Anderson, Evan J. MD*; Petrovic, Bojan D. MD†; Miller, Frank H. MD†; Noskin, Gary A. MD*
A 39-year-old woman with a medical history of rheumatoid arthritis and systemic lupus erythematosus was admitted with fever, chills, weight loss, and abdominal pain. She had been diagnosed 5 months before the current admission with rheumatoid arthritis at an outside hospital when she presented with arthritis involving her knees and wrists. She had a rheumatoid factor titer of 1:640. Hydroxychloroquine was initiated. Three months before the current admission, the patient was admitted again to an outside hospital with fever, arthralgias, and abdominal pain. She was noted to be leukopenic; prednisone was substituted for hydroxychloroquine. Her anti-nuclear antibody was positive at a titer of 1:160 with a nucleolar pattern. She was given the diagnosis of systemic lupus erythematosus. She also underwent endoscopic retrograde cholangiopancreatography for a common bile duct stone. The prednisone was continued until 2 months before her current admission.
One month before admission, she developed a fever of 104°F and chills. Over the 2 weeks before admission, she lost 16 lb. She subsequently developed nausea, vomiting, and right upper quadrant and epigastric abdominal pain. Her arthralgias were unchanged.
The patient had emigrated from India 13 years before her current admission. She had received BCG vaccination as a child. She had visited India on a yearly basis, most recently 9 months before admission. She was married and had no history of tobacco, alcohol, or drug use. On physical examination, she was febrile to 103°F. She appeared cachectic and somnolent. She had decreased breath sounds at the bases of both lungs, mild abdominal distension, and abdominal tenderness with no rebound or guarding. A liver edge and spleen tip were palpable. Her musculoskeletal examination was unremarkable, and she had no rash.
Laboratory examinations included a white blood cell count of 4500/μL with 87% polymorphonuclear cells, hemoglobin of 8.3 g/dL, and a platelet count of 93,000/μL. Chemistries were notable for sodium of 126 mEq/L, potassium of 2.8 mEq/L, blood urea nitrogen of 4 mg/dL, creatinine of 0.4 mg/dL, alanine aminotransferase of 34 IU, aspartate aminotransferase of 110 IU, albumin of 2.2 g/dL, total bilirubin of 0.7 mg/dL, alkaline phosphatase of 82 IU, and total protein of 5.3 g/dL. She had an erythrocyte sedimentation rate of 96 mm/h and a C-reactive protein of 2.6 mg/dL. A noncontrast head computed tomography (CT; not shown) was unremarkable; lumbar puncture revealed one white blood cell, no red blood cells, and a normal protein and glucose. A chest radiograph was obtained (Fig. 1), which demonstrated random, diffuse, bilateral, micronodular opacities. A chest CT (Fig. 2) showed randomly distributed, diffuse, bilateral, small nodular opacities bilaterally. An area of tree-in-bud appearance was noted within the right middle lobe. A CT scan of the abdomen and pelvis (Fig. 3) showed innumerable small low-attenuation foci within the spleen, several low attenuation lesions within the liver, subtle stranding of the mesentery and omentum, and thickening and enhancement of the peritoneal membrane (Fig. 4).
The patient was empirically placed on isoniazid, rifampin, pyrazinamide, and ethambutol. A purified protein derivative (PPD) was placed which was positive at 17 mm. Induced sputum had moderate acid-fast bacilli (AFB) on smear. Culture grew Mycobacterium tuberculosis. An HIV ELISA was negative.
BACKGROUND AND PATHOPHYSIOLOGY
In 1700, John Jacob Manget noted the similarity between the gross pathology appearance of disseminated tuberculosis and the millet seed, prompting the term miliary.1 Miliary tuberculosis has subsequently been expanded to describe any progressive hematogenous dissemination of tuberculosis. Miliary tuberculosis comprises less than 2% of all tuberculosis disease.2,3 Miliary tuberculosis can occur through progression of primary pulmonary disease or reactivation of a latent focus of tuberculosis. Rarely iatrogenic introduction can occur such as through transplantation of a tuberculosis-infected organ.4
The wider application of the term miliary to any progressive hematogenous dissemination of tuberculosis incorporates several clinically and pathologically distinct forms. Acute miliary tuberculosis is seen most commonly. The typical clinical course is severe and progressive with the usual characteristic miliary chest radiograph appearance and typical caseating granulomas on pathology. Anergic or nonreactive tuberculosis is rarely seen and frequently has a typhoidal or septic course. Pathology reveals a neutrophilic response, large numbers of AFB, and the absence of granulomas.5 Finally, late generalized miliary tuberculosis is a pathological term used to describe chronic organ tuberculosis with continuous progressive hematogenous seeding. The clinical course is often chronic, and the diagnosis is frequently missed.5,6
Risk factors for development of miliary tuberculosis include extremes of age. Miliary disease among very young children is common, probably secondary to the immaturity of the immune system. Comstock et al7 demonstrated that 10% of tuberculosis among children younger than 6 years presents as meningitis or miliary disease. Advanced age is also a risk factor,3,8,9 presumably secondary to waning cellular immunity.
