Changes

Update

Goals

To support primary healthcare professionals to:

• Diagnose suspected parvovirus B19 infection (slapped cheek syndrome).
• Arrange laboratory investigations to confirm the diagnosis in pregnant women and people at increased risk of complications.
• Offer self-management advice for symptom relief.
• Arrange urgent referral to a specialist in fetal medicine if the diagnosis is confirmed at any stage of pregnancy.
• Arrange referral or urgent admission if a complication is suspected, if appropriate.

Outcome measures

Audit criteria

No audit criteria were found during the review of this topic.

QOF indicators

No QOF indicators were found during the review of this topic.

QIPP - Options for local implementation

No QIPP indicators were found during the review of this topic.

NICE quality standards

No NICE quality standards were found during the review of this topic.

What is it?

• Parvovirus B19 is a small single-stranded DNA virus and is a member of the Parvoviridae family (genus Erythrovirus).
  • The virus is usually transmitted by droplet spread through respiratory secretions, more rarely by vertical transplacental transmission from a pregnant woman with acute infection, or by blood transfusion.
  • The virus targets rapidly growing erythroid progenitor cells which form red blood cells found in bone marrow, fetal liver, umbilical cord, and peripheral blood.
  • The incubation period is about 14–21 days.
• Parvovirus B19 infection can cause slapped cheek syndrome (erythema infectiosum or fifth disease), commonly in school-age children. It is usually a mild, self-limiting illness.
  • It was named fifth disease as it was the fifth identified childhood exanthema. 

[Lamont, 2011; Slavov, 2011; AABB, 2013; UK NSC, 2014; PHE, 2017; PHE, 2019; Brown, 2020]

How common is it?

The precise incidence of parvovirus B19 infection in the UK is not known, it is not notifiable, may be asymptomatic, and the diagnosis can only be confirmed on laboratory testing.

• Parvovirus B19 infection is endemic in most countries — about 15% of pre-school children, around 50% of children aged 15 years, 50–60% of adults, 60–70% of women of childbearing age, and nearly 90% of older people have serological evidence of past infection.
• Infection with parvovirus B19 can occur at any age, but is most common in children aged 6–10 years. 
• About 1–3% of susceptible pregnant women develop serologic evidence of infection in pregnancy, rising to over 10% in epidemic periods.
• Seasonal outbreaks of parvovirus B19 infection occur every 3–4 years in the UK, mainly in late winter and early spring.

 [Lamont, 2011; AABB, 2013; Crane, 2014; UK NSC, 2014; PHE, 2017; PHE, 2019; Brown, 2020]

What are the complications?

Complications of parvovirus B19 infection are rare in healthy children and adults. Pregnant women, and people who are immunocompromised or have haematological disorders such as hereditary anaemias, are at increased risk of serious and potentially life-threatening complications.

