Hospital Medicine

Parvovirus

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I. What every physician needs to know.

Parvovirus B19 causes erythema infectiosum (fifth or “slapped check” disease in children), transient aplastic crisis in patients with diseases reducing the life-span of a normal red blood cells, persistent anemia in immunocompromised patients, and a symmetric polyarthritis in adults that can be acute or chronic. When the polyarthritis is symmetric and chronic, it can mimic rheumatoid arthritis.

Infection during pregnancy can result in hydrops fetalis and congenital anemia. However, approximately 50% of women are already immune to the virus and cannot develop the infection. Women who become infected are usually asymptomatic or have minimal symptoms; however, in 2-6%, miscarriage may ensue. The estimated risk of transplacental infection is 30%.

Parvovirus B19 has been only identified in humans. The active mitotic activity seen in the bone marrow is critical for the virus to replicate, thus the clinical manifestations often observed involving red cell lineage. When the erythroid progenitor cell lines are infected, apoptosis ensues, causing an abrupt cessation of all red blood cell production. The normal host is able to tolerate the transient red cell progenitor destruction. However, patients with decreased erythrocytes or erythrocyte life-spans (human immunodeficiency virus [HIV], sickle cell disease, spherocytosis, or thalassemia) are predisposed to transient aplastic crisis, possibly requiring red blood cell transfusions. The skin and joint manifestations are immune-mediated and manifest after viremia decreases in the normal host.

II. Diagnostic Confirmation: Are you sure your patient has Parvovirus?

Detection of parvovirus B19 deoxyribonucleic acid (DNA) can be done with polymerase chain reason (PCR) or dot-blot hybridization (>106genome copies/mL). Virus titers high-enough to be detected are only present for 2-4 days during the flu-like illness phase, thus most diagnosis is done with an IgM assay (which persists for 8-12 weeks after the acute infection). IgG is not helpful in the diagnosis of acute infection. The virus cannot be isolated from samples in the clinical setting. See Figure 1.

Figure 1.

Parvovirus B19. Timeline of viremia, virus detection (Dot blot, PCR), serologic response, and clinical presentation in the normal host. Adapted from various sources.

A. History Part I: Pattern Recognition:

Most patients infected with parvovirus B19 are asymptomatic or minimally symptomatic. A biphasic presentation includes a “flu-like” syndrome during the viremia peak, followed by immune-mediated manifestations, the most common of which is the “slapped-cheeks” disease seen in children. During the acute infection and at the viremia peak, patients complain of fever, chills, headache, and myalgia; such symptoms occur within 14 days after inoculation. The rash and polyarthralgia present after the third week of inoculation when the viral titers have already decreased to undetectable levels. See Figure 1.

Erythema infectiosum presents with a “flu-like” syndrome that may include nausea and diarrhea. During the second phase of the illness, and after the "flu-like" syndrome, a red cheek eruption appears (“slapped cheek”). A circumoral pallor is characteristic. An erythematous macular papular rash may appear on the chest, abdomen, and extremities. As the rash fades, a lacy appearance predominates. The rash can recur or have a fluctuating nature (sometimes triggered by emotions, sunlight, heat, or exercise). Characteristically, although not frequently seen, patients complain of extreme itching in palms and soles. In adults and in people with darker skin pigments, the rash is often times uncharacteristic and difficult to see. Rubella-like, vesicular, or purpuric rashes have also been associated with parvovirus B19 infection. Adults not previously immune can also develop fifth disease.

Transient aplastic crisis in patients with sickle cell and other hemolytic disorders may present with symptoms of profound anemia (dyspnea, high cardiac output heart failure, stroke, or even death). Patients at risk have chronic hemolysis, such as sickle cell disease, hemoglobin SC, hereditary spherocytosis, alpha-thalassemia, and autoimmune hemolysis. This can be life-threatening and may require blood transfusions; however, most patients recover within two weeks. Acute anemia in a normal host after parvovirus B19 infection is rare. Pancytopenia is also rare.Unlike erythema infectiosum or polyarthritis, which are mediated by immune-complexes and occur after viremia has decreased, patients are highly contagious during aplastic crisis.

Persistent anemia, or pure red-cell aplasia, can be seen in immunocompromised patients such as patients with congenital immunodeficiency, HIV, lymphoproliferative disease, and patients with transplanted organs or receiving immunomodulating agents such as rituximab. Such patients have persistent viremia and undetectable IgG titers against the virus, remaining contagious. Rare manifestations include the hemophagocytic syndrome. Fetal infections are not reviewed in this chapter.