Other risk factors for development of miliary tuberculosis include alcohol abuse, pregnancy, malignancy, malnutrition, renal failure, connective tissue diseases, and immunosuppression. Miliary tuberculosis is the initial presentation of tuberculosis in 10% to 38% of patients with AIDS10,11 and is associated with a low CD4 lymphocyte count (average of 148).12 Antitumor necrosis factor α antibody infliximab has been associated with disseminated disease13; the mechanism of this has been reviewed.14 Many patients with miliary disease do not have an identifiable risk factor.
The clinical manifestations of miliary tuberculosis are nonspecific and develop subacutely in most patients with average symptom duration of 3 to 15 weeks.3,8 Early presentation can be seen in immunosuppressed patients or in those with an anergic response. Symptoms in these patients can include shock, adult respiratory distress syndrome, disseminated intravascular coagulation, and multisystem organ failure. Late generalized miliary disease frequently has symptoms, present for months or longer, which can retrospectively be attributable to tuberculosis. Miliary disease can sometimes complicate primary infection with tuberculosis.
As tuberculosis disseminates hematogenously, organs receiving large amounts of blood such as the lungs, liver, kidney, spleen, and bone marrow are frequently seeded. Constitutional symptoms predominate and include fever, malaise, weakness, anorexia, night sweats, and weight loss. Cough is the most frequent focal symptom associated with miliary disease and is seen in two thirds of patients.2,3,9,15 Abdominal symptoms can suggest the possibility of peritonitis or retroperitoneal lymphadenitis. Fever and abnormalities on lung examination are the most common physical signs.2,9,16 Physical findings such as lymphadenopathy, hepatomegaly, splenomegaly, and skin lesions are infrequent but suggestive of disseminated disease. Headache, altered mental status, or meningismus should prompt aggressive evaluation for tuberculosis meningitis, which occurs in 10% to 30% of patients with miliary disease.2,3,8 A dilated eye examination can reveal choroidal tubercles, which are granulomas in the choroid of the retina, but these are more frequently seen in children.16,17
Laboratory examinations are generally not particularly helpful. Anemia is encountered commonly with other cell lines occasionally affected.3,9,15,16 Elevation of the erythrocyte sedimentation rate and hypergammaglobulinemia can be suggestive.2,9 Hyponatremia is commonly encountered9,16 and can be associated with tuberculosis meningitis or syndrome of inappropriate diuretic hormone.3 Sterile pyuria occurs occasionally.9
Chest radiographs, CT, and ultrasound are the imaging modalities most commonly used in the evaluation of miliary tuberculosis. The random, diffuse, well-demarcated pulmonary micronodules measuring 1 to 3 mm in size seen on chest radiograph often suggest miliary tuberculosis. These micronodules are epithelioid granulomas with occasional central caseating necrosis and have a characteristic "millet seed" appearance.18-21 In approximately 10% of films, some nodules will measure larger than 3 mm.22 Figure 1 demonstrates a typical miliary pattern on chest radiograph. Although the classic "miliary" pattern has been used to describe pulmonary miliary tuberculosis, it is present in only 50% cases.1 The sensitivity of a single chest radiograph in diagnosing miliary tuberculosis has been reported to be between 59% and 69% with specificity that approaches 100%.22 Early in the disease, 20% to 45% of patients have normal chest radiographs.23 Miliary tuberculosis can also present in a nonmiliary pattern in 10% to 30% of cases with asymmetrically distributed nodules that can coalesce, a mottled/snowstorm appearance, or airspace consolidation.1 A reticulonodular pattern is seen when tubercles are not perfectly aligned.1 Areas of bilateral, diffuse, ground-glass attenuation can occasionally be visualized as a result of intrathoracic lymphatic disruption or in patients with impending adult respiratory distress syndrome.1,19-21 Repeating a chest radiograph can be helpful, although it can take 3 to 6 weeks for the characteristic miliary pattern to emerge.23 Lateral chest radiographs may be superior to frontal chest radiographs in allowing detection of the micronodular lesions of miliary TB, particularly for micronodules in the retrocardiac space.24
CT and high-resolution CT are superior to chest radiographs in early detection of pulmonary tuberculosis.1,20,25 The chest CT appearance of a miliary pattern is displayed in Figure 2. In addition to a miliary pattern, high-resolution CT of the chest may demonstrate small nodules, interlobular septal thickening, intralobular reticulation, and parenchymal tuberculomas.20 Radiographically, tuberculomas are characterized by a nodule with surrounding satellite nodules and possible internal cavitation.26 In some cases, the micronodules of miliary tuberculosis may be confused with blood vessels; in these cases, thin-section chest CT may allow visualization of the branching pattern of small vessels.22,27
Although miliary tuberculosis typically spreads hematogenously throughout the lungs and to extrapulmonary sites, a pattern usually seen with bronchogenic spread in postprimary tuberculosis may sometimes be seen in miliary tuberculosis with centrilobular nodules and branching linear structures producing a "tree-in-bud" appearance1,20 (Fig. 2).