• Pregnancy — in the majority of cases of maternal infection the fetus is unaffected, however it can result in:
  • Non-immune hydrops fetalis. 
    • Infection of fetal erythroid progenitor cells in the bone marrow and liver may cause profound anaemia, hypoalbuminaemia, heart failure, and hydrops fetalis (defined as subcutaneous oedema in at least two fetal compartments). There may be associated hepatic impairment and myocarditis in the fetus.
    • These complications usually occur 3–5 weeks after the onset of maternal infection, but can occur later.
    • This occurs in 3–11% of cases if infection occurs between 9–20 weeks' gestation, and may cause fetal loss in about 40–50% of cases, if untreated.
  • Fetal death. 
    • The overall fetal loss rate is 5–10% — this may occur with or without evidence of hydrops fetalis.
    • Infection in the first 20 weeks of pregnancy increases the risk. 
    • Most fetal deaths occur in the second trimester of pregnancy, following exposure in weeks 9–20. The absolute risk of fetal loss in the first trimester in a Danish study was 0.1%. 
  • Maternal pre-eclampsia-like syndrome ('mirror syndrome'). 
    • This is rare, and is the development of maternal oedema secondary to fetal hydrops. It is usually associated with severe pre-eclampsia. 
    • It is so-called because the maternal signs reflect those present in the fetus.
  • Note: universal screening of pregnant women for past parvovirus B19 infection is not recommended, as there is no vaccine or prophylaxis treatment available. 
• People who are immunocompromised (for example leukaemia, lymphoma, HIV infection, receiving chemotherapy, or bone marrow or solid organ transplantation) or have a haematological disorder (for example sickle cell disease, thalassaemia, hereditary spherocytosis, or autoimmune haemolytic anaemia) are at increased risk of complications, including:
  • Transient aplastic crisis/anaemia. 
    • People with an underlying haemolytic disorder or who have increased red blood cell turnover are at increased risk. 
    • This usually causes a severe, transient anaemia, however potentially life-threatening aplastic crisis may occur when there is severe anaemia associated with absent reticulocytes (which may cause angina, heart failure, and bone marrow necrosis).
    • Affected people may initially present with severe anaemia associated with pallor, weakness, lethargy, fever, tachycardia, and tachypnoea.
  • Pure red cell aplasia. 
    • People who are immunocompromised are more at risk.
    • Persistent parvovirus B19 infection may cause chronic bone marrow suppression with chronic, severe anaemia and potentially life-threatening pancytopenias.
  • Neurological complications. 
    • These include encephalitis, meningitis, stroke, and peripheral neuropathy.
  • Other complications (rare).
    • These include myocarditis, cardiomyopathy in children, nephritic syndrome, hepatitis, and vasculitis.

[Lamont, 2011; Slavov, 2011; MacMahon, 2012; AABB, 2013; Barah, 2014; Crane, 2014; O'Grady, 2014; UK NSC, 2014; SOGC, 2018; PHE, 2019; UK NSC, 2019; BMJ, 2020; Brown, 2020; PHE, 2021]

What is the prognosis?

• For most healthy people, parvovirus B19 infection causes a mild, self-limiting illness which is followed by life-long immunity.
  • In children, the erythematous rash, which can develop on the torso and extremities after the initial facial rash, usually resolves after 1–3 weeks, but may recur following exposure to sunlight, heat, or stress. 
  • In adults, a symmetrical polyarthropathy may persist for several weeks, but rarely may persist for months, or may recur several months after the acute infection.
• In pregnant women with confirmed parvovirus B19 infection the prognosis partially depends on the gestational age at infection. The risk of transmission to the fetus is increased at 9–20 weeks' gestation. 
  • Transplacental transmission occurs in about 30% of women depending on gestation. Complications usually occur 3–5 weeks after the onset of maternal infection, but can be later.
  • The fetus is most vulnerable when it is infected in the second trimester, with the peak risk occurring at 17–24 weeks' gestation.
  • At less than 20 weeks' gestation, the estimated excess fetal loss rate during pregnancy is about 9%. 
  • Babies who are born at full term are usually healthy with no evidence of congenital malformations or developmental problems secondary to infection.
• People who are immunocompromised may develop persistent infection and are at increased risk of haematological complications.

[Lamont, 2011; Slavov, 2011; Crane, 2014; UK NSC, 2014; Allmon, 2015; PHE, 2019; BMJ, 2020; Brown, 2020]

When should I suspect parvovirus B19 infection?

In healthy children the diagnosis of parvovirus B19 infection is usually made on clinical grounds.

• Suspect infection in children if they present with an acute biphasic illness with a characteristic macular erythematous facial rash, that appears on one or both cheeks (resembling a 'slapped cheek'). 
  • Prodromal symptoms are common and occur 1 week after exposure and 1–2 weeks prior to onset of the exanthema. These can include low-grade fever, headache, nasal discharge, abdominal pain, pharyngitis, and coryza. 
  • A maculopapular rash may develop 1–4 days after the initial facial rash, spread to the extremities and torso, and evolve into a lacy reticular appearance. The rash usually resolves after 1–3 weeks, but may persist for longer. 
  • Symmetrical polyarthropathy affecting the small joints of the hands and occasionally the knees, ankles, and wrists may occur although this is uncommon in children, and rarely the rash can present as papular-purpuric gloves and socks syndrome.

