Quantiferon Gold in Latent TB Screening: The New Gold Standard for Children Who Have Received BCG Vaccination

Link to article:  http://www.cdc.gov/mmwr/pdf/rr/rr5905.pdf

Article Review:

(Written by Scott Cohen, MD; John Belko, MD; Tara Greenhow, MD)

For over 100 years, the Purified Protein Derivative (PPD) has been utilized for diagnosing latent Mycobacterium tuberculosis (TB) infection.  While highly sensitive, this test is also fraught with false-positive results in children who have received the BacilleCalmette-Guerin (BCG) vaccination or in children with infections with non-tuberculous strains of mycobacteria.  It should be noted that PPD reactivity to BCG immunization classically wanes over time for the majority of immunized patients.  Thus, a positive PPD in the setting of a past history of BCG immunization does NOT exclude the possibility of TB infection. BCG is very good at preventing CNS or disseminated TB in children but has not been shown to be of benefit in protecting against development of pulmonary TB.

Historically in the United States, the majority of cases of TB were identified in individuals from TB endemic countries who had a positive PPD. This observation led to the recommendations in 2001 to treat all children with a positive PPD irrespective of underlying BCG status. However, new data has shown that the Quantiferon Gold (TB-IGRA) blood test is more reliable in determining which children have had a true exposure to TB.  

This report from the Center for Disease Control represents a departure from current practice in managing children who have received the BCG vaccination.  One of the most important advantages of the TB-IGRA test is that previous vaccination with BCG vaccination will not result in a false-positive blood test.

Highlights of this report include:

TB Screening for Asymptomatic Children Under Age 5 Years:

·       If the PPD is negative, no further workup is needed, regardless of BCG status.

·       If the PPD is positive, and there is no history of BCG, begin 9 months of Isoniazid (INH) and vitamin B6 (pyridoxine) therapy if the chest x-ray (CXR) is negative.  [Call pediatric ID if the CXR is positive]. Please do not start therapy until the CXR has been read as negative by radiology.

·       If the child with a history of receiving BCG, has a positive PPD and a negative CXR, order a TB-IGRA blood test.

o   If TB-IGRA is negative, INH therapy may be delayed.

o   If the TB-IGRA is positive, begin 9 months of INH and vitamin B6 (pyridoxine) therapy.

o   Please call your local Pedi ID doctor before ordering the TB-IGRA in a child 2 years of age or younger.

TB Screening for Asymptomatic children Age 5-18 Years :

·       If a PPD is negative, regardless of BCG vaccination, no further workup is needed.

·       If a PPD is positive and no history of BCG vaccination, order a CXR. Start 9 months of INH and vitamin B6 (pyridoxine) therapy if CXR is negative.

·       If  a child with a history of BCG vaccination has a positive PPD, order TB-IGRA.  NB: TB-IGRA is preferred over PPD in all children who received BCG vaccination. 

·       If the BCG status is unknown, a PPD may be given, and if positive, a TB-IGRA should be ordered.

·       If TB-IGRA is negative, no further workup is needed.

·       If TB-IGRA is positive, a CXR should be ordered.  Nine months of Isoniazid and vitamin B6 (pyridoxine) should be prescribed if the CXR is negative.  A Pediatric Infectious Disease specialist should be consulted if the CXR is positive.

Editor’s Commentary:

BCG vaccination is given to newborns in developing countries where TB disease is endemic.  While the BCG vaccine is not effective in preventing pulmonary tuberculosis, it is effective in preventing disseminated tuberculosis (miliary TB) including Tuberculosis meningitis.  Immigrant children who have received this vaccine have posed difficulties in interpreting their PPD results.  Many of these children have thus been subjected to nine months of INH therapy for a (+) PPD test.  These new guidelines, which liberalize the use of the Quantiferon Gold blood test (TB-IGRA), offer a precise diagnosis of M. Tuberculosis exposure resulting in latent TB.

TB-IGRA is useful in children under age 5 years, who have had a history of BCG vaccination and a recent (+) PPD.  The result of the TB-IGRA is the final determinant to decide if the child has latent TB or not.  However, in this younger age group, the PPD is the recommended first-line test for TB screening.  A discussion with your local Pediatric ID doctor is recommended before ordering the TB-IGRA in a child younger than 2 years of age.

