Chikungunya fever: Treatment and prevention

INTRODUCTION — Chikungunya virus is an arthropod-borne alphavirus transmitted by mosquitoes that causes acute febrile polyarthralgia and inflammatory arthritis, as well as cutaneous eruptions and other systemic manifestations [1]. Further, many patients develop chronic joint involvement. In these patients, treatment with immunomodulatory or immunosuppressive drugs may achieve disease control. The name chikungunya is derived from an African language and means "that which bends up" or "stooped walk" because of the incapacitating joint involvement that may complicate the disease.

The treatment and prevention of chikungunya fever are discussed here. The epidemiology, clinical manifestations, and diagnosis of chikungunya infection are discussed separately. (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis".)

Issues related to other viral causes of arthritis are also presented separately. (See "Viral arthritis: Causes and approach to evaluation and management".)

TREATMENT — Treatment is influenced by the phase and duration of the illness and the response to therapy. Acute disease, including both articular and nonarticular disease, is typically treated symptomatically and if needed, with supportive measures. (See 'Acute disease' below.)

Following the acute phase, most patients who remain symptomatic have joint disease; chronic joint disease may benefit from medications commonly employed in other forms of chronic inflammatory arthritis, such as rheumatoid arthritis (RA), including disease-modifying antirheumatic drugs (DMARDs). (See 'Post-acute and chronic arthritis' below.)

Inflammatory arthritis evident on physical examination and chronic arthralgia without physical findings are treated similarly; the latter is also presumed to be due to ongoing inflammatory synovitis, although this is based upon limited evidence.

Most descriptions of disease and their sequelae rely upon data from large outbreaks. Persistent and sometimes severe polyarthralgia is the most prominent feature, often without objective signs of inflammation on examination, such as swelling and erythema. These patients typically have prolonged morning stiffness and may respond to conventional DMARDs, suggesting that post-infectious, inflammatory arthritis may be the underlying cause.

Moreover, a few ultrasound studies have demonstrated inflammatory synovitis during the acute phase of infection [2], as well as in patients with both post-acute and chronic joint pain [3]. However, studies of these populations with synovial fluid analysis or histology are lacking, as are studies that explore whether acute arthritis should be treated differently than chronic arthralgia and chronic arthritis. (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

Acute disease — Treatment during the acute phase of disease consists of supportive care with rest and fluids. It may include acetaminophen, followed as needed by nonsteroidal antiinflammatory drugs (NSAIDs). There is no specific antiviral therapy for acute chikungunya virus infection [4-6].

The acute illness typically lasts approximately 7 to 10 days, but acute disease requiring treatment may persist up to a month. In patients with clinical manifestations of acute chikungunya infection (eg, acute pain, fever, and arthralgia), we suggest acetaminophen (paracetamol; up to 500 to 1000 mg three times daily) or, once dengue is excluded and if acetaminophen is inadequate for symptom relief, NSAIDs (eg, naproxen 375 to 500 mg twice daily, ibuprofen 400 to 800 mg three times daily, or another NSAID); any NSAID may be used.

Typically, an NSAID should be tried for two weeks, and if it is ineffective, patients should be switched to a different NSAID. Both acetaminophen and NSAIDs should be used in the lowest dose and for the shortest duration necessary and avoided in patients with contraindications including known liver disease or elevated aminotransferases. There is no evidence that any one NSAID is superior to another or that in chikungunya infection, any specific NSAIDs should be avoided. Contraindications to NSAIDs and adverse effects of these agents (including renal, gastrointestinal, and cardiovascular disease) are discussed in detail separately. (See "Nonselective NSAIDs: Overview of adverse effects" and "Overview of COX-2 selective NSAIDs", section on 'Toxicities and possible toxicities'.)