In miliary tuberculosis, pleural effusions are rare but, when present, are often bilateral.24 In contrast, primary or postprimary tuberculosis usually has a unilateral effusion.24,28 Effusions are more commonly seen in immunocompromised patients.20,22
CT scans frequently reveal lymphadenopathy in miliary disease. Mediastinal and hilar lymph nodes can be involved and are sometimes calcified.24,28 Generalized lymphadenopathy exists in 40% of patients with miliary tuberculosis.24 On contrast-enhanced CT, tuberculous lymphadenitis appears as an enlarged lymph node with a central area of low attenuation and peripheral rim enhancement.29 The central areas of low attenuation likely correspond to areas of caseation necrosis.30 It has been suggested that in HIV-seropositive patients, findings of low-attenuation nodes are sufficient to warrant instituting empiric antituberculous therapy.30 With treatment, involved lymph nodes diminish in size, and the areas of low attenuation resolve, although residual mediastinal masses may be identified years later.30 Lymph nodes in patients with inactive disease are more likely to be calcified than those in patients with active disease.30
Abdominal imaging, such as in our patient, can suggest the possibility of miliary tuberculosis. Parenchymal liver involvement can present in local or miliary forms; a hepatobiliary (tubular) form also exists in which tuberculosis infects the intrahepatic ducts.31 Local disease presents as either focal abscesses or as nodular lesions (pseudotumors or tuberculomas).31 Although involvement of the liver and spleen is common in miliary tuberculosis, focal micronodules may not be appreciable. The most common appearance is nonspecific organomegaly.31,32 When miliary lesions are seen in the liver or spleen on CT, they typically manifest in a micronodular form as small hypoattenuating foci scattered throughout an enlarged organ.32-34 These changes were appreciable in the patient in this case (Fig. 3). Sometimes, the lesions present as diffuse punctate or small nodular calcifications.31,32
Hepatosplenic involvement of tuberculosis can also be evaluated with ultrasound or magnetic resonance imaging. Ultrasound may reveal hepatosplenomegaly, diffuse disease, or para-aortic lymph nodes.24 T1-weighted magnetic resonance images display hypointense and minimally enhancing honeycomblike lesions. On T2-weighted images, hepatic lesions are hyperintense with a rim that is hypointense in comparison to the surrounding liver parenchyma.31,33 The pancreas and adrenal glands can also be involved.
