Pediatric Aseptic Meningitis

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Background

Pediatric aseptic meningitis is an inflammation of the meninges caused mainly by nonbacterial organisms, specific agents, or other disease processes. Aseptic meningitis (including viral meningitis) is the most common infection of the central nervous system (CNS) in the pediatric population, occurring most frequently in children younger than 1 year. Despite advances in antimicrobial and general supportive therapies, CNS infections remain a significant cause of morbidity and mortality in children.

Because the classic signs and symptoms are often absent, especially in younger children, diagnosing pediatric CNS infections is a challenge to the emergency department (ED). Even when such infections are promptly diagnosed and treated, neurologic sequelae are not uncommon. Clinicians are faced with the daunting task of distinguishing the relatively few children who actually have CNS infections from the vastly more numerous children who come to the ED with less serious infections.

Pathophysiology

Organisms colonize and penetrate the nasopharyngeal or oropharyngeal mucosa, survive and multiply in the blood stream, evade host immunologic mechanisms, and spread through the blood-brain barrier. Infection cannot occur until colonization of the host has taken place (usually in the upper respiratory tract). The mechanisms by which circulating viruses penetrate the blood-brain barrier and seed the cerebrospinal fluid (CSF) to cause meningitis are unclear.

Viral infection causes an inflammatory response but to a lesser degree than bacterial infection does. Damage from viral meningitis may be due to an associated encephalitis and increased intracranial pressure (ICP).

The pathophysiology of aseptic meningitis caused by drugs is not well understood. This form of meningitis is infrequent in the pediatric population.

Etiology

Although many agents and conditions are known to be associated with pediatric aseptic meningitis, often a specific cause is not identified, because a complete diagnostic investigation is not always completed. Viruses are the most common cause, and enteroviruses (EVs) are the most frequently detected viruses. The use of molecular diagnostic techniques (eg, polymerase chain reaction [PCR] assay) has significantly increased diagnostic accuracy.

Viruses

EV is a frequent cause of febrile illnesses in children and is frequently found in asymptomatic children.[1] Other viral pathogens include human parechovirus,  paramyxovirus, herpesvirus, influenza virus, rubella virus, and adenovirus. Meningitis may occur in as many as 50% of children younger than 3 months with EV infection. EV infection can occur at any time during the year but is associated with epidemics in the summer and fall.

Viruses associated with aseptic meningitis include the following:

Enteroviruses species A-D: this encompasses enterovirus, echoviruses, coxsackie viruses and polio viruses.[2]

                Enterovirus A: EV-A71 and Coxsackie A2-8, 10, 12, 14, 16

                Enterovirus B: EV-B75, Coxsackie B1-6, Echovirus 1-33,[3]

                Enterovirus C: Poliovirus 1-3, Coxsackie A 1, 11, 13, 17, 19-24,

                Enterovirus D: EV –D68, 70[4]

Human parechoviruses (HPeV) (16 serotypes; HPeV types 1 and 2 were previously classified as echovirus types 22 and 23 within the genus Enterovirus), type 3 (and less commonly type 5) has been associated with childhood CNS infections.[5, 6, 7]

Arbovirus (eastern, western, and Venezuelan equine encephalitis viruses; Powassan virus; California group viruses [primarily LaCrosse virus]; St. Louis encephalitis virus; West Nile virus; and Colorado tick fever)

Mumps virus

Herpes simplex virus (HSV) types 1 and 2

Cytomegalovirus (CMV)

Epstein-Barr virus (EBV)

Human herpesvirus type 6 (HHV6) and type 7 (HHV7)

Varicella-zoster virus (VZV)

Adenovirus types 3 and 7

Human immunodeficiency virus (HIV)

Lymphocytic choriomeningitis (associated with contact with guinea pigs, hamsters, and pet mice)

Rhinovirus

Measles virus

Rubella virus

Influenza A and B viruses, including H1N1[8, 9]

Parainfluenza virus

Parvovirus B19

Rotavirus

Coronavirus

Variola virus

Flavivirus[10]

Toscana Virus[11]

 

Skin lesions due to echovirus type 9 on neck and chest of young girl. Echoviruses belong to genus Enterovirus and are associated with illnesses including aseptic meningitis, nonspecific rashes, encephalitis, and myositis.