In a patient who could have dengue virus infection, aspirin and other NSAIDs should not be used until dengue has been excluded or until 14 days after symptom onset, with the patient afebrile ≥48 hours and no warning signs for severe dengue (severe abdominal pain, persistent vomiting, mucosal bleeding, pleural effusion or ascites, lethargy, enlarged liver, and increased hematocrit with decrease in platelet count). This is important given the risk of bleeding complications associated with dengue infection, which could be worsened by aspirin or other NSAIDs, and because of the potential risk of Reye syndrome in children treated with salicylates. Coinfection with dengue and chikungunya viruses can occur, so acute dengue infection needs to be excluded even if diagnosis of chikungunya infection is confirmed. The diagnosis of dengue fever, chikungunya fever, and related diagnoses are described separately. (See "Dengue virus infection: Prevention and treatment" and "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis' and "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Differential diagnosis'.)

In patients with acute disease and severe pain who are unable to take acetaminophen and NSAIDs, or who do not respond adequately to these agents, we selectively use opioid analgesics (eg, tramadol or oxycodone) in the lowest dose for the shortest duration necessary.

In general, systemic glucocorticoids and other immunosuppressive medications should be avoided during acute infection. The safety of immunosuppression during acute infection is not well established, and there is concern that use of these agents may exacerbate the infection, especially during the viremic phase, which lasts approximately nine days [6]. (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Acute infection'.)

In patients with acute chikungunya fever, the rash resolves spontaneously and does not require treatment.

Most patients experience improvement in their symptoms within a month, regardless of therapy. Hospitalization is required infrequently, typically in infants, older adults, or immunocompromised patients with organ-threatening disease or severe complications related to an underlying medical condition.

Our treatment approach is based upon reports from case series [4,5], our clinical experience, and recommendations from expert groups [6,7]. There are only a few randomized trials; they have a number of limitations [8]. As examples:

●Treatment with daily NSAIDs and glucocorticoids (beginning in the second week of acute illness) has been associated with some symptomatic benefit during the first six weeks of illness. In one trial involving 120 patients with acute chikungunya fever and arthritis, patients randomly assigned to treatment for six weeks with either aceclofenac (an NSAID) monotherapy (200 mg daily), aceclofenac plus hydroxychloroquine (HCQ; 400 mg daily), aceclofenac plus prednisolone (10 mg daily), or aceclofenac plus HCQ plus prednisone, all groups had showed benefit from therapy and had increased difficulty performing activities of daily living upon discontinuation of medications at week 6 [9]. Greater pain relief was observed among the patients who received prednisolone compared with the patients who did not receive prednisolone (an approximate reduction in pain scores from baseline of 75 versus 30 to 40 percent).

●Limited evidence demonstrates no benefit of chloroquine or HCQ in patients with acute symptoms. In a randomized trial involving 54 patients, there was no improvement in acute or chronic pain or in the level of viremia in the first three days in patients receiving chloroquine compared with placebo [10]. In this report, it was unclear whether the patients were being treated during the acute and/or subacute phase of infection. Greater pain was reported at day 200 among patients who received chloroquine.

Post-acute and chronic arthritis — Management of persistent or relapsed manifestations, particularly joint disease, depends upon the duration of the symptoms. Symptomatic control of articular manifestations with antiinflammatory drugs and analgesics is appropriate in the several months immediately following the acute phase of disease. More chronic disease (beyond three months after onset of infection) may require the use of DMARD therapy, such as methotrexate (MTX).

For patients who present with severe post-acute or chronic symptoms, it is important to confirm chikungunya virus infection by establishing that patients are seropositive (positive anti-chikungunya virus immunoglobulin G [IgG]). Furthermore, other types of arthritis must be excluded (eg, seronegative spondyloarthritis [SpA], RA, or crystalline arthritis) before attributing symptoms to chikungunya virus. (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis' and "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Differential diagnosis'.)

Post-acute arthritis — In patients with joint symptoms persisting into the post-acute phase (between one month and up to the end of the third month after onset of infection), we suggest continued analgesia (eg, acetaminophen) and, if needed, NSAIDs. (See 'Acute disease' above.)

As in patients with acute symptoms, the minimal necessary dose and duration of medications is used. Periodically, an effort should be made to reduce and discontinue medications. Joint symptoms may gradually resolve over several months, and ongoing treatment may no longer be required.

