Systemic Lupus Erythematosus and Pregnancy
Introduction
Background
Systemic lupus erythematosus (SLE) is one of the most common autoimmune disorders that affect women during their childbearing years. Typical clinical symptoms of SLE include fatigue, fever, arthralgias, arthritis, a photosensitive rash, serositis, Raynaud phenomenon, glomerulonephritis, vasculitis, and hematologic abnormalities. Flares of SLE are uncommon during pregnancy and are often easily treated. The most common symptoms of these flares include arthritis, rashes, and fatigue.SLE increases the risk of spontaneous abortion, intrauterine fetal death, preeclampsia, intrauterine growth retardation, and preterm birth. Prognoses for both mother and child are best when SLE is quiescent for at least 6 months before the pregnancy and when the mother's underlying renal function is stable and normal or near normal.
The mother's health and fetal development should be monitored frequently during pregnancy. In addition, an obstetrician with experience in high-risk care should conduct the follow-up of pregnant women with SLE.
Pathophysiology
The pathophysiology of disease activity during pregnancy remains unknown.Increased SLE disease activity is expected during pregnancy because of increased levels of estrogen, prolactin, and T–helper cell 2 cytokines. The incidence of exacerbations during pregnancy and the postpartum period, especially in women in remission at the beginning of pregnancy, has been progressively diminishing in the last 30 years. Possible causes for flare-ups during the postpartum period include decreased levels of anti-inflammatory steroid, elevated levels of prolactin (ie, proinflammatory hormone), and changes in the neuroendocrine axis.
Frequency
United States
The prevalence of SLE is 14.6-50.8 cases per 100,000 general population.The frequency of exacerbation or persistently active disease varies with disease activity at conception. Rates range from 7-33% in women who have been in remission for at least 6 months to 61-67% in women who have active disease at the time of conception.
In the United States, the overall average incidence of SLE between 1950 and 1990 was estimated to be 1.8-7.6 cases per 100,000 person-years.
International
Incidences in 4 European cohorts from Iceland, England, and Sweden were similar to those observed in the United States. Rates in these cohorts were 3.3-4.8 cases per 100,000 person-years.Mortality/Morbidity
Over the past 50 years, the survival rate in patients with SLE has improved dramatically. In 1955, the 5-year survival rate was only 50%, whereas, in the 1990s, the 10-year survival rate approached or exceeded 90%, and the 20-year survival rate approached 70%. Factors contributing to this improvement include early diagnosis, increased potency of pharmaceutical agents, and improved treatments (eg, dialysis, kidney transplantation).Nonetheless, despite improved survival rates, mortality rates among patients with SLE remain 3-5 times greater than those in the general population.
As with studies of incidence and prevalence, research about factors predictive of mortality in patients with SLE has focused on the patient's sex, race or ethnicity, socioeconomic status, or age at disease onset.
In one prospective study, hypertension during pregnancy, preterm delivery, unplanned cesarean delivery, postpartum hemorrhage, and maternal venous thromboembolism were more common in women with SLE than in women without SLE. In addition, fetal growth restriction and neonatal deaths were most often seen in association with SLE.
Race
- Evidence suggests that SLE is more common in African American groups than in white populations. In general, prognoses are worse in African American or Hispanic patients with SLE than in white patients.
- In North America and Europe, prognoses are worse in patients with SLE who are of Asian, Indian, African Caribbean, or Hispanic race than in white patients.
- When the prevalence of SLE is stratified by race, the prevalence among African Caribbean individuals was approximately 5 times the rate observed in people of white descent.
- In the United States, the prevalence of SLE in female African Americans ranges from 17.9-283 cases per 100,000.
- A West Indian study of female patients with SLE reported a prevalence of 83.8 cases per 100,000.
Sex
The incidence of lupus is dramatically higher in women than in men. The race- and sex-specific incidence rates of definite SLE per 100,000 persons were 0.4 (95% CI, 0.2-0.7) in white males, 3.5 (95% CI, 2.9-4.2) in white females, 0.7 (95% CI, 0-2) in African American males, and 9.2 (95% CI, 6.8-12.5) in African American females.Age
SLE in pregnancy affects female adolescents and women of reproductive age.- The incidence peaks between ages 15 and 45 years, ie, the childbearing years, when the female-to-male ratio is about 12:1.
- In patients with SLE that begins during childhood or later, the female-to-male ratio is approximately 2:1.
Clinical
History
History taking is targeted at identifying disease activity, complications related to pregnancy, and adverse effects of various medications.- General considerations
- Currently, more than 50% of all pregnancies in women with lupus have a normal outcome.
- About 25% of women with lupus deliver healthy babies prematurely.
- Fetal loss due to spontaneous abortion occurs in less than 20% of cases.
- Symptoms due to pregnancy
- Nausea, vomiting, and morning sickness can occur during the first trimester.
- The aforementioned symptoms may prevent absorption of medications.
- Symptoms suggestive of lupus disease activity
- Constitutional symptoms may be present.
- Most patients with lupus report fatigue during pregnancy.
- The likelihood of developing renal disease during pregnancy is not increased if the patient was in remission at the time of conception.
- Differentiation of signs and symptoms of normal pregnancy from those of exacerbations of lupus
- Differentiate malar rash from chloasma.
- Differentiate proteinuria secondary to preeclampsia from proteinuria due to lupus nephritis.
- Differentiate thrombocytopenia in pregnancy (ie, hemolysis, elevated liver enzyme levels, and low platelet counts [HELLP] syndrome) from thrombocytopenia of lupus exacerbation (ie, thrombocytopenic purpura [TTP] or idiopathic TTP [ITP]).
- Pedal edema and fluid accumulation in joints, especially the knees, can occur in the late stages of pregnancy and should be differentiated from the arthritis of systemic lupus erythematosus (SLE).
Physical
- Flares
- In general, pregnancy does not cause flares.
- Flares that do develop often occur during the first or second trimester or during the first few months after delivery.
- Most flares are mild and easily treated with small doses of corticosteroids.
- Renal disease
- Patients with organ damage at the time of pregnancy may have difficulty because pregnancy adds to the burden on malfunctioning organs. This phenomenon is particularly important in patients with renal disease.
- Pregnancy in women with lupus nephritis is associated with an increased risk of fetal loss (up to 75%) and with worsening of the renal and extrarenal manifestations, as shown in most studies. Although the incidence is not high, severe renal exacerbations are possible. Thus, women with lupus nephritis should be encouraged to delay pregnancy until the disease can be rendered inactive for at least 6 months.
- Although the risk of adverse effects on the fetus are minimized if conception and pregnancy occur in the absence of glucocorticoids or other immunosuppressive drugs, continuing glucocorticoids at the lowest effective dose and/or cautious use of azathioprine may be preferred in some patients.