Symmetric polyarthritis in normal adults that can be acute, chronic, or recurrent. It usually involves small joints of the hand, wrist, feet and knees (distal symmetric) and lasts for less than 3 weeks. The polyarthritis can be chronic or recurrent, lasting from months to years, resembling rheumatoid arthritis. However, parvovirus B19 does not cause erosive arthritis. Importantly, the virus can induce a transient increase in rheumatoid factor titers. In children, the polyarthritis is mild and self-limited and affects 8% of patients. In adolescents and adults with parvovirus B19 infection, up to 60% are affected by arthralgia.

Other manifestations include hemophagocytic syndrome, myocarditis, meningoencephalitis, peripheral neuropathy, stroke, and glomerulonephritis (mostly in children).

B. History Part 2: Prevalence:

In the United States and other countries, IgG against parvovirus B19 is detected in about 50% of children by age 15 and in about 80% of elderly adults. Transmission usually occurs in respiratory secretions and persons at highest risk are any individuals in close contact with the affected person during the viremia peak. Rarely, parvovirus B19 has been transmitted by blood products. Since the disease is more prevalent in children, daycare workers and school personnel are often affected. During school outbreaks, up to 60% of children can become infected. It may take up to 3 weeks for the exposed individual to become symptomatic after exposure.

C. History Part 3: Competing diagnoses that can mimic Parvovirus.

Parvovirus B19 infection may resemble enterovirus, influenza, and other viral infections including measles and rubella. Rheumatoid arthritis, systemic lupus erythematosus, and reactive arthritis are also in the initial differential diagnosis.

Gloves and socks syndrome is also associated with hepatitis B, cytomegalovirus, measles, coxsackievirus B, Epstein-Barr virus, human herpesvirus 6, and drug reactions.

Other viral infections that may present with arthritis include Chikungunya fever and other alphavirus in the international traveler. Arthritis can also be seen in patients with hepatitis B/ C, rubella, and Treponema pallidum infections among others.

D. Physical Examination Findings.

The skin manifestations are characterized by red cheek eruption giving the characteristic “slapped cheek” appearance with circumoral pallor. An exanthem can also be prominent, the rash is characterized by an erythematous macular papular rash of the trunk and abdomen. As the disease evolves, the rash has a lacy appearance.

In some young adults, parvovirus B19 is associated with a papular, purpuric gloves and socks syndrome. It typically is symmetric, painful, and erythematous edema of the hands and feet. The condition progresses to petechiae and purpura and may develop into vesicles and bullae with skin sloughing.

In severe cases with anemia, pallor is observed. Pulmonary crackles and S3 are auscultated in patients presenting with high cardiac output heart failure.

Symmetric small joint, hand/feet, synovitis and arthritis may be seen.

E. What diagnostic tests should be performed?

Reticulocytes: In normal adults or children, the reticulocyte index decreases during the acute viremic phase; as the viremia resolves (after 14 days of innoculation), the reticulocyte index increases above normal values and resumes to normal after 2 months.

Complete blood count: A transient decrease of hemoglobin can be seen after 2-3 weeks of inoculation. Among patients who require hospitalization due to aplastic crisis or pure red-cell anemia, frequent assessment of blood counts and reticulocytes is warranted (especially in immunocompromised patients receiving IV IgG).

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Most patients exposed with parvovirus B19 do not require confirmatory testing. In the classic presentation of fifth disease witherythema infectiosum and polyarthritis, confirmatory testing is usually not needed.

Parvovirus B19 PCR or dot-blot hybridization. Peak occurs during the acute phase of the infection (<14 days after inoculation). Parvovirus B19 IgM titers rise after the acute prodromal and systemic symptoms and persist for 8-12 weeks after the acute infection. It is important to test for the B19 viral load, particularly in immunocompromised patients, as these patients may not be able to form IgM antibodies against the virus.

In patients with transient aplastic crisis, the bone marrow shows characteristic giant pronormoblasts and absent erythroid precursors. In patients with pure red-cell anemia, the virus titers remains high and IgG and IgM antibodies are not formed, indicating persistent infection with the virus.

Parvovirus B19. Timeline of viremia, virus detection (Dot blot, PCR), serologic response, and clinical presentation in the normal host is shown in Figure 1. The serologic titers response for abnormal hosts have been illustrated elsewhere (see "What's the evidence?" below).

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

None are usually needed.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Parvovirus B19 IgG serology is not helpful in the diagnosis of acute infection. IgG against Parvovirus B19 is detected in about 50% of children by age 15 and in about 80% of elderly adults.