For children over age 5 years who have received the BCG vaccination and require TB screening, a TB-IGRA blood test should be ordered instead of placing a PPD.

Commentary From Pediatric ID Specialists:  John Belko, M.D. and Tara Greenhow, M.D.

There is a clear advantage to the use of TB IGRAs in the diagnosis of latent TB infections in patients with a history of BCG vaccination.  Despite this, there are some important pitfalls to remember:

·       For patients who have suspected active TB, a negative quantiferon test does NOT exclude the diagnosis of active TB.  Similarly, a negative PPD does not exclude the diagnosis of active TB. This is because it can take up to 8 weeks for the body to develop its T-cell specific responses.  Therefore, in this setting TB-IGRA is not more sensitive, though more specific than a PPD test.  If there is a concern about possible active TB, based on clinical or radiographic grounds, a Pediatric ID doctor should be consulted.

·       For patients who are on immunosuppressant medications (Prednisone, Remicade, Methotrexate, Tacrolimus, etc.) or who are immunosuppressed due to medical disease (Rheumatologic conditions, oncologic conditions, congenital or acquired immunodeficiencies, severe malnutrition etc…) there is little data on whether a TB-IGRA is preferred over a PPD.  Any condition that affects the function of T cells will affect either of these tests negatively. In these patients, the use of either the PPD or the TB-IGRA should be discussed with a Pediatric ID specialist.

Augmentin Is First-Line Therapy for Sinusitis

Link to article:

http://cid.oxfordjournals.org/content/early/2012/03/20/cid.cir1043.full

Article Review:

A report published in March 2012 by a multidisciplinary panel from the Infectious Diseases Society of America (IDSA) recommends changes to the diagnosis and treatment of rhinosinusitis in children and adults.

Existing criteria for differentiating viral versus bacterial sinusitis have resulted in inappropriate use of antibiotics.  In addition, changing microbiologic profiles in patients with sinusitis due in part by the emergence of pneumococcal species not covered by PCV-13 vaccine have been identified.  These issues, along with several other factors, have motivated a new investigation into a common infectious disease.

Most children with bacterial sinusitis will present with cough (80%), nasal discharge (76%) and fever (63%).  Often there are subjective reports of halitosis, while headache, facial pain and swelling are uncommon complaints.

Patients who meet the following predictive factors for acute bacterial rhinosinusitis warrant empiric treatment with antibiotics for 10 to 14 days:

·       Persistent symptoms of cough with nasal discharge lasting at least 10 days

·       Abrupt onset of severe symptoms with fever and purulent rhinorrhea or facial pain lasting 3 to 4 days

·       Any patient whose upper respiratory symptoms began to improve, and then worsened with fever and cough.

Augmentin (not amoxicillin) should be used as first-line therapy for suspected bacterial rhinosinusitis (45 mg/kg/day divided in 2 daily doses).  

High-dose Augmentin (90 mg/kg/day divided in 2 daily doses, up to 2 grams twice daily) should be given to the following patients:

·       Patients living in regions of the USA where there is a high rate of invasive penicillin-resistant S. pneumoniae.

·       Fever 102 F or higher

·       Daycare attendance

·       Recent hospitalization

·       Antibiotic use in the past month

·       Immunocompromised children

·       Age < 2 years

·       Failed treatment with Augmentin 45 mg/kg/day

Trimethoprim-sulfamethoxazole (TMP/SMX), monotherapy with Cephalosporins and Macrolides (Azithromycin) are all ineffective against more than 30% of pneumococcal strains and should not be used in treating bacterial sinusitis.

  

In Penicillin-allergic patients, Doxycycline (children over age 8) or Levofloxacin (10–20 mg/kg/day PO every 12–24 h) may be used.  Alternatively, a third generation cephalosporin such as Cefdinir, in combination with clindamycin may be used in penicillin-allergic patients.  Patients who fail to improve clinically after 3 to 5 days of antibiotics, should be switched to broader spectrum coverage.

The report also recommends saline irrigation as an adjunctive therapy, and intranasal steroids (Fluticasone) for patients who have a history of allergic rhinitis.