In healthy adults, it is difficult to make a diagnosis of parvovirus B19 infection on clinical grounds, as symptoms may be atypical, it may mimic other conditions, and 25–50% of infections (in adults and children) are asymptomatic.

• Suspect infection in adults if they present with a history of contact with parvovirus B19 infection (usually in a child), or if there is a known local outbreak. The infectious period is up to 10 days before the onset of the rash, including the day of onset.
  • Prodromal symptoms are more common in adults and may appear about a week after contact with the infection.
  • Self-limited symmetrical polyarthropathy of the small joints is often the most common presenting symptom, occurring in around 50% of adults and is more common in women.
    • This typically affects the small joints of the hands, wrists, knees, and ankles, and lasts several weeks, although rarely it may persist for months.
  • The characteristic facial rash seen in children may be absent in adults, but 2–3 weeks after the first prodromal symptoms, a maculopapular rash on the trunk, back, and limbs may develop, which fades to produce a lace-like, reticular rash. This usually resolves within a week.

Note: consider parvovirus B19 infection in people who are immunocompromised or who have an underlying haematological disorder, who present with sudden-onset or severe anaemia.

How should I investigate suspected parvovirus B19 infection?

In healthy children and adults, the diagnosis of parvovirus B19 infection should be based on clinical features — laboratory investigation to confirm the diagnosis is not required. 

• Note: parvovirus B19 infection is not a notifiable disease.

If a pregnant woman has suspected parvovirus B19 infection, contact the local virology, microbiology, or infectious diseases department immediately for further advice. This is likely to include urgent blood testing for:

• Parvovirus B19-specific immunoglobulin M (IgM). Note: serum from antenatal booking bloods or earlier samples may be available to help confirm the diagnosis, but initial blood testing should not be delayed.
  • If parvovirus B19-specific IgM is not detected, this excludes infection in the 4 weeks prior to the blood test. Infection cannot be excluded if the blood test is taken more than 4 weeks after the onset of rash or associated illness. Seek specialist advice on any additional testing needed, for example, of antenatal booking bloods.
  • If parvovirus B19-specific IgM is detected in the first 20 weeks of pregnancy, this suggests recent infection with parvovirus B19, and the diagnosis is confirmed by testing for high-titre viral DNA using polymerase chain reaction (PCR) analysis, or parvovirus B19-specific IgG in antenatal booking blood samples.
• Rubella infection, irrespective of the woman's previous testing or immunization status. See the CKS topic on Rubella for more information on laboratory tests to arrange and subsequent management. 

If a pregnant woman has had possible exposure to parvovirus B19 infection, contact the local virology, microbiology, or infectious diseases department immediately for further advice. This is likely to include urgent blood testing for:

• Parvovirus B19-specific IgG and IgM — if the parvovirus B19 Ig result is:
  • Positive for IgG and negative for IgM, reassure the woman that she has had past (but not recent) parvovirus B19 infection, and she is immune. Retesting is not necessary. Advise her to seek medical advice if a rash and/or symptoms develop.
  • Negative for both IgG and IgM, she is susceptible to infection. Repeat a blood test 1 month after last contact even if she remains asymptomatic (or earlier if symptoms develop). If the repeat test is:
    • Negative for both IgG and IgM, reassure the woman that there is no evidence of recent infection, but she remains susceptible to future infection. 
    • Positive for IgM and negative for IgG, repeat a blood test immediately. If this result is positive for IgM, this suggests recent infection with parvovirus B19, and the diagnosis is confirmed by testing for high-titre viral DNA using PCR analysis, or parvovirus B19-specific IgG in antenatal booking blood samples. 
  • Positive for IgM (irrespective of the IgG result), this suggests recent infection with parvovirus B19, and the diagnosis is confirmed by testing an antenatal booking blood sample or a repeat blood test after 7–10 days. Seek specialist advice on any additional testing needed.
• Rubella infection (if the woman is not known to be immune). See the CKS topic on Rubella for more information on laboratory tests to arrange and subsequent management. 