III. Default Management.

Supportive and symptomatic management. NSAID’s, blood transfusion for aplastic crisis. See the chapters on anemia, transfusion medicine, and congestive heart failure. The manifestations of parvovirus B19 infection can be controlled by discontinuing immunosuppressive agents or by starting anti-retroviral therapy in AIDS patients. In immunosuppressed patients, consider IV IgG (0.4 g/kg for 5 days in the acute phase). Among HIV-patients, a monthly IV IgG infusion maintenance therapy is sometimes warranted after 6 months if viremia or worsening of anemia recur.

Since the polyarthralgia and rash are immune-mediated, one may expect these to occur once IV IgG is administered to an immunocompromised patient with parvovirus B19 infection.

A. Immediate management.

None

B. Physical Examination Tips to Guide Management.

None

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Reticulocytes. In normal adults or children, the reticulocyte index decreases during the acute viremic phase; as the viremia resolves (after 14 days of innoculation), the reticulocyte index increases above normal values and resumes to normal after 2 months.

Complete blood count, a transient decrease of hemoglobin can be seen after 2-3 weeks of inoculation. Among patients who require hospitalization due to aplastic crisis or pure red-cell anemia, frequent assessment of blood counts and reticulocytes is warranted (especially in immunocompromised patients receiving IV IgG).

D. Long-term management.

Most adult patients with self-limited disease are not hospitalized. The long term management after hospitalization depends on the reason for hospitalization (transient aplastic crisis, pure-red cell aplasia in immunocompromised patients, or polyarthritis).

In pregnant women who are exposed to parvovirus B19, acute infection should be confirmed by testing for the IgM antibody. If acute infection is confirmed, the fetus should be monitored by weekly or biweekly ultrasonography for 10-12 weeks. After 12 weeks, the risk for hydrops fetalis dissipates. If hydrops occurs, fetal blood sampling and possible transfusion may be necessary.

E. Common Pitfalls and Side-Effects of Management.

N/A

IV. Management with Co-Morbidities.

No change in standard management.

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure.

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

No change in standard management.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

Assessment of profound anemia and response to therapy if blood transfused. Assessment of heart failure, if high cardiac output failure suspected. Assessment for side-effects of therapy (transfusion reactions after blood transfusion of IV IgG therapy). Anticipatory guidance for possible immune-mediated reactions which may occur after administration of IV IgG in immunocompromised patients.

B. Anticipated Length of Stay.

Although not well defined, length of stay will depend on the presence of complications and response to therapy. Often patients will remain hospitalized for 3-7 days.

C. When is the Patient Ready for Discharge.

Stabilized anemia and heart failure symptoms (according to each clinical presentation).

D. Arranging for Clinic Follow-up.

The time for clinic follow-up depends on the reason for admission and response to therapy.

1. When should clinic follow up be arranged and with whom.

Follow up should be arranged in 1 to 2 weeks with the patient’s primary care physician, HIV and hematologist specialists (according to the underlying comorbidity and clinical manifestations). Patients with high cardiac output heart failure should be seen within 1 week of discharge.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Complete blood count, reticulocytes.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Complete blood count, reticulocytes.

E. Placement Considerations.

None

F. Prognosis and Patient Counseling.

Normal hosts who present with anemia requiring hospitalization will improve. Immunocompromised patients are at risk of persistent viral titers and recurrence of anemia (or pure red-cell anemia). Pregnant persons, or in age of reproductive potential, should exercise universal precautions and droplet precautions for 7 days when caring for immunocompromised patients with parvovirus B19, this includes hospital personnel and family contacts.

Patients with pure red-cell aplasia should be isolated during the entire duration of hospital stay.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Vaccination is not available to prevent parvovirus B19 infection. Prophylaxis of contacts is not indicated.

VII. What's the evidence?

Young, NS, Brown, KE. "Parvovirus B19". N Engl J Med. vol. 350. 2004. pp. 586-97.

Servey, JT, Reamy, BV, Hodge, J. "Clinical presentations of parvovirus B19 infection". Am Fam Physician. vol. 75. 2007. pp. 373-6.

Douvoyiannis, M, Litman, N, Goldman, DL. "Neurologic manifestations associated with parvovirus B19 infection". Clin Infect Dis. vol. 48. 2009. pp. 1713-23.

Gutermuth, J, Nadas, K, Zirbs, M, Seifert, F, Hein, R, Ring, J, Brockow, K. "Papular-purpuric gloves and socks syndrome". Lancet. vol. 378. 2011. pp. 198.

Brown, KE. "Human Parvoviruses, Including Parvovirus B19V and Human Bocaparvoviruses". Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 2015. pp. 1840-1847.

Ohl, CA, Forster, D. "Infectious Arthritis of Native Joints". Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 2015. pp. 1302-1317.

Markoff, Lewis. "Alphaviruses Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases". 2015. pp. 1865-1874.

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