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Skin lesions due to echovirus type 9 on neck and chest of young girl. Echoviruses belong to genus Enterovirus and are associated with illnesses includ....

Viral vaccines

Viral vaccines related to aseptic meningitis include the following:

Mumps vaccine[12]

Measles-mumps-rubella (MMR) vaccine

Polio vaccine

Rabies vaccine

Yellow fever vaccine[13]

Nonpyogenic bacteria

Certain bacterial infections may give rise to aseptic meningitis (eg, partially treated bacterial meningitis or brain abscess). Nonpyogenic bacteria associated with aseptic meningitis include the following:

Mycobacterium tuberculosis

Leptospira

Treponema pallidum

Borrelia (relapsing fever, Lyme disease)

Nocardia

Bartonella

Atypical mycobacteria

Brucella

Other organisms

Atypical organisms associated with aseptic meningitis include the following:

Chlamydia

Rickettsia

Mycoplasma

Parasites associated with aseptic meningitis include the following:

Roundworms

Tapeworms

Flukes

Amoebae

Toxoplasma

Fungal meningitis is rare but may occur in immunocompromised patients; children with cancer, previous neurosurgery, or cranial trauma; or premature infants with low birth rates. Most cases occur in children who are inpatients receiving antibiotic therapy. Fungi associated with aseptic meningitis include the following:

Candida

Histoplasma

Cryptococcus

Additional organisms associated with aseptic meningitis include the following:

Blastomyces dermatitidis

Coccidioides immitis

Alternaria species

Aspergillus species

Cephalosporium species

Cladosporium trichoides

Drechslera hawaiiensis

Paracoccidioides brasiliensis

Petriellidium boydii

Sporotrichum schenckii

Ustilago species

Zygomycetes species

Diseases and other conditions or events

Diseases associated with aseptic meningitis include the following:

Leukemia

Behçet disease

Systemic lupus erythematosus (SLE)

Sarcoidosis

Sjögren syndrome[14]

Dermoid and epidermoid cysts[15]

CNS tumor

Kawasaki disease [16]

Recurrent benign endothelioleukocytic aseptic meningitis (Mollaret meningitis)[17]

Neonatal-onset multisystem inflammatory disorder (one of the cryopyrin-associated periodic syndromes [CAPS])[18]

Other conditions or events associated with aseptic meningitis include the following:

Immunoglobulin replacement therapy

Heavy metal poisoning

Intrathecal agents

Foreign bodies (eg, shunt or reservoir)

Drugs

Epidemiology

United States Statistics

The incidence of aseptic meningitis in the United States has been estimated to be approximately 75,000 cases per year. Before the introduction of the MMR vaccine program, the mumps virus was the most common cause, accounting for 5-11 of 100,000 cases of meningitis; it now accounts for approximately 0.3 of 100,000 cases, and EV has become the most common cause. In a North American study from 1998-1999, most cases occurred between July and October.[19]

International Statistics

In the United Kingdom, the causes of meningitis have changed since the introduction of vaccines against Haemophilus Influenza B (1992) Neisseria Meningitidis (1999) and Streptococcus Pneumoniae (2006).[20] Viruses are the predominate known cause of meningitis but 41% of patients with meningitis had no identifiable pathogen. During a similar time period in the United Kingdom, admission rates for viral meningitis fell by almost two thirds following the introduction of the MMR vaccine.[21]  Prior to the vaccine mumps meningitis was likely the leading cause of viral meningitis. Following its introduction, peaks in admissions were noted in association with known outbreaks of Echovirus 13 and 30. The overall decline in admissions was due to a fall in admissions in those age 1-14 years. Admissions with viral meningitis in those < 3 months has risen in recent years however this may be due to differences in clinical practice. Furthermore there were biannual peaks in admissions for infants < 3 months which may reflect the biannual spring time peaks reported in HPeV infections.[22] The proportion of cases recognized as being caused by enterovirus also rose which could be attributed partially but not wholly to improved detection.