For patients with suspected suppurative complications such as orbital or intracranial involvement, CT scan is the imaging modality of choice.

Reasons to refer to an ENT specialist for possible sinus aspiration and culture:

·       Worsening symptoms in the first 2 to 3 days of antibiotic therapy

·       Failure to respond to 2^nd line therapy of antibiotics

·       Patients who are clinically toxic, immunocompromised, and/or have recurrent sinus infections

Commentary by Tara Greenhow, MD and John Belko, MD, Pediatric ID Specialists: 

The Pediatric ID Chiefs would like to emphasize a few important points about the guidelines:

1.    Antibiotics are NOT recommended for healthy children with rhinosinusitis unless symptoms are severe, persistent or worsening.  Overall, 6 children would need to be treated with antibiotics before 1 additional patient would benefit.  60% of children in placebo groups improve.

2.    Amoxicillin-Clavulanate is now recommended as first-line therapy for sinusitis in children. This is due to the increasing prevalence of beta-lactamase producing Hemophilus influenzae and Moraxella catarrhalis in sinus isolates.

3.    Macrolides and TMP-SMX are NOT RECOMMENDED for empiric therapy due to high rates of resistance among S. pneumoniae.

4.    Second and third generation oral cephalosporins are NOT RECOMMENDED for empiric monotherapy due to variable resistance among S. pneumoniae. This includes cefdinir, a commonly used 3^rd generation cephalosporin, with resistance rates of 23-30%.

5.    Please contact your local pediatric ID colleagues for children with suspected or confirmed suppurative complications to assist in management.

Pediatric Rheumatology Video Conference Permanente Medicine Today

Review:

On June 8, 2012, Dr. Charles Wibblesman hosted a Permanente Medicine Today video conference with Kaiser Oakland’s  Pediatric Rheumatologists,  Suhas Radhakrishna, MD and Elizabeth Shaw.

This video conference can be viewed here:  http://insidekp.kp.org/ncal/tpmgphysicianed/media/video/pediatric_rheumatology/index.html

Drs Radhakrishna and Shaw reviewed several highlights from a recent publication from the Pediatric Clinics of North America.  This thorough review of pediatric rheumatologic disorders has several chapters.  One of the more informative chapters is:  Laboratory Testing in Pediatric Rheumatology.  

The entire publication can be found here.

Drs Radhakrishna and Shaw presented a case-based video conference reviewing the presentation, work-up, indications for referral and treatments for rheumatologic disorders.

With all cases, they stressed that the evaluation of rheumatologic disorders begins and continues with a through history and physical examination.  Laboratory studies should include basic labs and under most circumstances, ANA and Rheumatoid Factor are not indicated with the initial evaluation.

Highlights:

Arthritis, which is defined as joint pain, swelling, warmth, limited movement or pain with movement, should be differentiated from Arthralgia, which is joint pain without signs of inflammation.

The differential diagnosis of a child presenting with arthritis should include: infection, post infectious arthritis (benign toxic synovitis), malignancy (leukemia, bone lesion), Juvenile Idiopathic Arthritis (JIA), non-accidental trauma, and hemarthrosis.

Initial laboratory evaluation of a child with mono-articular joint swelling should include:

·       CBC with differential

·       ESR

·       LDH

·       Uric Acid

·       Lyme titers

·       ALT

·       Lytes

·       BUN and creatinine. 

In addition, a urinalysis and radiographs (to rule out cyst, malignancy) should be obtained and a PPD should be placed.

ANA and RF are not useful lab studies during the initial work-up.  15% of the population will have a positive ANA and have no clinical signs of rheumatic disease.  In patients who are already diagnosed with JIA, a positive ANA is helpful as it is associated with increased risk of uveitis.

For patients with poly-articular symptoms, Rheumatologic Factor (RF) and CCP antibody should be ordered as well as the above mentioned labs.

Ophthalmology referral to evaluate for uveitis should be considered in patients with suspected JIA.

