Fever of unknown origin (FUO) due to miliary BCG: The diagnostic importance of morning temperature spikes and highly elevated ferritin levels

Abstract

Fever of unknown origin (FUO) is defined as prolonged fever of >101 °F for at least 3 weeks that remains undiagnosed after a focused inpatient or outpatient workup. One of the most elusive FUO diagnoses is miliary tuberculosis (TB) which typically has few/no localizing signs/symptoms. Since the introduction of intravesicular Bacille Calmette-Guerin (BCG) treatment for bladder carcinoma, miliary BCG has only rarely been reported as a cause of FUO. As with miliary TB, there are few/no clues to suspect miliary BCG. We present an interesting case of FUO due to miliary BCG without any localizing signs, i.e., no lung, liver or prostate involvement. The only clues to the diagnosis of this FUO due to disseminated BCG were morning temperature spikes and otherwise unexplained highly elevated ferritin levels.

Introduction

Miliary tuberculosis (TB) results from hematogenous spread of M. tuberculosis. In most cases, miliary TB typically presents with fever (morning temperature spikes), night sweats, or weight loss (without anorexia). Hepatosplenomegaly, generalized lymphadenopathy or choroidal tubercles may or may not be present. The complete blood count (CBC) may show leukocytosis, relative lymphopenia, anemia, or thrombocytopenia. In some, subclinical liver involvement may be manifested by an increased alkaline phosphatase. In disseminated TB, the PPD is usually negative. Diagnosis of disseminated TB is suggested if a miliary pattern is present on chest radiography, but chest films are unremarkable early. With miliary TB, sputum smears are only positive in 20% of patients. Transbronchial biopsies have a diagnostic yield of 90% and liver or bone marrow biopsies have a diagnostic yield of 50%.1, 2

Bacille Calmette-Guerin (BCG), a strain of Mycobacterium bovis, local/systemic infection may occur following intravesicular BCG bladder cancer therapy. As a cause of FUO, disseminated BCG, i.e., disseminated BCGosis has been only rarely reported in the literature.3, 4, 5 Most case reports describe non-specific symptoms, e.g., usually either low grade fevers or fatigue occurring days after intravesicular BCG instillations. Other symptoms included chills, malaise, night sweats, weight loss, non-productive cough, shortness of breath, and in rare cases, hemoptysis, granulomatous hepatitis or choroiditis.6, 7, 8, 9, 10 Importantly, disseminated or miliary TB or miliary BCG are systemic infections but organ involvement is often subclinical, e.g., CNS, lungs, liver, prostate.

As with miliary TB, disseminated BCG may rarely present as a fever of unknown origin (FUO) without localizing signs or symptoms.¹¹ Laboratory abnormalities may include mild elevations of serum transaminases, C-reactive protein (CRP), or elevated alkaline phosphatase levels. The CBC is usually unremarkable.1, 2, 3, 12 Blood cultures, urine cultures, sputum acid fast smears and cultures as well as bronchoaleolar lavage cultures are almost always negative. Miliary BCG may have diffuse miliary micronodular pattern on chest radiography, but infiltrates are absent in 50% of cases. Late in the infection, splenomegaly may be present.¹⁰ Diagnosis of miliary BCG may be made by transbronchial lung biopsy, bone marrow biopsy or liver biopsy, but in most cases, the clinical diagnosis of disseminated BCG is based on empiric INH and rifampin response.12, 13, 14, 15