- Other comorbidities
- Patients with preexisting hypertension, proteinuria, and azotemia are at an increased risk.
- Pregnancy outcomes in women with SLE who receive renal transplants are remarkably similar to those of other transplant recipients.1
- Preeclampsia
- Preeclampsia is a frequent complication of pregnancy in SLE, occurring in approximately 13% of patients.
- Preeclampsia is often difficult to distinguish from lupus nephritis. Laboratory testing is occasionally useful in distinguishing preeclampsia from nephritis.
- Preeclampsia is most likely in patients with antiphospholipid antibodies, diabetes mellitus, or a previous episode of preeclampsia.
- Pre-existing thrombocytopenia may also be a risk factor.
- Thrombosis
- Pregnancy, and especially the postpartum period, represents an additional thrombotic risk in patients with SLE who have antiphospholipid antibodies.
- Patients who are already taking warfarin because of a past venous or arterial thrombotic event should be switched to therapeutic doses of heparin (either unfractionated or low molecular weight heparin) as soon as the pregnancy is recognized.
- Patients who have had only fetal losses or other pregnancy morbidity due to antiphospholipid antibody syndrome are treated with prophylactic doses of heparin and low-dose aspirin (81 mg) during subsequent pregnancies.
- Currently, no accepted prophylaxis is available for women with SLE who have antiphospholipid antibodies and no past morbidity, although many consider the use of low-dose aspirin (81 mg), with or without hydroxychloroquine.
- Other causes of morbidity
- In addition to the obvious morbidity from SLE flares and their treatment, other morbidity is also increased in a pregnancy associated with SLE.
- Rates of urinary tract infections, diabetes mellitus, hypertension, preterm premature rupture of membranes, and preeclampsia are all increased in SLE.
- Risk assessment: Risk assessment in terms of checking for antiphospholipid antibodies (for a risk of fetal loss) and for anti-Ro and anti-La antibodies (for a risk of neonatal lupus) should be performed before pregnancy.
- Neonatal lupus
- Neonatal lupus manifests as congenital heart block or as lupus rash. It is rare in SLE pregnancies, occurring in 3.5% of cases in one series. Neonatal lupus is highly associated with maternal anti-Ro (usually also with anti-La) antibodies, although the rash may occur with anti-RNP antibodies.
- Because not all pregnancies in the setting of anti-Ro/La antibodies are associated with congenital heart block, prophylactic treatment is not appropriate. Instead, fetal 4-chamber cardiac echocardiography performed at 16-28 weeks' gestation is recommended.
- If heart block of any degree is found, dexamethasone 4 mg/day is given to the mother because it crosses the placenta.
- Third-degree heart block is rarely reversible.
- In rare cases, neonatal lupus manifests as hepatic or hematologic involvement.
- Most babies with congenital heart block can be delivered at term; if severe hydrops is present, early cesarean delivery is necessary.
- Pacing is occasionally required in the neonate. Rare children with congenital heart block develop a connective tissue disease in adolescence.
- Fetal loss
- Rates of pregnancy loss are substantially increased in patients with SLE compared with control groups.
- Fetal loss is possible in any trimester.
- First-trimester losses are associated with antiphospholipid antibodies and with markers of lupus activity (eg, low complement concentrations and increased anti–double-stranded DNA [anti-dsDNA] antibodies) and renal disease.
- Late losses are associated with antiphospholipid antibodies.
- Hypercoagulable states other than antiphospholipid antibody syndrome are also associated with increased fetal loss.
- Women with SLE with fetal losses who are negative for antiphospholipid antibodies (including lupus anticoagulant, anticardiolipin, and anti-beta2 glycoprotein 1) should be screened for genetic causes of hypercoagulability, such as factor V Leiden, prothrombin mutation, and hyperhomocysteinemia.
- Breastfeeding
- Breastfeeding is feasible for most women with SLE. However, some medications may enter breast milk. Therefore, immunosuppressive agents are contraindicated, and long-acting NSAIDs are inadvisable. Short-acting NSAIDs, antimalarials, low-dose prednisone (<15-20 mg/d), warfarin, and heparin seem to be safe.
- Women with anti-Ro/SSA and anti-La/SSB antibodies may have detectable amounts of these antibodies in breast milk, but no evidence suggests that neonatal lupus results from breastfeeding.
- Fertility: SLE is not associated with infertility unless the woman has been treated with cyclophosphamide, which leads to premature ovarian failure.
Differential Diagnoses
Glomerulonephritis, Diffuse ProliferativePreeclampsia (Toxemia of Pregnancy)
Systemic Lupus Erythematosus
Other Problems to Be Considered
Lupus disease activity should be distinguished from other complications seen during pregnancy.Renal disease secondary to an exacerbation of lupus may be difficult to differentiate from preeclampsia.
Lupus nephritis is often associated with proteinuria and/or an active urine sediment (RBCs, WBCs, and cellular casts), whereas only proteinuria is seen in patients with preeclampsia.
Flares of systemic lupus erythematosus (SLE) are likely to be associated with hypocomplementemia and increased titers of anti-DNA antibodies; in comparison, complement levels are usually (but not always) increased in patients with preeclampsia.
In pregnant patients with renal disease, renal biopsy should be performed to differentiate preeclampsia from active lupus nephritis when differentiation on clinical grounds is not possible.
Thrombocytopenia, elevated serum levels of liver enzymes and uric acid, and decreased urinary excretion of calcium are more prominent in patients with preeclampsia than in those with lupus nephritis. However, thrombocytopenia may also be associated with antiphospholipid antibodies, thrombotic TTP, and immune thrombocytopenia, each of which may complicate pregnancy in women with SLE.
Workup
Laboratory Studies
- At the first visit after or when pregnancy is confirmed, the following assessments are recommended:
- Physical examination, including blood pressure evaluation
- Renal function tests, including determination of the glomerular filtration rate, urinalysis, and tests of the urine protein–to–urine creatinine ratio
- CBC count
- Test for anti-Ro/SSA and anti-La/SSB antibodies
- Lupus anticoagulant and anticardiolipin antibody studies
- Anti-dsDNA test
- Complement (CH50 or C3 and C4) tests
- During the first 2 trimesters, a monthly platelet count or CBC count is recommended.
- The following evaluations are recommended at the end of each trimester of pregnancy:
- Determination of the glomerular filtration rate and measurement of the urine protein–to–urine creatinine ratio
- Anticardiolipin antibody measurement
- Complement (CH50 or C3 and C4) test
- Anti-dsDNA antibody study
Imaging Studies
- Women who have antibodies to Ro/SSA and/or La/SSB are at increased risk of pregnancies complicated by fetal heart block and may benefit from serial fetal echocardiographic monitoring.