The Austrian reference laboratory for poliomyelitis received 1,388 stool specimens for EV typing from patients with acute flaccid paralysis or aseptic meningitis between 1999 and 2007; 201 samples from 181 cases were positive for nonpoliomyelitis EV.[23] The mean patient age was 5-6 years, with 90% of cases in children younger than 14 years. Aseptic meningitis was identified in 65.6% of the cases. Echovirus 30 (E-30) was the most frequent viral cause of aseptic meningitis, due to an epidemic in 2000, followed by coxsackievirus B types 1-6 and EV 71. E-30 was also the leading viral pathogen in a Spanish study of aseptic meningitis.[3]

A new outbreak of E-30 occurred between April and September 2013 in Marseille, South-East France. A study concluded that almost all E-30 emerged from local circulation of one parental virus. The findings also showed that human enterovirus outbreaks cause an excess of emergency ward consultations but probably also an excess of consultations to general practitioners who receive majority of the non-specific viral illness.[24] Similar outbreaks have been reported in California, Germany, Finland, Italy and China.[25, 26, 27, 28, 29]

Outbreaks of meningitis caused by other types of enteroviruses also occur when new genetic variants develop.[30, 31]

Human parechovirus (HPeV) is an increasingly recognized viral cause of aseptic meningitis.[7]  Studies have shown that in young infants (< 3 months) HPeV is as least as common as enterovirus.[6] 16 types have been identified with types 1-8 being the most studied. In the pediatric population type 3 has been shown to cause meningitis and neonatal sepsis.[32] The other types are associated with gastroenteritis and respiratory illness.[6] Diagnostic assays for HPeV are not widely available and so its burden is thought to be underestimated.[5]

In an area of Southwestern Norway, where Lyme disease is endemic, it is the leading cause of meningitis.[33]

Age-related demographics

Aseptic meningitis is more common in children than in adults.[34] This reflects increased frequency of enteroviral infections in children.[35] Rates of enterovirus and HPeV in young infants have risen which may reflect reduced maternal seroprevalence and reduced transfer of maternal antibodies to the newborn.[36] In the UK admission rates for children with viral meningitis have fallen since the introduction of the MMR vaccine however rates have risen in infants under 1 year of age.

Sex-related demographics

Studies have shown a male predilection in aseptic meningitis. 59% of pediatric patients in a Texan study were male while a Greek study showed a male:female ratio of 1.8:1.[34, 37] Further studies in South Korea and Japan have also demonstrated higher proportion of males affected.[38, 39]

Race-related demographics

In the Texan study adults with aseptic meningitis were more likely to be Caucasian and children were more likely to be Hispanic.[37] No background demographic data was provided therefore the significance of this is uncertain.

Prognosis

Full recovery is usual after uncomplicated viral aseptic meningitis. Most cases resolve within 7-10 days.

Recurrence is possible (known as Mollaret, or benign recurrent meningitis). Associated viruses include Epstein-Barr virus (EBV), coxsackieviruses B5 and B2, echoviruses 9 and 7, herpes simplex virus (HSV)-1 and HSV-2, and human immunodeficiency virus (HIV).

Overall mortality and morbidity for aseptic meningitis are unclear. In a Taiwanese study of EV 71 infections, 78 of 408 hospitalized children died and among the children with rhombencephalitis due to EV infection, 14% died.[40]

Subsequent studies suggested better outcomes. No deaths  have been reported in Canadian, Korean, Greek and American studies.[38, 19, 34, 37] Overall, it is felt that there are no or minimal long term effects however there is a lack of data regarding long term morbidity and psychological impact.

Patient Education

For more information, visit the Meningitis Foundation of America Web site. The Meningitis Research Foundation offers useful material for nonexperts, parents, and health care professionals.

History

Headache, neck stiffness, and photophobia are classic symptoms of aseptic meningitis in older children. These symptoms may be absent in younger children, who more commonly present with rash, diarrhea, and cough. Fever may be present. Seizures are more common in aseptic meningitis caused by specific viruses (eg, arboviruses). Other nonspecific symptoms may include arthralgia, myalgia, sore throat, weakness, and lethargy and hypotonia.

Recent travel and potential exposure to ticks or other biting insects are important aspects of the patient’s history. The history varies according to the etiologic agent.

