What is the next step in managing a patient with persistent symptoms of chills, ear fullness (ear popping), cervical lymphadenopathy (swollen lymph nodes), headache, and myalgia (body aches) for 3 weeks, despite treatment with Z-pack (azithromycin) and prednisone, and without cough?

Next Step: Obtain Histoplasma Antigen Testing and Consider Empiric Itraconazole

The most critical next step is to test for disseminated histoplasmosis with urine and serum Histoplasma antigen, as this patient's constellation of persistent systemic symptoms with lymphadenopathy after failed antibiotic therapy strongly suggests reactivation of latent fungal infection rather than bacterial disease. 1

Why Histoplasmosis Should Be Your Primary Consideration

This clinical presentation—3 weeks of chills, headache, myalgias, and cervical lymphadenopathy without cough, unresponsive to azithromycin and prednisone—is highly characteristic of disseminated histoplasmosis reactivation:

• Prolonged fever is the most common presenting symptom in disseminated histoplasmosis, along with fatigue, weight loss, and lymphadenopathy 1
• Respiratory symptoms occur in only approximately 50% of patients with disseminated disease, so the absence of cough does not exclude this diagnosis 1
• Reactivation occurs when cellular immunity wanes, and the prior use of prednisone may have precipitated reactivation of dormant Histoplasma from previous exposure 1
• The failure to respond to azithromycin rules out typical bacterial causes including atypical pneumonia pathogens 2

Immediate Diagnostic Workup

Order these tests now:

• Histoplasma antigen in urine and serum - this is the most rapid and sensitive diagnostic method for disseminated disease 1
• Blood cultures using lysis-centrifugation technique - positive in >85% of disseminated cases 1
• Complete blood count with differential
• Comprehensive metabolic panel to assess liver function
• Chest radiograph to evaluate for pulmonary involvement 2

Treatment Decision Algorithm

If moderate-to-severe symptoms (persistent high fevers, significant constitutional symptoms, inability to maintain activities):

• Start liposomal amphotericin B 3 mg/kg/day IV for 3-10 days until clinical improvement, then transition to itraconazole 200 mg three times daily for 3 days, then 200 mg twice daily to complete 12 weeks 1
• Liposomal amphotericin B is more effective than standard formulation with more rapid response, lower mortality, and reduced toxicity 1

If mild-to-moderate symptoms (ambulatory, tolerating oral intake, stable vital signs):

• Start itraconazole 200 mg three times daily for 3 days, then 200 mg twice daily for 12 weeks 1
• Monitor itraconazole levels 2-4 hours post-dose; therapeutic concentration should be ≥1 mg/mL 2

Alternative Diagnoses to Exclude

While histoplasmosis is the priority, also consider:

Epstein-Barr virus (EBV) reactivation or primary infection:

• Can present with prolonged fever, lymphadenopathy, headache, and myalgias 2
• Order EBV VCA IgM, IgG, and EBNA antibodies
• However, EBV typically includes pharyngitis and would not explain 3-week duration without improvement

Toxoplasmosis:

• Can cause cervical lymphadenopathy with systemic symptoms 3
• Order Toxoplasma IgM and IgG antibodies
• Less likely given the duration and severity of symptoms

Cat-scratch disease (Bartonella henselae):

• Causes regional lymphadenopathy after cat exposure 3
• The Z-pack (azithromycin) should have been effective if this were the cause 4
• Order Bartonella serology if cat exposure history exists

Critical Pitfalls to Avoid

Do not assume this is a viral syndrome simply because antibiotics failed - the 3-week duration with persistent systemic symptoms demands investigation for fungal, mycobacterial, or other non-bacterial etiologies 2, 1

Do not give additional courses of prednisone without a definitive diagnosis - corticosteroids can precipitate or worsen disseminated histoplasmosis and other opportunistic infections 1

Do not delay antifungal therapy if the patient appears systemically ill - disseminated histoplasmosis can be fatal without treatment, and empiric therapy while awaiting diagnostic confirmation is appropriate in the right clinical context 2, 1

Assess for immunocompromising conditions - ask specifically about HIV risk factors, autoimmune diseases, organ transplantation, or other immunosuppressive medications, as these dramatically increase risk of disseminated disease 1

Obtain travel and exposure history - residence in or travel to endemic regions (Ohio/Mississippi River valleys, Central America) even years prior can be relevant for reactivation disease 1

If Histoplasmosis Testing is Negative

Consider mycobacterial infection (tuberculosis or nontuberculous mycobacteria), lymphoma, or other systemic infections. Lymph node biopsy for histopathology, culture, and flow cytometry would be the next diagnostic step 3