In patients whose symptoms are refractory to two to three two-week courses of different NSAIDs and who exhibit arthralgia or arthritis, tendinitis, or bursitis, especially those with evidence of severe synovitis and joint swelling and persistent elevation of inflammatory markers, we suggest systemic glucocorticoids (prednisone 10 to 20 mg daily for five days, depending upon severity, tapered over 10 days). We give the lowest effective glucocorticoid dose possible with a short trial, which is sometimes sufficient; however, the individual response to therapy varies substantially; more severely affected patients may require higher doses (0.5 mg/kg daily) [6], and some patients require up to one to two months of glucocorticoid therapy [11]. One expert guideline suggests limiting glucocorticoids when possible to no more than four weeks of therapy [6].

Intraarticular glucocorticoids are rarely, if ever, indicated because the usual pattern of joint involvement is polyarticular, with involvement of multiple small and large joints, and because there is no evidence to support the efficacy of this approach.

Additional analgesic benefit may be provided by use of medications for neuropathic pain (eg, pregabalin or gabapentin) (see "Pharmacologic management of chronic non-cancer pain in adults", section on 'Antiseizure medications'). Physical therapy may also be helpful.

The approach to patients who develop Raynaud phenomenon is the same as in other patients with this disorder. (See "Treatment of Raynaud phenomenon: Initial management".)

Our treatment approach is based upon reports from case series, our clinical experience, and recommendations from expert groups [6,7]. Randomized trials are lacking or have limitations and limited applicability [8,12].

Indications for referral — Patients with clinical manifestations (particularly suspected inflammatory arthritis) that persist at least three months after the onset of infection should preferably be referred to a rheumatologist for further assistance in management and to determine if treatment with a DMARD is appropriate.

Chronic arthritis — The use of DMARD therapy in chronic arthritis (duration >3 months after infection) is similar to treatment for other chronic inflammatory arthritides. MTX has been the most commonly used DMARD, typically using the same approach as in RA (see "Initial treatment of rheumatoid arthritis in adults"). There is more limited experience using sulfasalazine (SSZ) (see "Treatment of peripheral spondyloarthritis"). DMARD combinations have been used in some patients [13], and tumor necrosis factor (TNF) inhibitors have been effective in patients resistant to or unable to take MTX [14,15]. (See 'Initial therapy of chronic arthritis' below and 'Resistant to initial therapy for chronic arthritis' below and 'Duration of therapy' below.)

Initial therapy of chronic arthritis — Chronic arthritis occurs as a continuation of the subacute disease, and patients will generally have been treated with acetaminophen and usually NSAIDs by this point in their illness (see 'Post-acute arthritis' above). Some patients may be receiving glucocorticoids or require initiation of glucocorticoids, as in post-acute disease (see 'Post-acute arthritis' above), to control symptoms until DMARDs are effective.

In patients with chronic arthritis not controlled by NSAIDs or prednisone 5 to 7.5 mg daily (or equivalent), we suggest a conventional DMARD, usually MTX; SSZ or an alternative DMARD are other options, as described below. For patients on NSAIDs or glucocorticoids, periodic attempts (eg, monthly) should be made to taper therapy, given the natural history of gradual improvement over months in chronic chikungunya arthritis. Similarly, we discontinue MTX (or other DMARDs) within several months after patients respond. (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Chronic arthritis and arthralgia' and "Major adverse effects of systemic glucocorticoids".)

Limited evidence suggests that MTX is the best available DMARD for patients with chronic chikungunya arthritis:

●Chronic peripheral arthritis – In most patients with chronic peripheral arthritis, especially that which resembles RA, who require ongoing therapy for symptomatic control, we suggest MTX, using the approach described in detail separately for patients with RA (see "Initial treatment of rheumatoid arthritis in adults" and "Use of methotrexate in the treatment of rheumatoid arthritis"). The adverse effects of MTX are described separately as well. (See "Major side effects of low-dose methotrexate".)

The dosing and absorption of MTX should be optimized, as in RA, by use of parenteral therapy or split oral doses (two doses 8 to 12 hours apart once weekly) in patients who do not respond to more than 15 mg once weekly by mouth. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Alternatives to once-weekly oral therapy'.)