In areas with widespread vaccination of children, enteroviruses are the most common causes of viral meningitis. Onset is usually acute but can be insidious over the week before presentation or can follow an acute febrile illness. Rash, when present, is erythematous, maculopapular, and vesicular, appearing on the soles of the feet, palms, or mucous membranes. Fever may last up to 5 days. Anorexia, nausea, respiratory symptoms and vomiting are common. Sore throat may occur. Rare symptoms include flaccid paralysis, pericarditis, myocarditis, and conjunctivitis.

In areas with low vaccination rates, mumps virus is often the most frequent cause of meningitis. Aseptic meningitis caused by mumps virus occurs 7-10 days after parotitis. Mumps virus, adenovirus, and varicella-zoster virus (VZV) infections tend to be more severe than enterovirus (EV) infections, and often evidence of encephalitis is present. Arbovirus infections frequently are associated with encephalitis and seizures.

In older teenagers and adults, aseptic meningitis may be associated with reactivation of herpes simplex virus (HSV)-2 infections. Reactivation of VZV infections is rare in immunocompetent children.

Aseptic meningitis associated with Mycoplasma pneumonia e infection usually occurs 3-21 days after the respiratory infection. Fungal meningitis occurs in immunocompromised patients and has a variable presentation. Lyme meningitis is characterized by a facial nerve palsy or symptoms headache and neck stiffness often being the sole symptom.[33]

Aseptic meningitis may be caused by drugs, usually nonsteroidal anti-inflammatory drugs (NSAIDs),[41]  chemotherapy agents,[42]  intravenous immunoglobulin (IVIg),[16] antiepileptics[43] or antibiotics. One review found 41 cases of Trimethoprim-sulfamethoxazole induced aseptic meningitis. Symptoms were similar those of viral meningitis. There was a female predominance and an association with autoimmune disease. Symptoms resolved when the drug was withdrawn however patients reacted to Trimethoprim and Sulfamethoxazole when given as single agents.[44]

Physical Examination

Physical examination findings vary widely, depending on the patient’s age and the organism or condition responsible for the meningitis. The younger the child, the less specific the signs: In a young infant, findings that definitely point to meningitis are rare, but as the child grows older, the physical examination becomes more reliable. Because clinical signs are unreliable, particularly in the younger patient, they should not be the only factors considered when deciding on investigations and lumbar puncture.[45, 20]

The infant may be febrile or hypothermic. Lymphadenopathy may be present. Bulging of the fontanel, diastasis of the sutures, and nuchal rigidity point to meningitis but are usually late findings. Examination should specifically exclude a nonblanching petechial rash, other signs of bacterial meningitis, and features suggestive of a noninfectious etiology.

Neurologic examination includes evaluating for signs of meningism (eg, headache, photophobia, neck stiffness, and positive Kernig or Brudzinski sign) and focal or generalized neurologic signs. Focal neurologic signs may be present in as many as 15% of patients and are associated with a worse prognosis.

A definitive diagnosis of meningitis requires examination of CSF via lumbar puncture. Lumbar puncture should not be carried out in the presence of any contraindications (listed below). The presence or absence of classic meningeal signs and symptoms should not be used as the sole criterion for referring patients for further diagnostic testing.[45, 46]

Contraindications to lumbar puncture, per the National Institute for Health and Care Excellence (UK), are as follows[47] :

Perform delayed lumbar puncture in children with suspected meningitis when contraindications are no longer present.

Complications

Serious complications are uncommon but can include unilateral deafness after mumps meningitis, chronic enteroviral meningitis (especially in patients with agammaglobulinemia), and hydrocephalus after lymphocytic choriomeningitis virus infection. Rhombencephalitis has been reported as a complication of EV 71 infection.[40]  A case of fatal leukoencephalitis has been reported due to echovirus 18 infection.[48]  HSV and arbovirus infections, as well as viral infections in AIDS patients, can result in severe neurologic disease.