- The goal is to detect fetal heart block at an early stage, when therapeutic interventions may prevent its progression.
Other Tests
- Fetal monitoring: Women with systemic lupus erythematosus (SLE) are at increased risk for intrauterine growth restriction and preterm birth. Therefore, menstrual dating should be confirmed with ultrasonography at the first prenatal visit to accurately estimate the gestational age.
Treatment
Medical Care
- Preconception counseling is recommended.
- Counsel patients about the teratogenicity and adverse effects of the medications used to treat systemic lupus erythematosus (SLE) before therapy is initiated.
- Patients may need to be reminded about the importance of using contraception while they are taking methotrexate, leflunomide, cyclophosphamide, and mycophenolate.
- Educate patients that, because of prolonged half-lives, some medications may need to be discontinued several months before the planned conception. In addition, measures may need to be undertaken to enhance elimination of some medications as soon as pregnancy is detected.
- In the absence of any historical features of antiphospholipid syndrome (recurrent pregnancy loss, venous or arterial thromboembolism), patients with lupus anticoagulant and/or high levels of anticardiolipin antibodies should receive low-dose aspirin. Some suggest the use of low-dose heparin and aspirin for such patients, even in the absence of previous pregnancy complications.
- Women with lupus and the antiphospholipid antibody syndrome require more frequent monitoring than those with SLE alone.
- In 2007, the European League Against Rheumatism (EULAR) released new recommendations for the treatment of SLE.
Surgical Care
Patients with SLE may have increased rates of emergency or cesarean delivery secondary to flares of renal disease or preeclampsia.Consultations
A rheumatologist, an obstetrician experienced with high-risk care, and a nephrologist (if renal disease present or if it develops later) should work as a team to care for a pregnant patient with lupus.Diet
- A low-salt diet is recommended in pregnancy to prevent weight increase and hypertension.
- An exercise program may help prevent bone loss and depression.
- Calcium and vitamin D supplementation may be advised to prevent osteoporosis.
Activity
Strenuous activity is best avoided when patients have flare-ups.Medication
None of the medications used in the treatment of systemic lupus erythematosus (SLE) is absolutely safe during pregnancy. Hence, whether to use medications should be decided after careful assessment of the risks and benefits in consultation with the patient. During the first trimester, most of the drugs listed should be avoided.Nonsteroidal anti-inflammatory drugs
(NSAIDs)
These agents have analgesic, antipyretic, and anti-inflammatory activity. Their mechanism of action is not known, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may also exist. These may include inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.
Ibuprofen (Motrin, Advil)
DOC for patients with mild to moderate pain. NSAIDs are used for their analgesic, anti-inflammatory, and antipyretic activities. NSAIDs should be stopped at the beginning of menstrual cycle when conception is planned; NSAIDs interfered with blastocyst implantation in animal studies. Possible maternal effects include prolonged gestation and labor, increased peripartum blood loss, and increased anemia. Potential adverse effects to the fetus include premature closure of ductus arteriosus, leading to pulmonary hypertension, impaired renal function with oligohydramnios, and increased cutaneous and intracranial bleeding. Short-acting NSAIDs (eg, ibuprofen, indomethacin, diclofenac) are preferred over long-acting agents.
Adult
400 mg PO q4-6h, 600 mg q6h, or 800 mg q8h while symptoms persist; start at low end of dosing range and titrate prn; not to exceed 3.2 g/d
Pediatric
20-70 mg/kg/d PO divided tid/qid; start at low end of dosing range and titrate prn; not to exceed 2.4 g/d
Coadministration with aspirin increases risk of serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; closely monitor prothrombin time (PT) (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may increase when administered concurrently
Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Category D in third trimester of pregnancy; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy
Indomethacin (Indocin)
Rapidly absorbed; metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation. Inhibits prostaglandin synthesis.
Adult
25-50 mg PO bid/tid; 75 mg SR PO bid; not to exceed 200 mg/d
Pediatric
1-2 mg/kg/d PO divided bid/qid; not to exceed 4 mg/kg/d or 150-200 mg/d
Coadministration with aspirin increases risk of serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; monitor PT closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may increase when administered concurrently
Documented hypersensitivity; GI bleeding or renal insufficiency
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Category D in third trimester of pregnancy; acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in pre-existing renal disease or compromised renal perfusion; reversible leukopenia may occur; discontinue if persistent leukopenia, granulocytopenia, or thrombocytopenia is present
Disease modifying agents
These agents modify immune responses to diverse stimuli.
Hydroxychloroquine (Plaquenil)
Inhibits chemotaxis of eosinophils and locomotion of neutrophils. Impairs complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate at 200 mg equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate.
Adult
200-400 mg/d PO in divided doses
Pediatric
Not established
Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption
Documented hypersensitivity; psoriasis; retinal and visual-field changes attributable to 4-aminoquinolones
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; perform periodic (eg, 6 mo) ophthalmologic examinations; test periodically for muscle weakness
Immunosuppressive drugs
These agents may suppress mechanisms responsible for autoimmune reactions.
Azathioprine (Imuran)
Purine analog that antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. In SLE, decreases levels of circulating B and T lymphocytes, immunoglobulin synthesis, and cytokine production. May be needed for patients with history of severe nephritis after cyclophosphamide or mycophenolate treatment. Can also be used as steroid-sparing agent.
Adult
1 mg/kg/d PO for 6-8 wk; increase 0.5 mg/kg q4wk until response or dosage 2.5 mg/kg/d
Pediatric
Not established
Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine
Documented hypersensitivity to azathioprine or any component of the formulation
Pregnancy
D - Unsafe in pregnancy
Precautions
Increases risk of neoplasia; caution in liver disease and renal impairment; hematologic toxicities may occur; check TPMT level before therapy and monitor liver, renal, and hematologic function; pancreatitis or neonatal immunosuppression in rare cases
Mycophenolate mofetil (CellCept, Myfortic)
Prodrug enzymatically broken down into active metabolite MPA. Mycophenolic acid inhibits purine synthesis and decreases lymphocyte production and adhesion.
Adult
2-3 g/d PO in divided doses
Pediatric
Not established
Combination with acyclovir or ganciclovir may increase levels of both because of competition for renal tubular excretion; aluminum and/or magnesium present in some antacids, and cholestyramine-containing products may decrease absorption, reducing levels (do not administer together); probenecid may increase levels; salicylates and azathioprine may increase toxicity; may decrease area under the concentration-time curve (AUC) for levonorgestrel; may decrease immune response to live-virus vaccine; may increase free-fraction levels of theophylline when used in combination
Documented hypersensitivity
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Increases risk for infection (monitor blood count); patients with severe renal impairment (CrCl <25 mL/min) may have increased adverse effects due to increased free MPA; caution in active peptic ulcer disease; incidence of malignancies and lymphoma consistent with those of other immunosuppressants (0.9%); constipation, nausea, diarrhea, urinary tract infection, and nasopharyngitis are common; interstitial lung disorders, colitis, pancreatitis, intestinal perforation, GI hemorrhage, gastric ulcers, duodenal ulcers, and ileus may occur (rare); do not chew, crush, or cut Myfortic tab
Cyclophosphamide (Cytoxan)
Should not be used in pregnancy. Long-term treatment for lupus cerebritis and/or nephritis should be followed by yearly urine cytology to screen for bladder cancer.