Alternatives to MTX in patients unable to take the drug include SSZ, as well as other conventional DMARDs, but there is little evidence to support the use of conventional DMARDs other than MTX and SSZ. Several studies suggest that HCQ is ineffective [9,10,12]. (See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults".)

●Chronic axial spondyloarthritis pattern – In patients with disease of the axial spine, in whom MTX may not be effective, we suggest a TNF inhibitor, using the approach described in detail separately for patients with axial SpA (see "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Inadequate response to NSAIDs'). This approach is based upon clinical experience and indirect evidence from the use of TNF inhibitors for the treatment of axial SpA, and patients should be closely monitored given the very limited safety data for the use of biologic DMARDs in the setting of this viral infection. Available information regarding the adverse effects of TNF inhibitor therapy is described in detail separately. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

Our treatment approach is based upon the available case series [5,11,14,16,17] and expert opinion [6,7,18], but there are no well-designed randomized trials comparing DMARDs for this condition. Evidence is also lacking as to whether any therapy protects against joint injury. In spite of these limitations [8] and given the risks of chronic glucocorticoids, the available reports suggest that MTX is warranted in patients with chronic polyarthritis [19,20]; well-designed randomized trials are needed to compare MTX with other agents.

Few DMARD randomized trials have been performed in patients with chronic arthritis [19]. As examples of the available evidence:

●In one of the largest retrospective observational studies involving 159 patients, 72 were treated with MTX 15 mg weekly, with a positive therapeutic response (no need for dose escalation or a switch in therapy). These results were achieved in patients with chronic RA, SpA, and undifferentiated polyarthritis disease patterns (67, 80, and 100 percent of patients, respectively) [5].

●In a randomized trial involving 72 patients with active arthritis for greater than a year despite treatment with HCQ, triple therapy with MTX (15 mg once weekly), SSZ (1 gram daily), and HCQ (400 mg daily) was more effective than HCQ alone. Patients assigned to triple therapy experienced greater pain relief (mean pain visual analog scale [VAS] 46 versus 61), less disease activity (Disease Activity Score-28 with Erythrocyte Sedimentation Rate [DAS28-ESR] 3.39 versus 4.74), and less disability (mean Health Assessment Questionnaire [HAQ] score 1.4 versus 1.9) after six months of such therapy, compared with those on HCQ monotherapy [13]. Patients were also treated during the trial with prednisolone (initially 7.5 mg daily and tapered off over six weeks) and acetaminophen or NSAIDs as needed.

●Small trials using antimalarials, either chloroquine or HCQ, for post-acute or chronic arthritis have not shown benefit and have limitations in study or trial design.

Resistant to initial therapy for chronic arthritis — The approach to patients with an inadequate response to at least three months of initial DMARD therapy depends upon the drugs that have already been tried and perhaps the pattern of joint involvement; evidence to guide treatment in this population is lacking. Reasonable strategies include the following:

●Resistant to MTX – Patients resistant to MTX monotherapy could be treated with combination therapy with other conventional DMARDs [13] or with an alternative conventional DMARD, such as SSZ or leflunomide. We do not use HCQ monotherapy. For patients in whom conventional DMARDs are ineffective, one expert group recommends a TNF inhibitor, among the biologic DMARDs, although the safety of biologic therapy has not been established in these patients [7]. (See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults".)

●Resistant to SSZ – In patients with chronic polyarthritis (RA-like disease) that is resistant to SSZ, MTX would be a preferred option (see 'Initial therapy of chronic arthritis' above). In patients with SpA-like disease, MTX would be an option if no significant axial involvement is present, but a TNF inhibitor would be preferred in patients with symptomatic axial involvement. Biologic agents should be used with caution in patients with chikungunya infection.

Duration of therapy — In patients with a complete response for at least six months, we attempt to discontinue DMARD therapy. This is consistent with the approach suggested by an expert panel, which recommended that DMARDs may be discontinued in most patients following symptom resolution [6]. However, this approach has not been systematically studied, and the optimal approach remains to be determined. We also prioritize discontinuation of glucocorticoids, but resume treatment if active disease recurs.