If parvovirus B19 infection is suspected in a person who is immunocompromised, has a haematological disorder, or is in early transient aplastic crisis, arrange urgent blood testing for: 

• High-titre viral DNA using PCR analysis, to confirm the diagnosis of parvovirus B19 infection. Contact the local virology, microbiology, or infectious diseases department if there is any uncertainty about blood tests to arrange.
• Full blood count (including reticulocyte count). 

If there is any uncertainty about laboratory investigations to arrange or how to interpret results, contact the local virology, microbiology, or infectious diseases department for further advice. 

What else might it be?

Conditions that may present similarly to parvovirus B19 infection include:

• Rubella 
  • In children, there may be a rash of coalescing pink macules starting on the head and neck, although it does not usually cause the 'slapped cheek' appearance with accompanying perioral pallor of parvovirus B19 infection.
  • The rash spreads to the trunk and extremities and there may be prodromal symptoms and petechiae on the palate.
  • In adults, rubella can cause rash, fever, and arthropathy.
  • See the CKS topic on Rubella for more information.
• Measles 
  • This causes florid characteristic erythematous, maculopapular lesions that may become confluent, with a similar distribution to parvovirus B19 infection. The rash starts on the face (usually behind the ears) and moves down the body.
  • There may be Koplik's spots (tiny red or white spots with a red halo) on the buccal mucosa.
  • Prodromal symptoms may include conjunctivitis, cough, and coryza, and they tend to be more severe than those in parvovirus B19 infection.
  • See the CKS topic on Measles for more information.
• Scarlet fever 
  • This is usually caused by Streptococcus infection.
  • Most children have a fever and sore throat 1–2 days before the rash develops on the upper trunk. The rash then spreads over the body, sparing the palms and soles, with associated perioral pallor.
  • The rash is typically confluent, erythematous, fine macules and sandpaper-like papules. There may be associated petechiae on the palate and erythematous, swollen papillae on the tongue ('strawberry tongue').
  • See the CKS topic on Scarlet fever for more information.
• Roseola infantum 
  • This is caused by herpesvirus type 6 and typically affects children younger than 3 years of age.
  • There may be mild rhinorrhoea, sore throat, and sudden onset of high fever.
  • As the fever subsides, the typical rash consists of tiny pink papules or is maculopapular, and not usually itchy. It starts on the trunk before spreading peripherally to the face and limbs.
• Enterovirus and adenovirus 
  • These are common causes of rubella-like rash.
• Rheumatoid arthritis
  • This often causes a symmetrical polyarthropathy, and people with parvovirus B19 infection may test positive for rheumatoid factor.
  • See the CKS topic on Rheumatoid arthritis for more information.

Other causes include:

• Tropical viruses, including alphaviruses and flaviviruses (for example Dengue fever) — should be considered if the person has recently travelled in the tropics. 
• Cytomegalovirus (CMV), HIV infection, glandular fever (infectious mononucleosis), Kawasaki disease, syphilis, toxoplasmosis — may all cause a rash with associated lymphadenopathy.
• Drug reaction, for example to anti-epileptic drugs.
• See the CKS topics on HIV infection and AIDS, Glandular fever (infectious mononucleosis), Syphilis, and Epilepsy for more information.

Scenario: Children and adults (not pregnant)

From birth to 12 years.

Scenario: Pregnant women

From age 13 years onwards (Female).

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of Parvovirus B19 infection.