Adult
500-750 mg/m2 IV qmo
Pediatric
Not established
Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; toxicity may increase with chloramphenicol; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia; coadministration with succinylcholine may increase neuromuscular blockade by inhibiting cholinesterase activity
Documented hypersensitivity; severely depressed bone marrow function
Pregnancy
X - Contraindicated in pregnancy
Precautions
Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; young male patients should be counseled about sperm banking; women should be made aware of infertility risk
Cyclosporine A (Neoral, Sandimmune)
Cyclic peptide of 11 amino acids and natural product of fungi. Acts on T-cell replication and activity. Specific modulator of T-cell function. Depresses cell-mediated immune responses by inhibiting function of T helper cells. Preferential and reversible inhibition of T lymphocytes in G0 or G1 phase of cell cycle suggested.
Binds to cyclophilin (intracellular protein), which, in turn, prevents formation of interleukin (IL)–2 and subsequent recruitment of activated T cells. Mechanism of action involves inhibition of cytotoxic T cells, decreasing production of IL-2.
Bioavailability about 30%, but interindividual variability is considerable. Specifically inhibits T-lymphocyte function with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires drug to be present during first 24 h of antigenic exposure.
Suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease) for various organs.
Adult
2.5-5 mg/kg/d PO in divided doses
Pediatric
Administer as in adults
Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin; mutual inhibition with methylprednisolone that increases plasma levels of both
Documented hypersensitivity; uncontrolled hypertension or malignancies; risk of preterm delivery and/or low birth weight; do not administer concomitantly with PUVA or UVB irradiation in psoriasis (may increase risk of cancer)
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzyme levels; may increase risk of infection and lymphoma; reserve IV use for only patients who cannot take PO; not teratogenic in animals or humans, but isolated case of renal damage reported in fetal rat
Corticosteroids
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
These drugs are used to treat the fetus in mothers with positive anti-SSA antibodies.
Dexamethasone (Decadron)
Has many pharmacologic benefits but clinically significant adverse effects. Stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentration, inhibits prostaglandin and proinflammatory cytokines (eg, tumor necrosis factor [TNF]–alpha, IL-6, IL-2, and interferon [IFN]–gamma). Inhibition of chemotactic factors and factors that increase capillary permeability inhibits recruitment of inflammatory cells into affected areas. Suppresses lymphocyte proliferation by direct cytolysis and inhibits mitosis. Breaks down granulocyte aggregates and improves pulmonary microcirculation.
Adverse effects include hyperglycemia, hypertension, weight loss, GI bleeding or perforation synthesis, cerebral palsy, adrenal suppression, and death. Most adverse effects of corticosteroids are dose or duration dependent.
Readily absorbed from GI tract and metabolized in liver. Inactive metabolites excreted through kidneys. Lacks salt-retaining property of hydrocortisone.
Can be switched from IV to PO regimen in 1:1 ratio. Given to pregnant mother if fetal heart block detected in patients with anti-SSA antibodies. Crosses placenta.
Adult
4 mg IV divided q6-12h
Pediatric
Not established
Effects decrease with coadministration of barbiturates, phenytoin, and rifampin; dexamethasone decreases effect of salicylates and vaccines for immunization
Documented hypersensitivity; viral, fungal, or tubercular skin infections
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
Increases risk of several complications, including severe infections; monitor adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use
Prednisone (Deltasone, Orasone, Sterapred)
May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. If steroid treatment desired for mother, prednisone, cortisone, or hydrocortisone should be chosen, as low concentration of active steroid reaches fetus.
Adult
5-60 mg/d PO qd; administer lowest effective dose
Pediatric
0.05-2 mg/kg/d PO divided tid/qid
Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics; may alter levels of warfarin
Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, fungal or tubercular skin infections; GI disease
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use; high doses may result in growth retardation and cleft palate in fetus; if used during pregnancy, newborn must be monitored for adrenal suppression and infection
Methylprednisolone (Medrol, Solu-Medrol)
Decreases inflammation by suppressing migration of polymorphonuclear (PMN) leukocytes and reversing increased capillary permeability. Metabolized by placenta; thus, lowered concentrations reach fetus. Therefore, this is the preferred corticosteroid treatment.
Adult
5-20 mg/d PO qd; 1 g/d for 3 d IV in life-threatening disease (renal disease secondary to lupus nephritis or cerebritis); administer lowest effective dose
Pediatric
Not established
Further Inpatient Care
- Patients may require admission for management of the complications of labor and delivery.
Further Outpatient Care
- All patients should be screened for postpartum depression.
- Patients must be monitored closely after delivery because some are likely to have flare-ups during the postpartum period.
Inpatient & Outpatient Medications
- Patients can breastfeed if they are not taking azathioprine, methotrexate, cyclophosphamide, or mycophenolate.
- Hydroxychloroquine is also secreted in breast milk; therefore, this drug should be used with caution. Hydroxychloroquine may displace bilirubin, resulting in kernicterus.
- Prednisone can be used safely during breastfeeding because small amounts (5% of the glucocorticoid dose) are secreted in breast milk. At doses of prednisone higher than 20 mg once or twice daily, breast milk should be pumped and discarded 4 hours after the dose to minimize drug exposure to the infant.
- NSAIDs can be used with caution in newborns without jaundice because NSAIDs can displace bilirubin and predispose the fetus to kernicterus.
Transfer
- Transfer to intensive care unit may be required for emergency intervention or monitoring during flares.
Deterrence/Prevention
- Patients should avoid pregnancy when lupus is active, especially in the presence of renal disease.
- Patients should use contraception while they are taking immunosuppressive disease-modifying drugs.
Complications
- Complications due to flare of the disease during pregnancy or the adverse effects of drugs on the fetus are possible.
Prognosis
- The long-term effect of pregnancy in patients with systemic lupus erythematosus (SLE) is unknown.
- Data from retrospective studies suggest no clinically significant adverse or positive effect of pregnancy on the course of SLE.
Patient Education
- Patients should be aware of the potential teratogenic effects of the drugs they are taking.
- Preconception counseling must be stressed.
- Use of contraception must be stressed frequently while patients are taking teratogenic medications.
