What are the differential diagnoses for a patient presenting with arthralgia, myalgia, fever, respiratory symptoms, and pancytopenia?

Differential Diagnoses for Arthralgia, Myalgia, Fever, Respiratory Symptoms, and Pancytopenia

The most critical immediate differentials to consider are Adult-Onset Still's Disease (AOSD), hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), disseminated infections (particularly Q fever, mycobacterial infections, and fungal infections in immunocompromised states), and hematologic malignancies, with urgent evaluation required to distinguish life-threatening conditions from treatable inflammatory diseases. 1

Primary Rheumatologic/Autoinflammatory Conditions

Adult-Onset Still's Disease (AOSD)

• AOSD is a leading consideration given the constellation of fever (present in 95.7% of cases), arthralgia/myalgia (75-100% of cases), and systemic inflammation 1
• The typical fever pattern is spiking with temperature ≥39°C (102.2°F), often accompanied by an evanescent salmon-pink rash on trunk and proximal limbs 1
• Arthralgia affects 64-100% of patients, most commonly involving knees, wrists, and ankles in a symmetric polyarticular pattern 1
• Myalgia is reported in 56-84% of cases 1
• Critical distinction: Pancytopenia in AOSD should immediately alert to macrophage activation syndrome (MAS), which requires prompt immunosuppressive treatment and carries significant mortality risk 1
• Laboratory findings typically show marked neutrophilic leukocytosis (50% have WBC >15×10⁹/L), elevated ESR/CRP, and hyperferritinemia—not pancytopenia unless MAS is present 1
• Respiratory involvement occurs in 10-53% with pleuritis or pneumonitis 1

Macrophage Activation Syndrome/Hemophagocytic Lymphohistiocytosis

• MAS is the most life-threatening complication that can occur at Still's disease onset or during its course, even in remission 1
• Pancytopenia is the hallmark feature distinguishing MAS from uncomplicated AOSD 1
• Can present with fever, cytopenias, hepatosplenomegaly, coagulopathy, and hyperferritinemia 1
• Bone marrow examination showing hemophagocytosis confirms diagnosis 2

Infectious Etiologies

Q Fever (Coxiella burnetii)

• Q fever presents with fever, myalgia, arthralgia, and pneumonia in a pattern closely matching this presentation 1
• Most frequently reported symptoms include fever, fatigue, chills, and myalgia, with pneumonia as an important manifestation 1
• Severe headache (often retroorbital with photophobia) is characteristic and can be misdiagnosed as migraine 1
• Arthralgia is a common extrapulmonary manifestation 1
• Fever lasts median 10 days in untreated patients, with 60% of patients >40 years having fever >14 days 1
• Pancytopenia is not typical but can occur with severe systemic involvement 1
• Airborne transmission means lack of direct animal contact should not exclude diagnosis 1, 3

Disseminated Mycobacterial Infection (MAI/TB)

• Disseminated Mycobacterium avium-intracellulare (MAI) can present with fever, arthralgia, and pancytopenia, particularly in immunocompromised states 4
• Associated with myelodysplastic syndrome, immunodeficiency states, or prolonged corticosteroid therapy 4
• Hepatosplenomegaly and lymphadenopathy develop with dissemination 4
• Bone marrow, blood, and tissue cultures are diagnostic 4

Invasive Fungal Infections (Aspergillosis, Histoplasmosis)

• Invasive aspergillosis presents with fever, respiratory symptoms, and can cause pancytopenia in immunocompromised patients, particularly those with SLE on high-dose corticosteroids 5
• Carries 80% mortality in SLE patients 5
• Histoplasmosis with hemophagocytosis can present with fever and pancytopenia, particularly in HIV-positive patients 2
• Bone marrow examination may reveal organisms and hemophagocytosis 2

Viral Infections (EBV, CMV)

• Epstein-Barr virus can cause persistent high-grade fevers with severe pancytopenia in immunocompromised patients, particularly those with common variable immunodeficiency (CVID) 6
• Flow cytometry shows markedly elevated CD8 counts with abnormal CD4/CD8 ratio 6
• Real-time PCR demonstrates high viral load even when monospot is negative 6
• Can progress to shock and multiorgan failure 6