Seizure disorders, behavioral problems, and speech delay (unrelated to hearing loss) have been reported. In a Korean study, 0.7% of children had neurologic problems such as seizures, amnesia, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and hydrocephalus, though none were permanent.[38]

Recurrence is possible (known as Mollaret, or benign recurrent meningitis). There is one case report with a familial association.[49]

Other Tests

When the clinical presentation of aseptic meningitis is typical, imaging studies (ie, early computed tomography [CT] or magnetic resonance imaging [MRI]) are rarely required for initial management,  unless (1) other pathology must be ruled out before lumbar puncture or (2) focal neurologic signs are present.[37]  Imaging may be useful to check for abscesses, subdural effusions, empyema, or hydrocephalus. Normal CT findings do not rule out increased intracranial pressure (ICP).

EEG

Electroencephalography (EEG) may be considered if atypical febrile seizures have occurred. A neuroimaging study is required for complicated cases, including children with meningoencephalitis.

Laboratory Studies

The following studies are indicated in patients with suspected aseptic meningitis:

White blood cell (WBC) count

C-reactive protein (CRP) – one study suggests that a CRP of >80 is associated with bacterial meningitis.[54]

Procalcitonin (PCT) – PCT is a potentially useful predictor for distinguishing between bacterial and aseptic meningitis  and is increasingly available. It rises faster than CRP thus making it potentially more useful in early diagnosis of bacterial meningitis.[55, 56]

Blood glucose (to compare with CSF glucose)

Blood culture to exclude bacterial meningitis

Viral culture of throat swab, nasopharyngeal aspirate, and stool sample

Serology – Save serum for paired convalescent sample comparison of serology at 2-3 weeks following acute illness

Lumbar Puncture and CSF Analysis

The most important laboratory study is examination of the cerebrospinal fluid (CSF). Accordingly, lumbar puncture should be considered in the absence of contraindications (see below). CSF evaluation should include opening and closing pressures, as well as the following:

Cell count

Gram stain

Culture and sensitivity

Glucose

Viral PCR

Protein and antigen

Acid-fast bacillus

Fungal stains

Typical findings include the following:

CSF pressure that is within the reference range or increased

WBC count that is usually below 500/µL, with greater than 50% lymphocytes; although the lymphocytic predominance in the CSF is typical, neutrophils can predominate in the early stages The white cell count can be normal in viral meningitis.[57, 6]  If the white cell count is normal it may indicate that the primary infection is systemic rather than meningitic.

CSF protein concentration of 0.5-2 g/L

CSF glucose concentration that is within the reference range (>66% blood glucose level) or low

Negative Gram stain results

CSF interleukin (IL)-6 and IL-12 levels are significantly higher in bacterial meningitis and are therefore useful markers for distinguishing this condition from aseptic meningitis.

CSF lactate has been proposed as a useful differentiator between viral and bacterial meningitis in adults.[58]  Its use alongside the Bacterial Meningitis score has been trialed with promising results however further data is needed.[59]

If bleeding occurs during the lumbar puncture and the CSF is contaminated with blood, interpretation becomes more difficult. In such situations, it is better to treat and wait for the results of the CSF culture. In very bloody lumbar punctures, a drop of the fluid on the sterile dressing usually will produce a double ring if there is CSF present. When in doubt, treat and attempt the lumbar puncture again later.

Formulas to adjust for the WBC count in the CSF analysis have not increased the specificity or sensitivity in traumatic lumbar puncture and still risk misclassifying patients.[60]

Polymerase chain reaction (PCR) assay for many of the common etiologic agents of aseptic meningitis is increasingly available through state health departments, the Centers for Disease Control and Prevention (CDC), and research laboratories.

PCR assay for enteroviruses (EVs) is specific and faster and more sensitive than viral culture. It should be considered as an initial investigation where available. Culture is no longer necessary for clinical diagnosis and is recommended only in patients with PCR-positive results to obtain isolates for typing purposes.[61, 62] ,[63]

Routine CSF EV PCR testing has been shown to reduce the length of hospitalization and the duration of antibiotics in pediatric patients with suspected aseptic meningitis.[64]  Its use also reduces hospital costs, one Dutch study showed an average reduction of more than US$1450 of mean sots per patient.[65]

PCR assay of CSF can detect as few as 10 copies of viral nucleic acid. The ability to amplify DNA from herpes simplex virus (HSV)–1 and HSV-2, varicella-zoster virus (VZV), cytomegalovirus (CMV), human herpesvirus 6A (HHV6A) and HHV6B, and Epstein-Barr virus (EBV) in a single reaction has revolutionized diagnosis of EV and other viral infections (eg, HHV7 and West Nile virus). PCR assay of CSF in EV 71 infection can often yield negative results; higher diagnostic yields are obtained from PCR of respiratory and gastrointestinal (GI) tract specimens.[66]

Approach Considerations

Management of pediatric aseptic meningitis is primarily supportive. Consultation with a pediatrician, an infectious disease specialist, a critical care specialist, or combinations thereof may be needed.