- When treatment is recommended during pregnancy, patients must be informed of the potential adverse effects of the drugs on the fetus.
Miscellaneous
Medicolegal Pitfalls
- Failure to inform patients of the teratogenic effects of certain immunosuppressive drugs
- Failure to inform patients about the potential adverse maternal and fetal effects of the drugs recommended during pregnancy
- Failure to diagnose pregnancy before teratogenic disease-modifying agents are started
- Failure to inform patients to not breastfeed while they are taking certain drugs (eg, azathioprine, mycophenolate, cyclophosphamide)
Echovirus
Echovirus
Introduction
Background
Echoviruses (EVs) are RNA viruses of the genus Enterovirus and the family Picornaviridae. EVs were first isolated from the feces of asymptomatic children early in the 1950s, soon after the development of cell culture techniques. EVs cause cytopathic effects in primate cell cultures, although not initially associated with any disease condition. These orphan viruses were initially termed ECHO, an acronym for enteric cytopathic human orphan virus, which was later simplified to echovirus.A committee sponsored by the National Foundation for Infantile Paralysis categorized EVs and other enteroviruses (ie, coxsackievirus group A and group B, polioviruses) together in 1957. They are grouped together and distinguished from other viruses on the basis of physicochemical characteristics and because they share common epidemiology, clinical manifestations, and pathogenesis. Enterovirus groups are differentiated based on host specificity. To date, 67 serotypes of enterovirus have been identified, 32 of which belong to the echovirus group.
EVs cause a wide range of common and uncommon clinical presentations. These agents and other members of the Enterovirus group are among the leading causes of acute febrile illness in infants and young children; they are the most common cause of aseptic meningitis. Infection in the first 2 weeks of life is particularly troublesome because it can cause severe systemic disease and is associated with high fatality rates. Another significant concern with enteroviral infections is that they can mimic symptoms caused by other common bacteria and viral infections; thus, enteroviral infections are often treated with therapies aimed for other infections.
EVs are small, measuring 24-30 nanometers (nm) under electron microscopy. They are composed of a naked protein capsid, constituting about 75% of the particle and enclosing a dense central core of single-stranded RNA. This RNA is approximately 7.5 kilobase (kb) long and contains an RNA replicase, viral-coded proteases, a single polyprotein that is responsible for forming structural polypeptides, and other proteins necessary for cellular replication. All EVs contain polypeptide chains (eg, virus protein 1 [VP1], virus protein 4 [VP4]). These structural proteins are important to determine host range and tropism, and they play a crucial role in delivering the RNA genome into the cytoplasm of new host cells.
Although EVs originally were classified into 34 serotypes, EV-10 later was reclassified as a reovirus and EV-28 as rhinovirus type 1; EV-9 now is considered the same as coxsackievirus A23.
At least 2 cellular receptors for EV have been identified: a subunit of the integrin molecule VLA-2 that binds types 1 and 8, and a complement regulatory protein (ie, a decay accelerating factor) that binds types 6, 7, 12, and 21.
Pathophysiology
Some viral replication occurs in the nasopharynx after exposure, with spread to regional lymph nodes. However, most inoculum is swallowed and reaches the lower GI tract, where the virus presumably binds to specific receptors on enterocytes. The virus traverses the intestinal epithelium, probably undergoing replication in the process but without causing any cellular effects, and reaches the Peyer patches in the lamina propria mucosae. Here, the virus undergoes substantial multiplication. A minor viremia develops on about the third day, seeding many secondary infection sites, including the CNS, liver, spleen, bone marrow, heart, and lungs. Additional replication at these sites causes a major viremia that coincides with onset of clinical disease, usually 4-6 days after exposure. The delayed appearance of CNS disease symptoms suggests viral spread can develop during both the minor and the major viremia.Enteroviruses can infect all tissues of the human body. The tropism of each virus for certain tissues is not well understood and is neither unique nor specific. Infections involving a single serotype may vary widely in their presentation; multiple serotypes can produce the same clinical syndrome.
The incubation period for EV is difficult to establish because both symptomatic and healthy individuals spread the virus. Incubation is believed to range between 2 days and 2 weeks. EV is communicable over a long period of time. The virus can be shed from the upper respiratory tract for 1-3 weeks and in stools for more than 8 weeks after primary infection.
Frequency
United States
Several studies confirm enteroviruses account for more than 50% of spring and fall emergency department visits by infants and young children for fever without a source. EV infections only sporadically develop in other seasons. In addition to this seasonality, EV types vary strikingly in their contribution to human disease. Some EVs remain endemic in patterns that vary from area to area each year in the United States. Other serotypes (eg, EV-9, EV-11, EV-30) can cause widespread outbreaks in which the responsible strain can account for more than 90% of all isolated strains of enterovirus.Infections by this group of viruses are most prevalent among lower socioeconomic groups, a fact easily explained by overcrowded living conditions and poor hygiene.
International
EV infections occur in all human populations. Transmission and infection occur throughout the year in the tropics and predominantly during summer and fall in temperate regions, with sporadic cases in other seasons. A few epidemics have been nearly global, such as one caused by EV-9 at the end of the 1950s and another by EV-11 in 1979 and 1980. More recently, an outbreak of EV-13 and EV-30 was reported in Germany,1 and outbreaks of EV-13 were reported in Lithuania and Israel.2,3 An outbreak of EV-11 has also been reported in neonates in Taiwan.4 Particular serotypes are endemic or epidemic for unknown reasons. One hypothesis is that some epidemic strains such as EV-9 may spread rapidly in a "critical mass" of susceptible patients necessary for continuous transmission, whereas endemic strains may not be as contagious.Mortality/Morbidity
EV infections during the first 2 weeks of life can cause severe systemic disease associated with high fatality rates. EV and other enteroviruses account for 10-20% of documented viral causes of encephalitis. Neonates with disseminated encephalitis have a poor prognosis and many die. Infant death rates from perinatal EV infection are unknown, although some studies report high numbers. Neonatal mortality is usually caused by either overwhelming liver failure or myocarditis, rather than CNS involvement.Children and older patients with disseminated encephalitis have a better prognosis, but fatalities occasionally occur. Acute myopericarditis, resulting from the well-established tropism of enterovirus for the heart, can be fatal in approximately 5% of cases, although most patients recover without major sequelae.
Sex
For unknown reasons, forms of EV disease such as meningitis and neonatal sepsis are far more common among male patients.Age
Although EV infections can occur in all age groups, incidence inversely relates to age; specific antibodies directly increase with time. Several studies performed during epidemics and for surveillance show that infants become infected at significantly higher rates than older children and adults.Clinical
History
Because echovirus (EV) has been found in the stools of healthy individuals, most children with EV and other enteroviral infections are assumed to be asymptomatic. Finding the virus in the stools of healthy individuals, however, may be misleading because enterovirus can be excreted in feces for a long time, and no clear indication exists of what happened during the initial infection. Patients may have symptoms with infection, but the symptoms may be trivial and not recognized.- Nonfocal, acute febrile illness is the most common presentation of symptomatic enteroviral infection in young infants and children.
