behavior.

The infant had achieved developmental milestones appropriately and had been immunized. Her medical and family history were unremarkable. There was no history of recent travel or ill contacts. She lived with her mother, father, and brother, who were all healthy. During the day the patient stayed with her grandmother and aunt.

Physical examination showed her vital signs to be normal except for a temperature of 38.9°C. She was ill-appearing but well nourished and well developed. Her conjuctiva and mucosa were pink. She had no cough, tachypnea, or retractions, and her lung auscultations were clear. The liver, spleen, and lymph nodes were not enlarged. Physical examination results included normal tympanic membranes, normal cardiovascular findings, normal joints, normal neurological findings, and no rashes.

Initial laboratory evaluation included a serum leukocyte count of 15 x 10⁹/L, with a differential cell count of 0.01 cellbands, 0.63 segmented neutrophils, 0.27 lymphocytes, and 0.06 monocytes; a hemoglobin level of 73 g/L with normal indices; a platelet count of 7.2x10⁹/L; and an erythrocyte sedimentation rate of 114 mm/h. The remainder of her serum chemistry test results and urinalysis were normal. A chest radiograph (Figure 1 and Figure 2) was performed because of the history of persistent fever. A lumber puncture was performed and the cerebrospinal fluid revealed a leukocyte count of 12.2x10⁹/L with a differential cell count of 0.55 segmented neutrophils, 0.26 lymphocytes, and 0.16 monocytes; glucose and protein values of 2.4 mmol/L (44 mg/dL) and 63 g/L, respectively; and a negative Gram stain. Cerebrospinal fluid, blood, and urine cultures were performed.

Figure 1.

Figure 2.

Denouement and Discussion

Miliary Tuberculosis With Meningitis

Figure 1. Radiographic examination showing diffuse nodular and interstitial opacities within the lungs.

Figure 2. Radiographic examination showing diffuse nodular and interstitial opacities within the lungs.

Fever of unknown origin is described as a temperature greater than 38.4°C for 2 or more weeks in the absence of localized findings on physical examination. The differential diagnosis for fever of unknown origin is extensive and includes neoplasia, collagen vascular disease, inflammatory bowel disease, and infections such as osteomyelitis, meningitis, tuberculosis (TB), and human immunodeficiency virus. Initial evaluation for fever of unknown origin will include a complete blood cell count and blood culture, urinalysis and urine culture, erythrocyte sedimentation rate, tuberculin skin test with purified protein derivative (PPD) test, and chest radiograph.^1-2 A PPD test was performed and gastric aspirates were obtained for acid-fast bacilli. A positive PPD result (12 mm) developed and the acid-fast bacilli stain from a gastric aspirate was positive. A diagnosis of miliary TB with meningitis was made. Six weeks after her initial lumbar puncture, the cerebrospinal fluid culture was positive for Mycobacterium tuberculosis.

Mycobacterium tuberculosis is an aerobic, gram-positive, acid-fast bacillus. Transmission of this organism is from person to person through inhalation of respiratory droplets³; however, transmission through the skin, gastrointestinal tract, mucous membranes, placenta, and by infected amniotic fluid have occurred.⁴ Tuberculosis is either an infection or a disease. Tuberculosis infection is defined by a positive PPD test result without physical findings and a chest radiograph that is either normal or has granulomas or calcifications. Tuberculosis disease is defined by signs, symptoms, and/or radiographic manifestations.⁴ The onset of infection after exposure may be from 2 weeks to several years, with a median time of 3 to 4 weeks. Postpubertal adolescents and children younger than 5 years, especially infants, have the greatest risk of developing TB disease after exposure. All reported cases of pediatric TB infection or disease result from exposure to an infected adult.^4-7

Manifestations of TB are fever, cough, weight loss, diarrhea, vomiting, night sweats, chills, weakness, lymphadenopathy, hepatomegaly, splenomegaly, respiratory distress, hemoptysis, and meningitis. Laboratory evaluation may include leukocytosis or leukopenia, anemia, and hyponatremia, as well as elevated erythrocyte sedimentation rate and elevated alanine aminotransferase, bilirubin, or alkaline phosphate levels.^{4, 6, 8}

Tuberculosis has various radiological manifestations, which include parenchymal granulomas, unifocal or multilobar parenchymal consolidation, lobar or segmental atelectasis, hilar or mediastinal lymphadenopathy, pleural effusion, or miliary parenchymal disease. In infants and children, parenchymal consolidation occurs more frequently in the upper lobes.^3-6