Administer adequate analgesia. Treat seizures with appropriate emergency therapies. Referral to a specialized pediatric intensive care unit (ICU) is appropriate if the level of consciousness is reduced and the airway cannot be maintained.

If meningoencephalitis is suspected, administer high-dose intravenous (IV) acyclovir until herpes simplex virus (HSV) infection can be excluded.

If bacterial meningitis cannot be excluded on the basis of the initial history, examination, and investigation, antibiotics should be given. Use an IV third-generation cephalosporin in combination with IV vancomycin until a pyogenic (ie, primarily pneumococcal or meningococcal) bacterial cause is ruled out. Practice guidelines for the management of bacterial meningitis are available from the Infectious Diseases Society of America (IDSA).[67]  The National Institute for Health and Clinical Excellence (NICE) guidelines "Bacterial meningitis and meningococcal septicaemia: Management of bacterial meningitis and meningococcal septicaemia in children and young people younger than 16 years in primary and secondary care ” are also available for the United Kingdom.[47]

If tuberculous meningitis is suspected or proved, administer specific antimicrobial therapy and IV corticosteroids. In pediatric patients older than 3 months, the use of steroids is recommended for bacterial meningitis.[47]  (See Pediatric Bacterial Meningitis.) Steroids are not recommended for use in aseptic meningitis.

Pleconaril, is capsid binding anti-viral agent with activity against most strains of enterovirus (EV). One small randomized controlled trial of pleconaril in newborns with suspected enterovirus has shown some efficacy although further data is needed.[68] Many potential targets for anti-enteroviral treatments have been identified however a very small number have been pursued in clinical trials.[69]

EV-71 specific immunoglobulin has been trialed in mice however clinical trials in humans are awaited.[70]  Vaccines are also in development against EV-71 and have been trialed in China with promising results.[71, 72]  The vaccines appeared safe and reduced the burden of associated hand, foot and mouth disease and herpangina. Further data is needed to assess the vaccines impact on neurologic disease caused by EV-71.

Recovery can be prolonged, and rest is occasionally advised. Children with suspected viral meningitis who appear well may receive care as outpatients, with only symptomatic treatment required. Routine follow-up is not required unless there are specific indications.

Medication Summary

Drug therapy is currently not a component of the standard of care for pediatric aseptic meningitis. Follow standard local analgesic regimens.

Ceftriaxone (Rocephin)

Clinical Context:  Ceftriaxone is a third-generation cephalosporin with broad-spectrum gram-negative activity; it has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. It arrests bacterial growth by binding to 1 or more penicillin-binding proteins (PBPs).

Cefotaxime (Claforan)

Clinical Context:  Cefotaxime is a third-generation cephalosporin with a gram-negative spectrum; it has lower efficacy against gram-positive organisms. It arrests bacterial cell wall synthesis, which, in turn, inhibits bacterial growth.

Vancomycin

Clinical Context:  Vancomycin is a potent antibiotic directed against gram-positive organisms and active against Enterococcus species. It is indicated for patients who cannot receive or have failed to respond to penicillins and cephalosporins or who have infections caused by resistant staphylococci. For abdominal penetrating injuries, it is combined with an agent active against enteric flora, anaerobes, or both.

To prevent toxicity, the current recommendation is to assay vancomycin trough levels after the third dose, 30 minutes before the next dose. Use the creatinine clearance to adjust dosing in patients diagnosed with renal impairment.

Class Summary

Ceftriaxone, cefotaxime, and vancomycin should be considered if bacterial meningitis cannot be excluded.