- Enteroviral infections are the most common cause of hospital admission for suspected sepsis in children aged 2-3 months during summer and fall.
Physical
EV causes a remarkable range of diseases. Benign forms of disease are well recognized by clinicians (eg, nonspecific exanthems, herpangina) and do not warrant major diagnostic or therapeutic actions. Severe forms of disease, such as meningitis, encephalitis, neonatal sepsis, myocarditis, and chronic infection with meningoencephalitis in patients with altered immunity, are strong reasons for concern.- Nonspecific, acute febrile illness: Several studies have shown enterovirus can account for more than 50% of summer and fall emergency department visits for fever of unknown origin in infants and young children.
- Fever onset is usually abrupt and without a prodrome, often exceeding 39° C. Fever, which may be the sole presentation, often is accompanied by irritability. High temperatures, irritability, and the nonspecific nature of the illness prompt the hospitalization of many infants for suspected bacterial sepsis. At least 50% of these patients have a history of poor feeding, and 25% of infants have vomiting or diarrhea. Affected infants resume feeding within 2 days of initial symptoms, and their GI manifestations are not the reason for hospital admission.
- A large number of these patients have had thorough evaluations that included blood, urine, and cerebrospinal fluid (CSF) cultures and have received antibiotics for 48-72 hours while awaiting culture results. Differentiating patients infected with enterovirus from those with bacterial infections is impossible based solely on clinical findings.
- Most young patients recover from the febrile episode in 2-10 days without complications.
- Exanthems
- Skin rashes are more common with EV infections than with infections from other enteroviruses. The first exanthematous disease induced by an enterovirus was linked to EV-16.
- Exanthems may be maculopapular, morbilliform, macular, petechial, or papulopustular in nature.
- Likelihood of an exanthem being present appears directly related to the EV type causing infection. For example, EV-6, which has been among the most prevalent serotypes causing infection during the past 25 years, is associated only sporadically with skin manifestations. Conversely, infections with EV-5, EV-9, and EV-25 are associated with skin rashes in as many as 35% of patients.
- Skin findings with EV infections are self-limited and without sequelae.
- Viral meningitis
- As many as 90% of community-acquired viral meningitis cases result from EVs or coxsackie B viruses. CNS involvement is most likely with infections by EV serotypes 4, 6, 9, 11, 13, 16, and 30. More than 10,000 cases of enteroviral meningitis are reported annually to the Centers for Disease Control and Prevention (CDC), and actual numbers probably are 10 times higher.
- Infants younger than 3 months have the highest incidence of recognized meningitis. This diagnosis is not based on specific neurological findings; instead, young infants are more likely to undergo a lumbar puncture for evaluation of a fever. Most young children with meningitis present with fever and irritability.
- Older children with meningitis typically present with fever and severe headache. Headaches in older children and adults can be sufficiently severe to require narcotics for pain control.
- Nuchal rigidity occurs in less than two thirds of patients and does not occur in infants.
- Patients can have symptoms of photophobia, nausea, and vomiting.
- About 10% of hospitalized infants with echoviral meningitis have neurologic manifestations (eg, seizures, altered mental status, increased intracranial pressure).
- The classic results of CSF analysis are a mononuclear pleocytosis (100-300 cells/mm3), mildly elevated protein levels, and glucose concentrations within reference ranges. Higher WBC counts with a predominance of neutrophils occur early in the course of disease.
- Illness duration typically is less than a week.
- Despite current studies of antiviral drug therapies, standard treatments are limited to alleviating symptoms. Although the short-term prognosis appears good for young children with echoviral and other enteroviral meningitis, controversy continues about long-term cognitive, developmental, and language abnormalities among children who suffered meningitis in early life. Some prospective reports have indicated virtually no measurable long-term effects, even among patients who had neurologic findings during their illness.
- Encephalitis
- Clearly distinguishing encephalitis from enteroviral meningitis is important. Encephalitis is more rare, is a more devastating acute disease, and has long-term sequelae.
- EV and other enteroviruses account for 10-20% of documented viral-caused encephalitis. Common serotypes that cause encephalitis include EV types 4, 6, 9, 11, and 30. EVs are more commonly associated with a global encephalitis and generalized neurological depression.
- Clinical manifestations range from altered mental status to coma and decerebration. Some patients manifest with focal disease (eg, partial motor seizures, hemichorea, cerebellar ataxia), symptoms that may suggest a diagnosis of herpes simplex encephalitis. Brain imaging by CT scan or MRI and electroencephalography usually show the extent of involvement. The results of CSF analysis in patients with encephalitis are similar to the results from patients with only aseptic meningitis.
- The prognosis for neonates with disseminated encephalitis is poor, and many die. The prognosis for similarly affected children and older patients is better, but fatalities sometimes occur.
- Other neurological syndromes
- Although rare, EV can cause a syndrome of acute motor weakness and paralysis indistinguishable from poliomyelitis. Sporadic cases of acute paralysis have been reported with EV-6 and EV-9. The myelitis caused by EV usually is less severe than that caused by poliovirus.
- Guillain-Barré syndrome has been associated with EV-6 and EV-22 infections. Acute cerebellar ataxia has been related to infection with EV-6 and EV-9. Acute transverse myelitis has occurred in patients with EV-5 infection.
- Chronic meningoencephalitis can occur in association with coxsackievirus or EV in patients who have acquired or congenital B-lymphocyte function defects. These patients present with an insidious course, manifested by headache, lethargy, motor dysfunction, or seizures. Symptoms may fluctuate in severity, wane, or gradually progress. Persistent pleocytosis and high protein levels in CSF are typical. Recovery of the virus from several other tissues suggests the possibility of disseminated disease. Prognosis for these patients generally is poor. The results of using intravenous immunoglobulin (IVIG) to treat these patients have been inconsistent.
- Muscle and joint infections
- EV infections sporadically involve muscles; both focal and generalized myositis has been described. Patients usually present with myalgia associated with elevated levels of skeletal muscle enzymes in serum. The course is self-limited and hastily resolves.
- In patients with B-lymphocyte dysfunction, skeletal muscles can become chronically infected, manifested by a dermatomyositislike syndrome. Although other enteroviruses can be the cause, EV infection is most common.
- EV-9 is associated with both acute and subacute arthritis.
- Pleurodynia (ie, Bornholm disease)
- First described more than 2 centuries ago, pleurodynia is characterized by fever and spasmodic pain in the chest wall or upper abdomen. The hallmark of pleurodynia is its paroxysmal nature.