Travel-Related Infections

• Malaria, dengue, enteric fever, and rickettsial diseases must be excluded in any patient with fever and arthralgia who has traveled to endemic areas within the past year 3
• Dengue presents with fever, arthralgia/myalgia, thrombocytopenia, and can progress to hemorrhagic fever 3
• Enteric fever causes fever, myalgia, and relative bradycardia with leukopenia 3
• Leptospirosis and schistosomiasis (Katayama syndrome) should be considered with fresh-water exposure 4-8 weeks prior 3

Hematologic Malignancies

Acute Leukemia

• Acute lymphoblastic leukemia can present with arthralgia, fever, rash, and pancytopenia, mimicking connective tissue disease 7
• May show only mild leukopenia, anemia, and thrombocytopenia initially with increased lymphocyte proportion 7
• Bone marrow examination with morphology, flow cytometry, and cytogenetics is essential when diagnosis is uncertain with persistent symptoms 7
• Can be misdiagnosed as reactive arthritis or connective tissue disease, leading to inappropriate corticosteroid treatment 7

Myelodysplastic Syndrome

• MDS can present with pancytopenia and predispose to disseminated infections due to immunodeficiency 4
• Dysplasia and cytogenetic abnormalities (e.g., trisomy 8) on bone marrow examination are diagnostic 4

Autoimmune/Connective Tissue Diseases

Systemic Lupus Erythematosus (SLE)

• SLE can present with fever, arthralgia, and pancytopenia (from autoimmune destruction or bone marrow involvement) 5
• Respiratory involvement with pneumonitis or pleuritis is common 5
• High risk for opportunistic infections (aspergillosis, mycobacterial) when treated with high-dose corticosteroids 5
• Serologic testing (ANA, anti-dsDNA, complement levels) aids diagnosis 5

Polymyositis/Inflammatory Myositis

• Proximal muscle weakness (not just myalgia) is the hallmark, with difficulty standing, lifting arms, and moving 1, 8
• Elevated CK levels (present in 64% of cases) distinguish true myositis from polymyalgia-like syndromes 8
• Can present with fever and respiratory involvement if myocarditis develops 1, 8
• Pancytopenia is not typical unless there is concurrent autoimmune disease or drug toxicity 8

Diagnostic Algorithm

Immediate Evaluation

• Document fever pattern (spiking vs. continuous), presence of rash (salmon-pink, evanescent), and joint involvement pattern 1
• Obtain complete blood count with differential to characterize pancytopenia (all three cell lines vs. selective) and look for neutrophilia (AOSD) vs. lymphocytosis (viral/leukemia) 1, 7
• Measure inflammatory markers: ESR, CRP, ferritin (markedly elevated in AOSD and MAS), LDH, fibrinogen 1, 8
• Check liver enzymes, coagulation studies (DIC in MAS), and triglycerides 1

Infection Workup

• Blood cultures (bacterial, mycobacterial, fungal) before antibiotics 3, 4
• Chest imaging for pneumonia or pleuritis 1, 5
• Travel history and geographic exposures to guide testing for malaria, dengue, Q fever, rickettsial diseases 1, 3
• Viral serologies/PCR (EBV, CMV, HIV) particularly if immunocompromised 6, 2
• Q fever serology if acute presentation with pneumonia and arthralgia 1

Bone Marrow Examination

• Mandatory when pancytopenia is present to evaluate for hemophagocytosis (MAS), hematologic malignancy, or disseminated infection 1, 4, 7, 2
• Include morphology, flow cytometry, cytogenetics, and cultures 4, 7
• Careful examination may reveal subtle infections (histoplasmosis, mycobacteria) 2

Rheumatologic Workup

• Autoantibody panel: ANA, RF, anti-CCP, anti-dsDNA, complement levels, myositis-specific antibodies 1, 8
• Muscle enzymes (CK, aldolase, AST, ALT) if myositis suspected 8
• Imaging: Joint ultrasound/MRI for synovitis, muscle MRI if weakness present 1, 8

Critical Pitfalls to Avoid

• Do not dismiss pancytopenia as part of AOSD—it signals MAS requiring urgent treatment 1
• Do not start empiric corticosteroids before excluding infection and malignancy, as this can worsen outcomes in disseminated infections or mask leukemia 4, 5, 7
• Do not rely on negative monospot to exclude EBV in immunocompromised patients—use PCR 6
• Do not assume lack of animal contact excludes Q fever—airborne transmission occurs 1
• Bone marrow examination should not be delayed when diagnosis is uncertain with persistent symptoms and pancytopenia 7, 2