Erythema Infectiosum

Erythema infectiosum is a rash illness caused by parvovirus B19. Erythema infectiosum is also known as fifth disease, being 5th in the historical list of rash-causing childhood infectious diseases: measles (1st), scarlet fever (2nd), rubella (3rd), Dukes’ disease (4th), and roseola (6th). Transmission is through respiratory secretions. Diagnosis is generally clinical, suspected in patients presenting with an erythematous malar rash with circumoral pallor (“slapped cheek”). A rash over the trunk and extremities occurs afterward. The illness is self-limited and has no specific therapy. Complications can occur, however, due to the viral tropism for erythrocyte precursors. Patients with hemoglobinopathies can experience aplastic crisis, while the immunocompromised may have chronic infection producing pure red cell aplasia.

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Overview

  • Erythema infectiosum: illness caused by parvovirus B19, associated with fever and a characteristic rash
  • Epidemiology:
    • Infection affects all ages but is more common in children between 3 and 15 years of age.
    • Outbreaks occur commonly in schools and childcare settings.
    • Occurrences of infection are more frequent in late winter and early summer.
  • If a person is immunocompetent, immunity is usually conferred following infection.

Pathophysiology

Mode of transmission

  • Respiratory secretions via:
    • Saliva
    • Mucus
    • Fomites
  • Contact with infected blood or blood products
  • Vertical/transplacental transmission in nonimmune women (can result in congenital infection)

Incubation

The incubation period is 4–21 days.

Pathogenesis

  • Initial B19 viral infection: 
    • Entry into the upper respiratory tract → viremia (prodromal symptoms) 5–10 days from exposure
    • Virus spreads and is cytotoxic to rapidly dividing erythroid precursor cells in the bone marrow → transient ↓ reticulocytes and anemia
    • In healthy individuals: Bone marrow effect is not clinically significant.
    • In individuals with hematologic conditions: severe anemia/aplastic crisis occurs.
    • In immunocompromised patients, viremic state can be prolonged.
  •  Rash:
    • 2–5 days later, erythematous malar rash with circumoral pallor (“slapped cheek”) appears.
    • Followed by lace-like erythematous rash on the trunk and extremities
    • Rash appearance represents resolution of viremia (appearance of immunoglobulin M (IgM)) → no more constitutional symptoms
    • May recur weeks later, triggered by sunlight, stress, or exercise

Clinical Presentation

Initial prodromal symptoms (viremia)

  • Low-grade fever
  • Headache
  • Nausea
  • Diarrhea
  • Cold-like symptoms
  • Pruritus

Later symptoms (viremia resolved)

  • Days 2–5
  • Rosy-red rash, mainly on cheeks
    • Classic slapped-cheek appearance
    • Rash extends over rim of the nose or mouth.
  • Morbilliform → reticulated (lacey) rash:
    • Upper arms
    • Torso
    • Legs
  • Rash more common in children

Complications

  • Arthritis:
    • Acute symmetric joint pain (hands, knees, ankles)
    • More common in teenagers and adults (women > men)
    • Up to 10% of children may have stiff joints.
    • Can last 3 weeks or longer
    • No degenerative joint changes
  • Transient aplastic crisis: 
    • Rapid decline in RBCs
    • Seen in patients with sickle cell disease, spherocytosis, and other hematologic diseases
    • Patients present with weakness/lethargy and pallor.
  • Maternal infection and fetal effects: 
    • Rare but a serious infection (leading to fetal RBC destruction), especially when onset is in the 1st 20 weeks of pregnancy
    • Hydrops fetalis, miscarriage, intrauterine fetal death
  • Chronic infection in immunocompromised patients:
    • These patients cannot mount an immune response to viremia, increasing the risk for chronic infection.
    • Results in pure red cell aplasia (giant pronormoblasts in the bone marrow) and severe anemia (reduced reticulocytes)
Transient aplastic crisis in Parvovirus B19 infection

Transient aplastic crisis in parvovirus B19 infection
Image shows bone marrow cytology. Yellow arrow indicates a giant pronormoblast.

Image: “Parvovirus B19 infection presenting with severe erythroid aplastic crisis during pregnancy in a woman with autoimmune hemolytic anemia and alpha-thalassemia trait: a case report” by Chen CC, Chen CS, Wang WY, Ma JS, Shu HF, Fan FS. License: CC BY 4.0

Diagnosis and Management

Diagnostic approach

  • Diagnosis based on clinical features
  • Additional test(s) in patients with signs and symptoms of anemia:
    • Complete blood count (hemoglobin drops by 2 g/dL from baseline)
    • Reticulocyte count decreased
  •  IgG and IgM antibody testing: 
    • For pregnant women
    • Patients with hemoglobinopathies/hemolytic conditions
    • Severe or persistent arthropathy
    • Not utilized in immunocompromised patients, as they cannot produce detectable antibody levels
  • In immunocompromised patients with pure red cell anemia: Polymerase chain reaction (PCR) for parvovirus B19 detects infection.