- Spasmodic periods persist from a few minutes to half an hour or longer. Pain can be severe, and patients often appear pale and diaphoretic, sometimes leading physicians treating older adults to consider the possibility of a myocardial infarction. Patients present with shallow, frequent respirations that usually suggest pleural inflammation or pneumonia. Physical examination rarely reveals pleural friction rubs; pleural effusions occur in fewer than 10% of patients. Pain usually is more severe at presentation and gradually wanes over 4-6 days, although pain occasionally persists 3 weeks. Analgesics and restricted physical activity usually suffice to reduce pain. Abdominal wall involvement occurs almost exclusively in children and often mimics appendicitis or peritonitis.
- Pleurodynia can occur in epidemics involving adults and children, or in sporadic form. EV-1 and EV-6 are associated with epidemics of pleurodynia, and almost all other EV types have been linked to sporadic cases.
- Myopericarditis
- EV's tropism for the heart is well established. Group B coxsackieviruses 2 and 5 traditionally have been linked to acute myopericarditis; however, many other enterovirus types, including EV, have been related to acute heart disease. Although enterovirus-induced myocarditis occurs in all age groups, the highest risk is among physically active adolescents and young adults.
- Myopericarditis is clinically indistinguishable from diseases caused by other viruses (eg, adenoviruses, influenza A, mumps) that can infect the myocardium. Approximately 65% of patients report an upper respiratory infection preceding manifestations of substernal chest pain, fever, dyspnea, and exertion intolerance. Physical examination reveals a pericardial friction rub in as many as 80% of these patients and a gallop rhythm in 20%.
- Electrocardiography (ECG) invariably reveals abnormal findings; ECG also can reveal acute ventricular dilatation and diminished ventricular ejection fraction. Cardiac enzyme serum levels are often high.
- Although the acute course of myopericarditis can be complicated by arrhythmias and congestive heart failure (CHF), most patients recover without major sequelae. About 5% of cases are fatal. Approximately 10-30% of cases continue to show ECG abnormalities; about the same percentage of patients present with recurrent CHF that indicates permanent myocardial damage. Most affected patients need supportive care.
- Corticosteroid use is controversial for cases of acute myocarditis; experts disagree about the benefits and potential adverse effects of systemic use. Some have reported benefits from administering high-dose IVIG, but this therapy remains far from the standard of care.
- Neonatal infections
- Neonates during their first 2 weeks of life are particularly susceptible to potentially lethal diseases caused by an EV infection. Vertical transmission from an infected mother or, more rarely, a nosocomial source is the most likely mechanism for acquiring infection.
- Passive acquisition of immunoglobulin G (IgG) antibodies from the mother appears to determine the outcome of a neonatal infection more than any other factor. The critical issue is the amount of time between maternal infection and the delivery.
- Neonates who are infected present with a sepsislike syndrome, with fever, irritability, lethargy, respiratory distress, and an exanthem. Many patients show radiographic evidence of pulmonary involvement, and CSF analysis provides evidence of meningitis. Major systemic manifestations can develop as the disease progresses, such as hepatic necrosis, myocarditis, and disseminated intravascular coagulation. CNS disease may progress to encephalitic characteristics with seizures and focal abnormalities. Because clinical features can imitate neonatal sepsis by bacterial agents and either disseminated or localized herpes simplex infection, patients are often treated for both possibilities.
- EV-11 specifically has been linked to a clinical syndrome of disseminated sepsis in which the dominant feature is neonatal hepatitis, accompanied by extensive necrosis of the liver and overwhelming hepatic failure. Other serotypes able to cause neonatal liver disease include EV serotypes 6, 7, 9, 14, 17, 19, and 21. In addition, EV-6, EV-9, and EV-11 have been linked to a severe form of perinatal pneumonitis with a high mortality rate. Incidence of infant death due to perinatal EV infection is unknown, although some studies report high numbers. Mortality usually results from either overwhelming liver failure or myocarditis rather than CNS involvement.
- Other infections
- EV-4 and EV-11 have been reported as sporadic causes of mild cases of croup.
- EVs have sporadic associations with bronchitis and bronchiolitis.
- Pneumonia in children has been associated with infections with EV serotypes 6, 7, 9, 11, 12, 19, 20, and 30.
- Conjunctivitis, whether alone or in conjunction with other symptoms, has been reported with EV serotypes 1, 6, 9, 20, and 30.
- Several reports link echovirus and enterovirus infection to a risk of developing type 1 diabetes.
Causes
Overcrowded conditions and poor hygiene easily explain the high prevalence of EV infections among lower socioeconomic groups.- EV is transmitted person-to-person; the fecal-oral route is the predominant mode, and transmission sometimes occurs via respiration of oral secretions.
- Indirect transmission occurs through numerous routes, including contaminated water, food, and fomites. Contaminated swimming and wading pools can transmit the virus. Well-documented reports detail transmission via the contaminated hands of hospital personnel.
- EV is communicable over a long period of time. The virus can be shed from the upper respiratory tract for 1-3 weeks and in stools for more than 8 weeks after primary infection.
Differential Diagnoses
Neonatal SepsisOther Problems to Be Considered
Bacterial sepsisBacterial meningitis
Neonatal herpes simplex infection
Herpes simplex virus encephalitis
Arbovirus encephalitis
Fever without localizing signs
Viral exanthems
Pharyngoconjunctival fever
Workup
Laboratory Studies
Until recently, the criterion standard laboratory procedure to diagnose echovirus (EV) and other enterovirus infections was to isolate the virus in cell culture. An etiologic diagnosis is confirmed when virus is isolated from blood, CSF, tissue, or pericardial fluid. EV can also be isolated from stool or oropharynx, although these findings are less indicative of disease because asymptomatic shedding from these sites can occur for several weeks after acute infection.- Enteroviruses grow rapidly in cell culture, yet viral recovery occurs too slowly to provide data for decisions about treatment. Virus detection in cell culture typically takes 3-8 days, requires multiple cell lines for optimal recovery, is labor intensive and costly, and is not readily available in all clinical facilities. Antiviral therapy for enterovirus requires a faster and more efficient mechanism for diagnosis.
- Enterovirus polymerase chain reaction (EV-PCR), based on amplification of conserved genetic sequences, has been thoroughly studied and is superior to viral culture for revealing many enteroviral infections, particularly enteroviral meningitis.5,6,7
- EV-PCR can be used in samples other than CSF, although experience is not as extensive. EV-PCR has been successfully used in urine and serum to document neonatal infection and on throat swabs to document common outpatient illnesses.