Treatment for Juvenile Arthritis can include NSAIDs such as Naprosyn 5 to 10 mg/ kg per dose, (500mg max per dose).  If naproxen is not working, a rheumatology specialist will consider steroid injection of the affected joint.  A single corticosteroid injection in a patient with mono-articular JIA could elicit years of dormancy.  Close follow-up is maintained as relapses can happen. 

Patients with poly-articular involvement need systemic treatment with immunosuppressants.

Editor’s Commentary:

This case-based videoconference offers the physician a methodical and strategic approach in evaluating rheumatologic disorders and other similar conditions.   If not already viewed, this videoconference is well worth the time to do so now.

The Oakland Pediatric Rheumatology eConsult page is rich with clinical pearls that help guide the primary care physician.  It offers synopses of clinical presentations and laboratory recommendations for pediatric rheumatologic disorders such as Dermatomysitis, Fever of Unknown Origin, Pain Syndrome, Periodic Fever, Raynauds, Scleroderma, SLE (Lupus), Vasculitis, and Juvenile Arthritis.   All pediatricians and family practice doctors are encouraged to review this eConsult site.http://insidekp.kp.org/ncal/tpmgphysicianed/media/video/pediatric_rheumatology/index.html

Propranolol: A New and Safe Treatment for Infantile Hemangiomas

Link to article (book chapter):  http://viewer.zmags.com/publication/0777a968#/0777a968/93

Article Review:

Doctors Pristine Lee (Pediatric Dermatologist, Kaiser San Rafael) and Ilona Frieden from the University of California, San Francisco, published a recent report at the American Academy of Dermatology conference in 2011, reviewing the current literature on the use of beta-blockers for the treatment of Infantile Hemangiomas (IH).  The decision to intervene and treat an IH is predicated on the risk of long-term scarring or disfigurement, functional compromise of adjacent organs and life threatening complications from the IH.  Factors involving anatomic location, size, depth of the lesion, and the child’s age are all taken into consideration in determining treatments.

In 2008, Propranolol was discovered as a safe and efficacious treatment for Infantile Hemangiomas.  Since then, over 75 publications have demonstrated marked improvement and rapid involution of these lesions with both systemic and topical propranolol therapy.   A recent study by Holmes et al showed that over half of patients with IH had significant regression of their lesion after two weeks of therapy.  Historically, systemic corticosteroids have been used to treat some hemangiomas.  And, while steroids suppress the growth of hemangiomas, they are less successful than propranolol in promoting involution of these lesions.

Propranolol, either alone or in combination with steroids has been shown to be effective for hemangiomas of the airway and liver.  Propranolol has reduced the size of these lesions remarkably better than systemic steroids and chemotherapeutic agents.    Some patients with IH have had little or no response to propranolol, although these represent a minority of patients.  Rebound growth of IH has occurred in a subset of patients once the propranolol has been tapered or stopped.  These patients required a prolonged course of propranolol following this rebound phenomenon.The safety profile of propranolol in newborns and infants is well established, and is considered safer than systemic steroids.  At appropriate doses it is well tolerated, however some rare complications include bradycardia, bronchospasm, hypoglycemia and labile blood pressures.

While complex infantile hemangiomas requiring systemic propranolol will be managed in conjunction with a pediatric dermatologist, superficial infantile hemangiomas can be managed by the general pediatrician using topical propranolol, Timolol.   This is an opththalmic preparation of propranolol and has been used for glaucoma.    Studies and case reports have shown that twice-daily use over 1 to 3 months oTimolol has resulted in marked involution of IH.

** Permanente  Medicine Today will be sponsoring a videoconference on Pediatric Hemangiomas on August 10^th, 2012. **

Hemangioma Work-up

Where	What	Evaluation
Facial, large segmental	PHACE syndrome	Echocardiogram Ophthalmology MRI/MRA of the brain & neck
Periorbital and retrobulbar	Ocular axis occlusion, astigmatism, amblyopia, tear-duct occlusion	Ophthalmology
Nasal tip, ear, large facial	Permanent scarring, disfigurement
Segmental "beard area," central neck	Airway hemangioma	Otolaryngology
Perioral	Ulceration, disfigurement, feeding difficulties
Segmental overlying lumbosacral spine	Tethered spinal cord, genitourinary anomalies	MRI of lumbosacral spine, consider renal ultrasound
Perineal, axilla, neck, perioral	Ulceration
Multiple hemangiomas (>5)	Visceral involvement (especially liver), hypothyroidism	Liver ultrasound; if liver hemangiomas are present obtain TSH, T4, reverse T3

*In addition to evaluation by Pediatric Dermatology or other specialists.