Acyclovir (Zovirax)

Clinical Context:  Acyclovir is a prodrug activated through phosphorylation by a virus-specific thymidine kinase (TK) that inhibits viral replication. Herpesvirus TK (but not host cell TK) uses acyclovir as a purine nucleoside, converting it into acyclovir monophosphate, a nucleotide analogue. Guanylate kinase converts the monophosphate form into diphosphate and triphosphate analogues that inhibit viral DNA replication. Acyclovir inhibits the activity of both herpes simplex virus (HSV)–1 and HSV-2.

Class Summary

Antiviral agents inhibit viral replication and activity. Antiviral medications should be considered if viral encephalitis cannot be excluded.

Isoniazid

Clinical Context:  This is the drug of choice for preventive therapy and the primary drug in combination therapy for active TB. In patients receiving treatment for active TB, pyridoxine should be coadministered to prevent peripheral neuropathy.

Rifampin (Rifadin)

Clinical Context:  Rifampin is used in combination with at least 1 other antituberculous drug. It inhibits DNA-dependent bacterial, but not mammalian, RNA polymerase. Cross-resistance may occur.

In most susceptible cases, the patient undergoes 6 months of treatment. Treatment lasts for 9 months if the patient's sputum culture result is still positive after 2 months of therapy.

Pyrazinamide

Clinical Context:  This is a pyrazine analog of nicotinamide that is either bacteriostatic or bactericidal against M tuberculosis, depending on the concentration of drug attained at the site of infection. Pyrazinamide's mechanism of action is unknown.

Administer the drug for the initial 2 months of a 6-month or longer treatment regimen for drug-susceptible TB. Treat drug-resistant TB with individualized regimens.

Ethambutol (Myambutol)

Clinical Context:  Ethambutol diffuses into actively growing mycobacterial cells (eg, tubercle bacilli). It impairs cell metabolism by inhibiting the synthesis of 1 or more metabolites, which, in turn, causes cell death. No cross-resistance has been demonstrated.

Mycobacterial resistance is frequent with previous therapy. In such cases, use ethambutol in combination with second-line drugs that have not been previously administered. Administer q24h until permanent bacteriologic conversion and maximal clinical improvement are observed. Absorption is not significantly altered by food.

Streptomycin

Clinical Context:  Streptomycin sulfate is used for the treatment of susceptible mycobacterial infections. Use this agent in combination with other antituberculous drugs (eg, isoniazid, ethambutol, rifampin). The total period of treatment for TB is a minimum of 6 months. However, streptomycin therapy is not commonly used for the duration of therapy. The drug is recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated.

Rifapentine (Priftin)

Clinical Context:  This agent is used in once-weekly regimens along with isoniazid. Rifapentine should not be used in individuals with HIV infection or with positive cultures after 2 months of treatment.

Ethionamide (Trecator)

Clinical Context:  Ethionamide is a second-line drug that is bacteriostatic against M tuberculosis. It is recommended if treatment with first-line drugs (isoniazid, rifampin) is unsuccessful. Ethionamide can be used to treat any form of active TB. However, it should be used only with other effective antituberculous agents.

Cycloserine (Seromycin)

Clinical Context:  Cycloserine, a second-line drug, inhibits cell wall synthesis in susceptible strains of gram-positive and gram-negative bacteria and in M tuberculosis. It is a structural analogue of D-alanine, which antagonizes the role of D-alanine in bacterial cell wall synthesis, inhibiting growth.

Capreomycin (Capastat)

Clinical Context:  Capreomycin is a second-line drug obtained from Streptomyces capreolus for coadministration with other antituberculous agents in pulmonary infections caused by capreomycin-susceptible strains of M tuberculosis. Capreomycin is used only when first-line agents (eg, isoniazid, rifampin) have been ineffective or cannot be used because of toxicity or the presence of resistant tubercle bacilli.

Rifabutin (Mycobutin)

Clinical Context:  This is an ansamycin antibiotic derived from rifamycin S. Rifabutin inhibits DNA-dependent RNA polymerase, preventing chain initiation. It is used for TB treatment in individuals on specific HIV medications, when rifampin is contraindicated (most protease inhibitors).

Dapsone

Clinical Context:  Dapsone is bactericidal and bacteriostatic against Mycobacterium strains. Its mechanism of action is similar to that of sulfonamides, in which competitive antagonists of PABA prevent the formation of folic acid, causing bacterial growth inhibition. The use of dapsone in the treatment of TB is largely experimental.