Tuberculous peritonitis is usually associated with widespread abdominal disease. Although relatively rare in adults (4% of cases), it is common in children with abdominal tuberculosis (90%).32,34 Three types of peritoneal involvement have been described: the wet, fibrotic-fixed, and dry or plastic types.32,34 The wet type is most common, and free or loculated high-attenuation fluid is noted on CT.35 The patient presented may have had wet-type tuberculosis, but no diagnostic interventions were pursued (Fig. 4). The fibrotic-fixed type manifests in large omental masses, matted bowel loops, and loculated fluid collections.35,36 The dry or plastic type of tuberculous peritonitis has caseous nodules with associated dense adhesions and fibrous peritoneal reactions that can tether bowel loops.34
Critical to making a diagnosis of miliary tuberculosis is considering it in the differential. The history of a subacute progressive process with primarily constitutional symptoms should prompt consideration. Chest radiograph or chest CT often suggests the diagnosis and prompts further evaluation. A positive PPD is present in 28% to 79% of patients, although in most series, it is approximately 50% sensitive.2,3,8,15,16 Repeat administration of a PPD resulted in additional positives in some patients with initially negative tests.2,3 In contrast, only approximately 10% of AIDS patients with miliary disease have a reactive PPD.10-12 Some authors recommend dilated ophthalmologic examination in all patients with suspected dissemination to look for choroidal tubercles which are pathognomonic of miliary tuberculosis.1
If possible, material for culture and for pathology review should be obtained to establish the diagnosis. Bone marrow biopsy has a low yield with positive results obtained in 17% to 41% of patients in most series.3,8,9 Higher yields have been noted when bone marrow biopsies are performed in patients with leukopenia or thrombocytopenia.16 Maartens et al compiled data suggesting that up to two thirds of bone marrow biopsies may have granulomas, although caseation and a positive culture were infrequently observed.16 Culture of gastric aspirates is positive in 35% to 75% of patients.2,3,9 Sputum for acid-fast bacillus stain alone has a yield of 33% to 40% but, with culture, increases to 50% to 76%.2,3,9,16 Bronchoscopy and transbronchial biopsy increase the yield. Granulomas (caseating and noncaseating) are seen in 82% to 100% of liver biopsies in patients with miliary disease, although not all biopsy specimens are culture-positive.2,8,9,16 The sensitivity of these procedures for miliary disease in AIDS patients is similar, but on histological examination, necrotizing poorly formed granulomas with large numbers of AFB are frequently seen.10 Unlike non-HIV-infected patients, mycobacterial blood cultures are positive in approximately 50% of patients with AIDS and can be useful in confirming the diagnosis.11
TREATMENT AND OUTCOMES
Antituberculosis therapy should be initiated as soon as the diagnosis of miliary tuberculosis is strongly considered. Multiple authors note that most deaths occur within 2 to 4 weeks of hospital admission; this suggests the importance of early therapy.8,16 Miliary tuberculosis was universally fatal in the preantibiotic era.37 When mortality rates for miliary disease without meningeal disease were reviewed, the mortality rate with streptomycin alone was 47% but fell to 5% when combination therapy with isoniazid was instituted.37 Current initial regimens use isoniazid in combination with rifampin and pyrazinamide. Ethambutol is often added for the possibility of multidrug-resistant tuberculosis. After completing 2 months of therapy, the regimen can usually be narrowed to isoniazid and rifampin. Current guidelines recommend 6 months of therapy, unless meningitis is present, in which case treatment should be extended to 9 to 12 months.38 Children should also be treated for 9 months. Therapy is sometimes extended beyond the recommendations of the guidelines for patients with poor response to therapy, an anergic response, and comorbidities such as AIDS or significant immunosuppression.
During therapy, clinicians should be aware of possible complications, including adrenal insufficiency and syndrome of inappropriate antidiuretic hormone. The possibility of coexistent tuberculosis meningitis should be ruled out. Fever may persist after the initiation of isoniazid for a median duration of 1 week.16 Mortality still ranges 21% to 24% in recent series and has been associated with female sex, altered mental status, age older than 60 years, lymphopenia, thrombocytopenia, hypoalbuminemia, elevated transaminases, and treatment delay.9,16
Official guidelines from the Infectious Disease Society of America and the American Thoracic Society recommend against steroid use in miliary tuberculosis.38 These guidelines were based in part on a review of the topic that found insufficient data on whether steroids were beneficial in miliary disease and made no recommendation about adjuvant steroids.39 Steroids should be initiated in miliary disease when it is complicated by either adrenal insufficiency or meningitis. A large, randomized, double-blind, placebo-controlled trial of tuberculosis meningitis recently found that steroids reduced the risk of death but did not improve the proportion of severely disabled patients.40
Finally, prevention of miliary disease is important from a public health perspective. Several interventions can decrease the risk of developing miliary disease. PPD placement before initiating infliximab is recommended. Isoniazid decreases the risk of developing tuberculosis disease among patients with a positive PPD.41 Data from a meta-analysis suggest that BCG vaccination is protective against the development of disseminated tuberculosis but is not routinely used in the United States.42
The patient in this report has had multiple complications during treatment of her miliary tuberculosis. While receiving isoniazid, rifampin, pyrazinamide, and ethambutol, the patient developed significant hepatotoxicity, necessitating a regimen change. Subsequent treatment regimens have been complicated by hepatotoxicity, impaired drug absorption, and most recently, toxic epidermal necrolysis.
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