What are the symptoms of monkeypox, especially in immunocompromised patients, such as those with advanced Human Immunodeficiency Virus (HIV)?

Symptoms of Monkeypox

Classic Clinical Presentation in Immunocompetent Patients

Monkeypox typically begins with a prodromal phase lasting several days, characterized by fever, severe headache, lymphadenopathy (a distinguishing feature from smallpox), myalgia, and fatigue, followed 1-3 days later by a characteristic rash that progresses through distinct stages: macules, papules, vesicles, pustules, and finally crusted lesions. 1, 2, 3, 4

Prodromal Phase (Days 0-3)

• Fever (often high-grade, up to 104°F) is typically the first symptom 1, 2, 3, 4
• Severe headache occurs in most patients 2, 3, 4
• Lymphadenopathy (swollen lymph nodes) is a key distinguishing feature that differentiates monkeypox from smallpox and other orthopoxvirus infections 1, 2, 3, 4
• Myalgia (muscle aches) and widespread body aches are common 2, 5, 3
• Fatigue and malaise develop early in the illness 1, 2, 3
• Chills may accompany the fever 1, 3

Rash Phase (Days 1-3 after fever onset)

• Skin lesions typically erupt 1-3 days after fever onset 1, 2
• The rash is characteristically more concentrated on the face and extremities (including palms and soles) rather than the trunk 1
• Lesions progress through distinct stages: macules → papules → vesicles → pustules → crusts → scab shedding 3, 4
• All lesions in a given area tend to be in the same stage of development, unlike varicella (chickenpox) 1
• Lesions are typically painful 1

Modified Clinical Presentation in the 2022 Outbreak

Recent cases have shown a significant shift in clinical presentation, with anogenital skin lesions emerging as the predominant feature, often without the classic prodromal symptoms or widespread rash distribution. 1

• Anogenital lesions (involving genitals and anus) have become the primary presenting feature in many cases 1, 4
• Lesions may be localized rather than disseminated 1, 4
• Prodromal symptoms may be absent or minimal in some patients 1
• The rash may appear before systemic symptoms in atypical presentations 5

Severe Manifestations in Immunocompromised Patients (Including Advanced HIV)

Immunocompromised individuals, particularly those with advanced HIV infection, are at significantly higher risk for severe, prolonged, and potentially fatal monkeypox disease with atypical presentations. 1

Prolonged and Severe Course

• Episodes are usually longer-lasting and more severe than in immunocompetent hosts 1
• Lesions may extend across the face or involve extensive body surface area 1
• Oral cavity involvement is more common in immunocompromised patients 1
• Chronic ulcerations may develop without adequate treatment 6

Disseminated Disease

• Multi-dermatomal involvement (≥2 dermatomes) indicates severe disease requiring escalation of care 6
• Visceral dissemination can occur, affecting internal organs including liver (hepatitis), lungs (pneumonitis), and central nervous system (encephalitis) 6
• Hemorrhagic manifestations may develop in severe cases, similar to other severe poxvirus infections 7

Atypical Presentations

• Clinical presentation may be atypical in immunocompromised patients, making diagnosis more challenging 5
• Laboratory confirmation is essential when clinical presentation is atypical, as diagnosis cannot rely on clinical features alone 7, 5

Disease Duration and Natural History

• Incubation period: typically 6-13 days (range 5-21 days) 5, 3, 4
• Total illness duration: 2-4 weeks in immunocompetent patients 2
• Immunocompromised patients may develop new lesions for 7-14 days and heal more slowly, requiring extended treatment duration 8
• The disease is usually self-limiting in immunocompetent individuals 1, 2

Critical Diagnostic Considerations

It may be difficult to distinguish monkeypox based on clinical presentation alone, especially for atypical cases, because various conditions cause similar skin rashes. 5

• PCR testing of lesion material (swabs from vesicles, pustules, or crusts) is the gold standard for laboratory confirmation 2, 5, 4
• Testing should be offered to anyone meeting the suspected case definition, particularly with epidemiological risk factors 5
• In immunocompromised patients with atypical presentations, laboratory confirmation is mandatory before initiating specific treatment 7, 5

Common Pitfalls to Avoid

• Do not dismiss localized anogenital lesions as sexually transmitted infections without considering monkeypox in the current epidemiological context 1
• Do not assume absence of fever or lymphadenopathy excludes monkeypox, as the 2022 outbreak demonstrated atypical presentations 1
• Do not delay testing in immunocompromised patients even with atypical presentations, as early diagnosis is critical for optimal outcomes 7, 1
• Do not confuse the synchronous progression of monkeypox lesions with the asynchronous lesions of varicella 1