- Quality control from laboratory to laboratory is necessary because no commercial kit is available. Because of its extreme sensitivity, EV-PCR is subject to false-positive results from contamination within the laboratory. The greatest benefit of EV-PCR is that the test can provide results in 5-24 hours, which can expedite patient management decisions (eg, decrease length of hospitalization, antibiotic use, overall costs).
- Serologic tests for enteroviral infection diagnosis have limited value because they are slow, require acute and convalescent titers, and are not type-specific.
Treatment
Medical Care
No antiviral therapy has been available except IVIG therapy, which reportedly has some success in patients who are immunocompromised and have persistent enterovirus infections. The role of IVIG therapy for acute infections is unproven. A study evaluating its use in enteroviral infection in neonates failed to demonstrate a clear benefit. Another study evaluating the use of IVIG in 21 patients with myocarditis showed improved left ventricular function and survival when compared with 25 control patients. However, additional studies are needed.Corticosteroid use to treat viral myopericarditis remains controversial at best. Several antiviral agents have in vitro activity against a broad range of enterovirus types, and several clinical trials have been conducted on their use.
- The first of these agents to be studied was pleconaril, a drug that interferes with the binding of enterovirus to the cell membrane and the uncoating of virions by attaching to the virus protein capsid.8,9 Several clinical trials have demonstrated a benefit in children and adults with enterovirus meningitis.10 Pleconaril apparently may be on the verge of becoming readily available for clinical use as a new therapy option for echovirus (EV) and other enteroviral infections.
- Pleconaril at concentrations of 0.1 mg/mL has activity against more than 90% of the most common circulating enteroviruses. The drug has good bioavailability and a prolonged half-life, allowing oral administration 3 times a day. Adequate levels can be achieved in serum and CSF.
- Pleconaril has been studied in enteroviral meningitis, in respiratory tract infections, and in a limited number of patients who are immunocompromised and have viral myocarditis.
- Phase III clinical trials are underway, and initial results are promising. In the first placebo-controlled double-blind study, 221 children (aged 4-14 years) with signs and symptoms of viral meningitis, most confirmed as enterovirus with EV-PCR, received 2.5 or 5 mg/kg of pleconaril or placebo 3 times a day for 7 days.10 Initial findings showed a 38-50% improvement among treated patients when compared with patients receiving a placebo. Improvement was seen as early as 24 hours after therapy initiation. Similar results have been obtained in studies of adolescents and adults with enteroviral meningitis. Pleconaril is currently under investigation in a multicenter collaborative study of therapy for neonatal enteroviral sepsis sponsored by the National Institutes of Health.
- Schering-Plough lists pleconaril nasal spray as having completed phase II trials for preventing asthma exacerbation and common cold symptoms in asthmatic patients exposed to picornavirus.9
- As of spring 2008, pleconaril is not approved by the US Food and Drug Administration (FDA).
Follow-up
Further Outpatient Care
- The specific type of infection caused by echovirus (EV) should dictate follow-up care.
Prognosis
- Neonates with disseminated encephalitis have a poor prognosis and many die. Children and older patients have a better prognosis, but the disease is occasionally fatal.
- Acute myopericarditis is fatal in approximately 5% of cases; most patients recover without major sequelae.
- The short-term prognosis for children with EV and enteroviral meningitis early in life appears to be good. The long-term prognosis for similarly affected children is controversial in regard to cognitive, developmental, and language abnormalities. Some recent prospective reports have indicated virtually no measurable long-term effects, even among patients with neurologic findings during their illness.
- The prognosis is generally poor for patients with chronic meningoencephalitis who have coxsackievirus or EV infections and acquired or congenital B-lymphocyte function defects.
Chlorhexidine Wipes Fail to Prevent Newborn Deaths and Sepsis
Chlorhexidine Wipes Fail to Prevent Newborn Deaths and Sepsis
June 3, 2010 — Wiping vaginal areas before birth and swabbing newborns with chlorhexidine, an antiseptic solution, do not prevent sepsis (bacterial infection in the blood or tissues) or reduce the mortality rate of mothers or children, according to a study published in the June issue of Obstetrics & Gynecology.
In developed nations, where group B streptococci are most often the trigger for sepsis, antibiotics are showing their effectiveness, but in underdeveloped countries, where sepsis is a chief reason for neonatal death, the cause is more likely to be gram-negative bacteria (Klebsiella pneumonia and Escherichia coli), which may be transmitted during labor from the mother's genital tract to the fetus. No method of prevention has been proven, but antiseptic solutions have held promise.
"It has been proposed that peripartal infection of the fetus and mother may be prevented by intrapartum vaginal and neonatal wipes with an antiseptic solution," write Sarah Saleem, MBBS, from Aga Khan University, Karachi, Pakistan, and colleagues. "One such antiseptic solution is chlorhexidine, which has a wide range of effectiveness against aerobic and anaerobic gram-negative and gram-positive organisms."
The efficacy of chlorhexidine was suggested by a pilot study. Because subsequent research was plagued by methodological weaknesses, the researchers launched their randomized trial to determine the effect of chlorhexidine wipes on mortality of the unborn and newborns and on the morbidity caused by sepsis.
The investigators conducted a study of 5008 women from June 2005 through May 2008 in 3 Karachi hospitals that serve the poor. During this period, 2205 laboring women and their newborns were wiped with chlorhexidine and 2503 were wiped with a saline solution. A field team examined the mothers and infants at home at 7 days and 28 days. The primary outcome was infant death at 7 days or before or the presence of sepsis in living newborns.
There were few distinctions between groups regarding factors including the mother's age, number of previous births, gestational age, type of delivery, birth weight, sex, or Apgar score.
Maternal results revealed no important disparities between groups other than less frequent hospitalizations at 7 days for those who received chlorhexidine. Data on 1596 of the infants (32%) produced the following findings.
- There was little difference between groups regarding primary outcome (3.1% for the chlorhexidine group vs 3.4% for the control group; relative risk [RR], 0.91; 95% confidence interval [CI], 0.67 - 1.24; P = .57).
- No significant differences were found in the composite rate of neonatal sepsis or mortality at 28 days (3.8% vs 3.9%; RR, 0.96; 95% CI, 0.73 - 1.27; P = .79).
- On day 7, a lower rate of infant skin infection was found in the chlorhexidine group (3.3% vs 8.2%; P < .001).
There were no stated limitations to the study. The investigators encourage further research to diminish the widespread infections in developing countries.
"Despite the failure of chlorhexidine maternal and vaginal wipes to reduce sepsis, infection remains a major cause of neonatal morbidity and mortality in many developing-country settings," the authors write. "Thus, it is important to develop strategies that reduce or prevent newborn bacterial colonization and strategies that reduce death once infection occurs."
The National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research, the Bill and Melinda Gates Foundation, and Aga Khan University supported the study. A complete list of disclosed relevant financial relationships can be found in the article.