Treatment

  • Generally, a self-limited illness and treatment is thus supportive.
  • Severe transient aplastic crisis: Transfusion may be required.
  • Immunocompromised patients with chronic infection and anemia may need:
    • Reduced dose of immunosuppressive agents
    • Intravenous immunoglobulin treatment
    • In severe cases, bone marrow transplantation

Prevention

  • General infection-control practices
  • High-risk individuals should be informed of measures to avoid exposure and when to seek medical attention.

Differential Diagnosis

  • Hydrops fetalis: serious fetal condition that involves an accumulation of fluid in 2 or more fetal compartments including ascites, pleural effusion, pericardial effusion, and skin edema. The condition carries a poor prognosis for perinatal survival.
  • Aplastic crisis: occurs with significant reduced production of RBCs resulting in a rapid decline in the hemoglobin level with reticulocytopenia. With parvovirus B19 infection, the marrow function generally returns spontaneously within 1 week.
  • Arthritis: joint disorder characterized by joint pain and stiffness accompanied by other manifestations such as redness, warmth, swelling, and decreased range of motion in joints.
Table: Comparison of common childhood rashes
NumberOther names for the diseaseEtiologyDescription
1st disease
  • Measles
  • Rubeola
  • 14-day measles
  • Morbilli
Measles morbillivirus
  • Cough, coryza, conjunctivitis
  • Koplik’s spots (blue-white spots with a red halo) on the buccal membrane
  • Maculopapular rash begins on the face and behind the ears → spreads to trunk/extremities
2nd disease
  • Scarlet Fever
  • Scarlatina
Streptococcus pyogenes
  • Sandpaper-feeling maculopapular rash that begins on the neck and groin → spreads to trunk/extremities
  • Dark, hyperpigmented areas, especially in skin creases, called Pastia’s lines
  • Strawberry tongue: coated white membrane through which swollen, red papillae protrude
3rd disease
  • Rubella
  • German measles
  • 3-day measles
Rubella virus
  • Asymptomatic in 50% of cases
  • Fine macular rash on the face (behind the ears) → spreads to the neck, trunk, and extremities (spares palms/soles)
  • Forscheimer’s spots: Pinpoint red macules and petechiae can be seen over the soft palate/uvula
  • Generalized tender lymphadenopathy
4th disease
  • Staphylococcal Scalded Skin Syndrome
  • Filatow-Dukes’ disease
  • Ritter’s disease
Due to Staphylococcus aureus strains that make epidermolytic (exfoliative) toxin
  • Some believe that 4rh disease is a misdiagnosis and, thus, nonexistent.
  • The term was dropped in the 1960s and is only used for medical trivia today.
  • Begins with a diffuse erythematous rash that usually begins around the mouth → fluid-filled bullae or cutaneous blisters → rupture and desquamate
  • Nikolsky’s sign: Applying pressure on the skin with a finger (stroking) results in sloughing off of upper layers.
5th diseaseErythema infectiosumErythrovirus or parvovirus B19 (Primate erythroparvovirus 1)
  • Facial erythema (“slapped-cheek rash”) that consist of red papules on the cheeks
  • Begins on the face → spreads to the extremities → extends to trunk/buttocks
  • Initially confluent, then becomes net-like or reticular as it clears
6th disease
  • Exanthem subitum
  • Roseola infantum
  • Rose rash of infants
  • 3-day fever
Human herpesvirus 6B or human herpesvirus 7
  • Sudden onset of high fever
  • Nagayama spots: papular spots on the soft palate/uvula
  • Rash begins as fever resolves (the term “exanthem subitum” describes “surprise” of rash after the fever subsides)
  • Numerous rose-pink, almond-shaped macules on the trunk and neck → sometimes spreads to face/extremities

References

  1. Aqeel K.Z., & Turner A.R., & Mayeaux, Jr. E.J. (2019). Fifth disease. Usatine R.P., & Smith M.A., & Mayeaux, Jr. E.J., & Chumley H.S.(Eds.), The Color Atlas and Synopsis of Family Medicine, 3e. McGraw-Hill.
  2. Cennimo, D., Dieudonne, A. (2019). Parvovirus B19 infection. Medscape. Retrieved 24 Jan 2021 from https://emedicine.medscape.com/article/961063-overview
  3. Jordan, J. (2019). Clinical manifestations and diagnosis of parvovirus B19 infection. UpToDate. Retrieved 24 Jan 2021 from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-parvovirus-b19-infection
  4. Jordan, J. (2020). Treatment and prevention of parvovirus B19 infection. UpToDate. Retrieved 24 Jan 2021 from https://www.uptodate.com/contents/treatment-and-prevention-of-parvovirus-b19-infection

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