Patients with pre-existing rheumatic disease — The management of pre-existing rheumatic disease during acute chikungunya infection requires precaution regarding medications that increase risk of bleeding until dengue is excluded and immunosuppressive medications that could worsen viremia (see 'Acute disease' above). Otherwise, treatment of the patient's pre-existing rheumatic condition is unchanged.

In one small case series, patients with pre-existing inflammatory rheumatic diseases on nonbiologic and biologic DMARDs, including TNF inhibitors, were managed effectively with NSAIDs and rest; in spite of DMARD therapy, they experienced a normal course of chikungunya infection without exacerbation of their pre-existing rheumatic disease [21].

PROGNOSIS — Nearly all patients with chikungunya arthritis eventually recover, although the duration of chronic symptoms varies widely. In one prospective study, the predictors of chronicity were age >40, severity of acute disease, and underlying osteoarthritis [5]. Some studies have reported progressive joint injury [22], and there are ongoing studies attempting to define the long-term implications of the disease. An observational study from Reunion Island found that 17 out of 30 patients who had been diagnosed with chikungunya virus-induced arthritis continued to have persistent inflammatory joint symptoms 13 years later [23]. In these patients, there was no evidence of seroconversion to anti-cyclic citrullinated peptide (CCP) or rheumatoid factor (RF) positivity. Generally, joint damage due to chronic chikungunya arthritis typically has not been visible by radiography but has been appreciable by magnetic resonance imaging (MRI) in a subset of patients [24].

PREVENTION

Mosquito protection — Prevention of chikungunya virus infection consists of minimizing mosquito exposure [25]. Aedes mosquitoes bite primarily during the daytime; they breed in standing water (particularly containers) [26]. Measures to avoid mosquito bites include personal protection and environmental control measures. (See "Prevention of arthropod and insect bites: Repellents and other measures" and "Zika virus infection: An overview", section on 'Mosquito protection'.)

Individuals with chikungunya infection may reduce spread of infection to others by following precautions to avoid mosquito bites during the first week of illness (the likely period of viremia).

Vaccination — A live-attenuated chikungunya virus vaccine (VLA1553, or Ixchiq) was approved by the US Food and Drug Administration (FDA) in 2023. Approval was based on a double-blind, randomized trial based in the United States in which 4128 healthy adults (age ≥18 years) were randomly assigned to a single dose of vaccine or placebo [27]. Among the 266 patients who were assessed for immunogenicity, a seroprotective neutralizing antibody response occurred in 99 percent by 28 days after vaccination and persisted in 96 percent at 180 days. None of the placebo recipients developed a neutralizing antibody response. Response rates were similar among participants aged 18 to 64 years and those 65 years and older. Two serious adverse effects were attributed to the vaccine (myalgia and syndrome of inappropriate antidiuretic hormone secretion), both of which resolved. The most common adverse effects reported by all trial participants receiving the vaccine included headache (32 percent), fatigue (29 percent), myalgia (24 percent), arthralgia (18 percent), and fever (14 percent). Ongoing studies include assessing immunogenicity over five years and a double-blind, randomized trial among adolescents aged 12 to 18 in Brazil.

Development of other types of vaccines for prevention of chikungunya virus infection is also underway [28-33]:

●In a randomized trial including more than 260 healthy adults in non-chikungunya-endemic regions, a live-attenuated, measles-vectored vaccine expressing chikungunya virus structural proteins (MV-CHIK), or a measles vaccine prime and MV-CHIK, induced neutralizing antibodies against chikungunya virus after one or two immunizations [33]. Seroconversion rates in those who received MV-CHIK ranged from 50 to 93 percent after one dose and 86 to 100 percent after a two doses. Immune responses were durable up to six months after one or two doses and the vaccine was safe and well-tolerated. Additional clinical trials are ongoing.

●In a randomized phase 2 trial of a CHIK virus-like particle (VLP) vaccine, 400 adults in chikungunya-endemic Caribbean countries received two intramuscular injections or placebo. Among those who were seronegative at baseline, 88 percent had at least a fourfold increase from baseline neutralization titers [34]. The immune response was durable up to 72 weeks after vaccination, and the vaccine was safe and well-tolerated. Two phase 3 clinical trials evaluating an adjuvanted form of this vaccine (PXVX0317) are in progress [35,36].

