What is the differential diagnosis for a patient with headache, low-grade fever, dry cough, bilateral knee pain with swelling, and lower back pain?

Differential Diagnosis for Fever, Headache, Dry Cough, and Bilateral Knee Pain with Swelling

This constellation of symptoms—low-grade fever, headache, excessive dry cough, and bilateral knee swelling with lower back pain—most urgently requires consideration of tick-borne rickettsial diseases (particularly ehrlichiosis or anaplasmosis), viral respiratory infections with reactive arthritis, Lyme disease with musculoskeletal manifestations, or COVID-19 with inflammatory arthropathy.

Immediate Life-Threatening Considerations

Tick-Borne Rickettsial Diseases

• Ehrlichiosis and anaplasmosis present with fever (96%), headache (72%), malaise (77%), and myalgia (68%), matching this clinical picture 1
• The absence of rash does NOT exclude tick-borne disease, as rash appears late or is absent in a significant percentage of cases 1
• Patients with anaplasmosis typically have fever, headache, and myalgia; rash is rare 1
• Treatment with doxycycline should be initiated immediately if clinical suspicion exists—treatment decisions should never be delayed while awaiting laboratory confirmation 1, 2
• Leukopenia, thrombocytopenia, elevated hepatic transaminase levels, and mild anemia are characteristic laboratory findings 1

Bacterial Meningitis

• Fever with headache and malaise represents a classic presentation that strongly suggests CNS infection, even without neck stiffness 2
• The absence of neck stiffness does NOT rule out bacterial meningitis, as Kernig and Brudzinski signs have poor sensitivity (as low as 5%) 2
• Only 41-51% of bacterial meningitis cases present with the classic triad of fever, neck stiffness, and altered mental status 2
• Obtain two sets of blood cultures, complete blood count, ESR, and CRP immediately before starting antibiotics 2
• Start ceftriaxone 2g IV q12h immediately if clinical suspicion exists, and consider adding vancomycin for pneumococcal resistance coverage 2

High-Priority Infectious Etiologies

Lyme Disease with Musculoskeletal Involvement

• Lyme disease manifests with recurrent, brief attacks (weeks or months) of objective joint swelling in one or a few joints 1
• The expanding erythema migrans lesion is accompanied by fatigue, fever, headache, mildly stiff neck, arthralgia, or myalgia 1
• Musculoskeletal manifestations include recurrent, brief attacks of objective joint swelling, sometimes followed by chronic arthritis 1
• A two-test approach using a sensitive enzyme immunoassay or immunofluorescence antibody followed by Western blot is recommended for diagnosis 1

COVID-19 with Inflammatory Arthropathy

• COVID-19 presents with fever, dry cough, headache, malaise, and myalgia 1
• Bilateral and multi-lobe lung involvement were common in over 75% and 71% of adult patients 1
• Key laboratory results include leucocytes below or above the normal range, lymphocytes below normal range, and elevated C-reactive protein 1
• Differential diagnosis includes other viral respiratory infections caused by influenza virus, parainfluenza virus, adenovirus, and respiratory syncytial virus 1

Malaria

• Malaria presents with fever, headache, back pain, chills, sweats, myalgia, and cough 1
• The diagnosis should be considered for any person with these symptoms who has traveled to an area where malaria is endemic 1
• Demonstration of malaria parasites in blood films confirms the diagnosis 1

Rheumatologic Considerations

Reactive Arthritis Following Viral Infection

• Viral respiratory infections can trigger reactive arthritis with bilateral knee involvement 1
• The combination of respiratory symptoms with inflammatory arthritis suggests post-infectious arthropathy 1

Psoriatic Arthritis

• Consider when presentation includes psoriasis (current, history, or family history), inflammatory articular disease (joint, spine, entheseal), nail dystrophy, or dactylitis 1
• Juxta-articular new bone formation on hand or foot radiography supports this diagnosis 1

Axial Spondyloarthritis

• Consider when presentation includes inflammatory back pain, sacroiliitis, asymmetrical inflammatory arthritis, enthesitis, or dactylitis 1
• Pain responsive to NSAIDs, family history, HLA-B27 positivity, and elevated CRP support this diagnosis 1

Diagnostic Algorithm

Initial Laboratory Evaluation

• Complete blood count with differential leukocyte count, hepatic transaminase levels, serum sodium level, ESR, and CRP 1, 2
• Two sets of blood cultures before antibiotics 2
• Peripheral blood smear examination for morulae (anaplasmosis) or schistocytes 1
• Serologic testing for rickettsial diseases, Lyme disease, and COVID-19 1
• Blood smear for malaria parasites if travel history to endemic areas 1

Epidemiologic History

• Detailed questioning about tick exposure, recent travel, outdoor activities, time of year, and geographic location 1, 2
• History of tick bite is not required for tick-borne disease diagnosis 1
• Travel to malaria-endemic areas within the past 30 days 1

Physical Examination Priorities

• Thorough skin examination for rash (including scabs on lower legs), erythema migrans, or petechiae 1
• Detailed joint examination documenting swelling, warmth, effusion, and range of motion 1
• Neurologic examination including mental status, cranial nerves, and focal deficits 1, 2
• Assessment for neck stiffness, spinal tenderness, and lymphadenopathy 2

Imaging Considerations

• Chest radiograph to evaluate for pneumonia or bilateral lung involvement 1
• Knee radiographs to assess for joint effusion, osteochondritis dissecans, or signs of chronic injury 1
• MRI knee without contrast if radiographs are normal but pain persists, to evaluate menisci, articular cartilage, and bone marrow edema 1
• CT head before lumbar puncture if focal neurologic deficits, altered consciousness, or immunocompromised state 2

Critical Pitfalls to Avoid

• Do NOT delay empiric doxycycline treatment while awaiting laboratory confirmation if tick-borne disease is suspected—delay can lead to severe disease and death 1, 2
• Do NOT rely on absence of fever or neck stiffness to rule out meningitis, as these signs have poor sensitivity 2
• Do NOT exclude tick-borne diseases based solely on absence of rash 1, 2
• Do NOT dismiss the combination of respiratory and joint symptoms as simple viral illness without considering serious bacterial infections 1
• Do NOT assume bilateral knee pain with fever is purely musculoskeletal without excluding infectious causes 1, 2
• Because of nonspecific signs and symptoms, early empiric treatment often needs to be administered concomitantly for multiple conditions in the differential diagnosis 1

Red Flags Requiring Urgent Evaluation

• Persistent hypotension (systolic BP <90 mmHg) 2
• Altered mental status or confusion 1, 2
• Difficulty breathing or oxygen saturation <92% 2
• Petechial or purpuric rash 2
• Severe neck stiffness 2
• Focal neurologic deficits 2
• Thrombocytopenia with fever and headache (suggests rickettsial disease or TTP) 1