Aminosalicylic Acid (Paser)

Clinical Context:  This is a bacteriostatic agent that is useful against M tuberculosis. It inhibits the onset of bacterial resistance to streptomycin and isoniazid. Administer aminosalicylate sodium with other antituberculous drugs.

Class Summary

If tuberculous meningitis is suspected or proved, administer specific antimicrobial therapy and intravenous corticosteroids. The World Health Organization recommend treating with a 4 drug regimen (Isoniazid, rifampicin, pyrazinamide, ethambutol)  for 2 months then a 2 drug regimen (Isoniazid and Rifampicin) for a further 10 months.[73] Consideration of co-infection with HIV should be given in these children.

The goals of tuberculosis (TB) treatment are to shorten the clinical course of TB, prevent complications, prevent the development of latency and/or subsequent recurrences, and decrease the likelihood of TB transmission. Antituberculous medications should be considered if tuberculous meningitis cannot be excluded.

Author

Daniel Owens, BM, MRCPCH(UK), Clinical Research Fellow, NIHR Clinical Research Facility, Southampton General Hospital, UK

Disclosure: Nothing to disclose.

Coauthor(s)

Katrina Cathie, MD, MRCPCH(UK), BM(Hons), Consultant in General Pediatrics and Pediatric Research, University Hospital Southampton NHS Foundation Trust, UK

Disclosure: Nothing to disclose.

Saul N Faust, MBBS, PhD, MA, MRCPCH(UK), Senior Lecturer in Pediatric Immunology and Infectious Diseases, University of Southampton Faculty of Medicine; Director, NIHR Clinical Research Facility, Southampton University Hospital NHS Foundation Trust, UK

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Pfizer meningococcal vaccines<br/>Received research grant from: Pfizer<br/>Institution (no personal fees) received consulting fees from Pfizer, Sanofi, Sequerius, Merck, Medimmune, AstraZeneca.

Chief Editor

Russell W Steele, MD, Clinical Professor, Tulane University School of Medicine; Staff Physician, Ochsner Clinic Foundation

Disclosure: Nothing to disclose.

Additional Contributors

David Stuart Baguley, MBChB, Critical Care Registrar, The Alfred Hospital, Australia

Disclosure: Nothing to disclose.

Acknowledgements

Joseph Domachowske, MD Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York Upstate Medical University

Joseph Domachowske, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Robert Allan Felter, MD, FAAP, CPE, FACPE Professor of Clinical Pediatrics, Department of Pediatrics, Georgetown University School of Medicine; Medical Director, Pediatric Emergency Medicine and Inpatient Services, Inova Loudoun Hospital

Robert Allan Felter, MD, FAAP, CPE, FACPE is a member of the following medical societies: American Academy of Pediatrics and American College of Physician Executives

Disclosure: Nothing to disclose.

Jeffrey Hom, MD, MPH, FACEP, FAAP Assistant Professor, Department of Pediatrics/Emergency Services and Department of Emergency Medicine, New York University School of Medicine

Jeffrey Hom, MD, MPH, FACEP, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Simon Nadel MBBS, MRCP Honorary Senior Lecturer, Department of Paediatrics, Consultant Paediatric Intensivist, Paediatric Intensive Care Unit, Imperial College School of Medicine, St Mary's Campus, St Mary's Hospital, UK

Disclosure: Nothing to disclose.

Garry Wilkes, MBBS, FACEM Director of Emergency Medicine, Calvary Hospital, Canberra, ACT; Adjunct Associate Professor, Edith Cowan University, Western Australia

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Grace M Young, MD Associate Professor, Department of Pediatrics, University of Maryland Medical Center

Grace M Young, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Emergency Physicians

Disclosure: Nothing to disclose.

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Skin lesions due to echovirus type 9 on neck and chest of young girl. Echoviruses belong to genus Enterovirus and are associated with illnesses including aseptic meningitis, nonspecific rashes, encephalitis, and myositis.

Skin lesions due to echovirus type 9 on neck and chest of young girl. Echoviruses belong to genus Enterovirus and are associated with illnesses including aseptic meningitis, nonspecific rashes, encephalitis, and myositis.