Search dates

January 2017 - February 2022

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

• Parvovirus B19 Human/, human parvovirus.tw, Erythema Infectiosum/, fifth disease.tw, slap$ cheek.tw.
• (vertical transmission or mother-to-child transmission or MTCT).tw.
• Pregnancy Outcome/

Sources of guidelines

• National Institute for Health and Care Excellence (NICE)
• Scottish Intercollegiate Guidelines Network (SIGN)
• Royal College of Physicians
• Royal College of General Practitioners
• Royal College of Nursing
• NICE Evidence
• World Health Organization
• Guidelines International Network
• TRIP database
• Agency for Healthcare Research and Quality
• Institute for Clinical Systems Improvement
• National Health and Medical Research Council (Australia)
• Royal Australian College of General Practitioners
• British Columbia Medical Association
• Canadian Medical Association
• Alberta Medical Association
• Michigan Quality Improvement Consortium
• Singapore Ministry of Health
• National Resource for Infection Control
• RefHELP NHS Lothian Referral Guidelines
• Medline (with guideline filter)
• Driver and Vehicle Licensing Agency
• NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

• The Cochrane Library:
  • Systematic reviews
  • Protocols
  • Database of Abstracts of Reviews of Effects
• Medline (with systematic review filter)
• EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

• NIHR Health Technology Assessment programme
• The Cochrane Library:
  • NHS Economic Evaluations
  • Health Technology Assessments
• Canadian Agency for Drugs and Technologies in Health
• International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

• The Cochrane Library:
  • Central Register of Controlled Trials
• Medline (with randomized controlled trial filter)
• EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

• Bandolier
• Drug and Therapeutics Bulletin
• TRIP database
• Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

• Department of Health
• Health Management Information Consortium (HMIC)

Patient experiences

• Healthtalk
• BMJ - Patient Journeys

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

• British National Formulary (BNF)
• electronic Medicines Compendium (eMC)
• European Medicines Agency (EMEA)
• LactMed
• Medicines and Healthcare products Regulatory Agency (MHRA)
• REPROTOX
• Scottish Medicines Consortium
• Stockley's Drug Interactions
• TERIS
• TOXBASE
• Micromedex
• UK Medicines Information

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

• Clinical accuracy.
• Consistency with other providers of clinical knowledge for primary care.
• Accuracy of implementation of national guidance (in particular NICE guidelines).
• Usability.

Principles of the consultation process

• The process is inclusive and any individual may participate.
• To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.
• Comments received after the deadline will be considered, but they may not be acted upon before the clinical topic is issued onto the website.
• Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.
• External reviewers are not paid for commenting on the draft topics.
• Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
• All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.
• All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

Stakeholders

• Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
• Stakeholders identified from the following groups are invited to review draft topics:
  • Experts in the topic area.
  • Professional organizations and societies (for example, Royal Colleges).
  • Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer’s Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.
  • Guideline development groups where the topic is an implementation of a guideline.
  • The British National Formulary team.
  • The editorial team that develop MeReC Publications.
• Reviewers are provided with clear instructions about what to review, what comments are particularly helpful, how to submit comments, and declaring interests.

Patient engagement

Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

• Topic selection
• Scoping of topic
• Selection of clinical scenarios
• First draft internal review
• Second draft internal review
• External review
• Final draft and pre-publication

Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Evidence exclusion criteria

Our policy

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

• Animal studies
• Original research is not written in English

Possible exclusions for reviewed literature:

• Sample size too small or study underpowered
• Bias evident or promotional literature
• Population not relevant
• Intervention/treatment not relevant
• Outcomes not relevant
• Outcomes have no clear evidence of clinical effectiveness
• Setting not relevant
• Not relevant to UK
• Incorrect study type
• Review article
• Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

• Feasibility
  • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
• Organizational and Financial Impact Analysis
• Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
  • Eligible population
  • Current interventions
  • Likely uptake of new intervention or recommendation
  • Cost of the current or new intervention mix
  • Impact on other costs
  • Condition-related costs
  • In-direct costs and service impacts
  • Time dependencies
• Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Declarations of interest

Our policy

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

• Personal financial interests
• Personal family interest
• Personal non-financial interest
• Non-personal financial gain or benefit

Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Who should declare competing interests?

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

Competing interests declared for this topic:

None.