Primary TB occurs in patients not previously exposed and is the most common form of the disease.^3-4 The primary lesion may disseminate through lymphatic and venous channels, producing miliary and/or extrapulmonary TB. Miliary TB is defined by its "millet-seed" size of 1- to 2-mm yellowish nodules that are found to be granulomas on histological analysis.⁶ The distribution of nodules is diffuse. Miliary TB usually involves the lungs, liver, bone marrow, kidneys, or spleen, but can affect any organ. In cases of disseminated TB, most patients have radiographic findings of miliary TB.^3-4

The onset of TB meningitis may be rapid or insidious. It usually occurs in children younger than 4 years. This complication occurs from direct seeding of the meninges by hematogenous spread of organisms. These patients also have abnormal chest radiographic findings.^4-6 Results of cerebrospinal fluid testing are increased leukocyte count with a predominance of lymphocytes, although early in infection polymorphonucleocytes predominate. The glucose level of the cerebrospinal fluid is reduced while the protein level is elevated.^4-6 Computed tomographic scans of the brain may be normal or show diffuse edema, tuberculomas (ring-enhancing lesions with or without surrounding edema), or obstructive hydrocephalus.³

Definitive diagnosis of TB is made by isolation of the bacillus in culture. Sputum is the specimen of choice.⁴ Tuberculosis is slow-growing and difficult to culture, but therapy should not be delayed for a child with abnormal physical findings and/or radiographic evidence of the disease. Locating the probable adult source is important; in this case, the aunt had a cough and a positive PPD test result.

The treatment of patients with TB depends on the extent of the disease. This patient was prescribed a 4-drug regimen with corticosteroids, which has been shown to reduce long-term neurological impairment in patients with central nervous system involvement.^{4, 9-10}

AUTHOR INFORMATION
Accepted for publication March 31, 1998.

Reprints: Geoffrey A. Jackman, MD, Pediatric Emergency Medicine, Emory University School of Medicine, Egleston Children's Hospital, 1405 Clifton Rd, Atlanta, GA 30322.

REFERENCES
1. Lorin MI, Feigin RD. Fever without localizing signs and fever of unknown origin. In: Feigin RD, Cherry J, eds. Textbook of Pediatric Infectious Diseases.4th ed. Philadelphia, Pa: WB Saunders Co; 1998:820-830. 2. Green M. Pediatric Diagnosis: Interpretation of Symptoms and Signs in Infants, Children, and Adolescents. 5th ed. Philadelphia, Pa: WB Saunders Co; 1992:202-203. 3. McAdams HP, Erasmus J, Winter JA. Radiologic manifestations of pulmonary tuberculosis. Radiol Clin North Am. 1995;33:655-678. WEB OF SCIENCE | PUBMED 4. American Academy of Pediatrics. Tuberculosis. In: Peter G, ed. 1997 Red Book: Report of the Committee on Infectious Diseases.24th ed. Elk Grove Village, Ill: American Academy of Pediatrics; 1997:541-562. 5. Starke JR, Jacobs RF, Jereb J. Resurgence of tuberculosis in children. J Pediatr. 1992;120:839-855. FULL TEXT | WEB OF SCIENCE | PUBMED 6. Hopewell PC. A clinical view of tuberculosis. Radiol Clin North Am. 1995;33:641-653. PUBMED 7. Nemir RL, Krasinski K. Tuberculosis in children and adolescents in the 1980s. Pediatr Infect Dis J. 1988;7:375-379. WEB OF SCIENCE | PUBMED 8. Hussey G, Chisholm T, Kibel M. Miliary tuberculosis in children: a review of 94 cases. Pediatr Infect Dis J. 1991;10:832-836. WEB OF SCIENCE | PUBMED 9. Girgis NI, Farid Z, Kilpatrick ME, Sultan Y, Mikhail IA. Dexamethasone as an adjunct to treatment of tuberculous meningitis. Pediatr Infect Dis J. 1991;10:179-183. WEB OF SCIENCE | PUBMED 10. McGowan JE, Chesney PJ, Crossley KB, LaForce EM. Guidelines for the use of systemic glucocorticosteroids in the management of selected infections. J Infect Dis. 1992;165:1-13. WEB OF SCIENCE | PUBMED

SECTION EDITOR: BEVERLY P. WOOD, MD

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