●A messenger RNA (mRNA)-based vaccine (VLA-181388) is in phase 1 clinical trials [37,38].

Further studies are needed for all chikungunya vaccine candidates focusing on vaccine efficacy, cross-protection against multiple chikungunya virus strains, duration of immunity, and safety and efficacy in other populations, such as children.

SUMMARY AND RECOMMENDATIONS

●Supportive care – There is no specific antiviral therapy for treatment of chikungunya virus infection, and management during the acute phase is supportive, including rest, fluids, and antiinflammatory and analgesic agents (see 'Acute disease' above):

•In patients in whom dengue has been excluded, we suggest NSAIDs (eg, naproxen 375 to 500 mg twice daily, ibuprofen 400 to 800 mg three times daily, or another NSAID) rather than glucocorticoids for symptomatic relief (Grade 2C). Any NSAID may be used.

•Aspirin and other NSAIDs are avoided initially if dengue has not been excluded because of the risk of bleeding complications. Acetaminophen (paracetamol; up to 500 to 1000 mg three times daily) can be used in this setting. Aspirin should also be avoided in children because of the potential risk of Reye syndrome.

●Refractory arthritis – For patients not responsive to two to three two-week courses of NSAIDs who exhibit musculoskeletal symptoms, particularly patients with severe synovitis, joint swelling, or persistent elevation of inflammatory markers, we suggest systemic glucocorticoids (Grade 2C). A typical initial dose is prednisone 10 to 20 mg daily for five days, depending upon severity, then tapered off over the next 10 days. More severely affected patients may require higher doses (eg, prednisone 0.5 mg/kg daily), and some patients require up to one to two months of glucocorticoid therapy. We use the lowest effective dose possible. (See 'Post-acute arthritis' above.)

●Chronic arthritis – For patients with chronic arthritis (>3 months after initial infection) who are unable to taper prednisone without recurrence of symptoms, we suggest treatment with a disease-modifying antirheumatic drug (DMARD; eg, methotrexate [MTX], or if MTX is contraindicated, sulfasalazine [SSZ]), rather than continuing glucocorticoids alone (Grade 2C). The choice of DMARD may be guided by the pattern of joint involvement. We generally use the same approach to dosing and monitoring these medications as in RA but make an effort to taper medications after four to six months once patients have been asymptomatic for at least six months. (See 'Chronic arthritis' above.)

•Polyarthritis resembling rheumatoid arthritis – For most patients with chronic polyarthritis that resembles RA who require ongoing therapy for symptomatic control, we suggest MTX (Grade 2C). We use the approach described in detail separately for patients with RA, with initial titration of MTX to 15 to 25 mg once weekly. (See "Initial treatment of rheumatoid arthritis in adults" and "Use of methotrexate in the treatment of rheumatoid arthritis".)

For patients unable to take MTX, alternatives include SSZ and other conventional DMARDs as discussed separately. (See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults".)

•Axial arthritis – For patients with disease of the axial spine, we suggest a tumor necrosis factor (TNF) inhibitor (Grade 2C). The approach is the same as for patients with axial SpA, which is described in detail separately (see "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Inadequate response to NSAIDs'). Patients should be closely monitored given the lack of safety data for the use of these biologic agents in the setting of this viral infection.

●Prevention

•Mosquito protection – Minimizing mosquito exposure is the cornerstone of prevention. Individuals with chikungunya infection may reduce spread of infection to others by following precautions to avoid mosquito bites during the first week of illness (the likely window of viremia). (See 'Prevention' above.)

•Vaccination – One type of live-attenuated vaccine to prevent infection with chikungunya virus (VLA1553, or Ixchiq) was approved by the US Food and Drug Administration (FDA) in 2023. Development of other vaccine candidates is ongoing. (See 'Vaccination' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jonathan J Miner, MD, PhD, who contributed to an earlier version of this topic review.