Differentiating Disseminated Granulomatous Infections

History and Physical Examination

The American College of Physicians suggests that endemic fungal exposure within the past month is essential, such as coccidioidomycosis in southwestern US/Mexico, histoplasmosis in Ohio/Mississippi river valleys 2, 3
Recent travel to tuberculosis-endemic regions increases the risk of dissemination 1
High-dose corticosteroids, TNF inhibitors, organ transplant immunosuppression, or HIV infection dramatically increase dissemination risk 2, 4
Pregnancy, particularly third trimester, increases coccidioidomycosis dissemination risk 2, 4
Filipino or African descent confers higher dissemination risk for coccidioidomycosis 4
Diabetes mellitus or cardiopulmonary disease increases severity 4
Constitutional symptoms such as fever, drenching night sweats, weight loss, and extreme fatigue lasting weeks to months are common 2, 3
The absence of tissue-destructive focal lesions is strong evidence against disseminated infection 2, 3
Chronic skin ulceration or subcutaneous abscesses indicate cutaneous dissemination 2, 3
Lupus pernio is highly specific for sarcoidosis 5
Erythema nodosum suggests acute coccidioidomycosis or sarcoidosis but does not contain viable organisms 2, 3
Focal skeletal pain suggests osteomyelitis from disseminated infection 2, 3
Persistent or progressive headache with meningeal signs mandates lumbar puncture to evaluate for coccidioidal meningitis 2, 3
Seventh cranial nerve paralysis can occur with sarcoidosis 5
Uveitis or optic neuritis suggests sarcoidosis 5

The Infectious Diseases Society of America recommends that any positive anticoccidioidal antibody indicates recent or active infection 2, 3
Unlike most infections, coccidioidal antibodies return to negative as infection resolves—persistent positivity suggests ongoing disease 2, 3
Critical limitation: serology may be negative despite active infection, especially early or in immunosuppressed patients 2, 3
Complement-fixing antibody titers >1:16 suggest severe disease 4
Culture of sputum or bronchoscopic specimens may provide the only diagnosis when serology is negative or in severely ill patients 2, 3
Special stains are mandatory on all biopsy specimens to exclude mycobacteria and fungi before diagnosing non-infectious causes 1, 7
Coccidioidal antigen in urine/serum is typically positive only in extensive infections 2, 3
CSF coccidioidal antigen is highly sensitive for coccidioidal meningitis 2, 3
Chest CT: bilateral hilar adenopathy with perilymphatic nodules suggests sarcoidosis 5, 1
Necrotizing granulomas with cavitation suggest tuberculosis or endemic fungi 1
FDG-PET: parotid uptake suggests sarcoidosis 5
In neutropenic patients with persistent fever or right upper quadrant pain, imaging is essential to exclude chronic disseminated candidiasis 8

Biopsy with special stains is the gold standard 7, 1
Tuberculosis: robust necrotizing granulomas with central acellular necrosis 1
Histoplasmosis: large acellular necrotizing granulomas 1
Coccidioidomycosis: may show necrotizing or non-necrotizing patterns 2
Sarcoidosis: well-formed, concentrically arranged, non-necrotizing granulomas in perilymphatic distribution with minimal surrounding lymphocytes 5, 1
Hypersensitivity pneumonitis: poorly formed granulomas with extensive surrounding lymphocytic alveolitis in small airway distribution 1

Never diagnose sarcoidosis without excluding infection through special stains and cultures 1
Absence of pulmonary symptoms does not exclude disseminated fungal infection 2, 3
Negative serology does not exclude coccidioidomycosis 2, 3
Necrotizing granulomas are not exclusively infectious 1
Erythema nodosum and arthralgias in early coccidioidomycosis do not represent dissemination 2, 3