Commentary from Pristine Lee, M.D., Pediatric Dermatologist:

Hemangiomas should be separated into the categories of those that need treatment and those that do not. In general, this division will guide referrals: IH with functional or life threatening potential, those that cause pain, and those that could lead to scarring or disfigurement should all be referred. Examples of specific scenarios that should be referred immediately include any segmental hemangiomas, facial hemangiomas, lesions in the perineum (as they often ulcerate and can lead to significant pain), any located on the lip or nasal tip (as these can be severely disfiguring) or any causing pain or with ulceration/scar. There are many other cases, outside of those examples, that may require treatment and I am always available if you have questions or concerns.

Timolol is a great medication, but it is not without adverse events. There is some degree of systemic absorption, although the exact amount is uncertain. Timolol is also 8 times as potent as propranolol, so even a small amount of absorption can be significant.  Parents should be counseled on the potential for bradycardia, hypotension and hypoglycemia and warn against overuse. It is best used on superficial hemangiomas as it does not have a significant impact on the deeper components.  Typically I do not recommend treatment for superficial hemangiomas as they mostly self-resolve without significant residua.

Given the variability and complexity of hemangiomas, patients should be referred to a pediatric dermatologist prior to initiation of therapy (topical or systemic).

This is a fascinating time to be involved in hemangioma care as there has been an incredible surge in research and knowledge. Even with all the developments, most infantile hemangiomas are still the same ones you have been taking care of for years. I hope I can be a supplement whenever you need me and thank you for allowing me to participate in the care of your patients!

Below is an AVS handout that I give families whose children have Infantile Hemangiomas.  Please feel free to use as needed.

HEMANGIOMAS

WHAT ARE HEMANGIOMAS?

Hemangiomas are collections of extra blood vessels in the skin.  They are a common birthmark and are present in up to 10% of healthy full term newborns.  They may not be visible at birth, but rather develop in the first few weeks of life.  Initially they may look like a reddish-blue skin marking before they grow and become more apparent.

Hemangiomas take a special natural course:  Once they are present, they show rapid growth for 6-12 months (proliferative phase).  Then, they tend to stay stable with very little change for several months (plateau phase), before they slowly start to shrink (involution phase).

Though it is difficult to predict how one particular hemangioma is exactly going to behave, it is important to remember this natural course, especially during the time of rapid growth.  We understand that this is very worrisome to parents, and we would like to follow your child closely during those months and provide the needed support!  The first signs noted when the hemangioma starts to resolve are a change of color from bright red/blue to grayish and no further increase in size.  It may take months or years for the hemangioma to completely go away, but the cosmetic result at the end is usually excellent without any treatment.  As a rule of thumb, clinical experience has shown that by age 3 years, 30% of hemangiomas have completely resolved; by age 5 years, 50% and by age 9 years, 90% will have gone away spontaneously.

 

CONCERNS ABOUT HEMANGIOMAS

Since hemangiomas can occur anywhere on the body and come in all shapes and sizes, there are some situations when they may cause problems and may need treatment. 

Location is an important factor.  If a hemangioma is found near the eye, nose, mouth, ear or groin/buttocks, it may cause pressure and interfere with the normal function of important body parts.  It may cause problems with vision, breathing, feeding and toileting. 

Ulceration can occur during the rapid growth phase of a hemangioma.  If this happens, it is often painful, will leave a scar and may get infected.

Bleeding of the hemangioma may happen, particularly if the area has been accidentally hit.  Since a hemangioma is made up of many extra blood vessels, it tends to bleed heavily and this can be extremely frightening to the parents.  It is important to apply firm pressure to the area which will stop the acute bleeding in most cases!

If any of the situations mentioned above occur, we would like to hear about it and see your child again!  There are different treatment options and combination of treatments available, which we would discuss with you in each individual situation.

** Permanente  Medicine Today will be sponsoring a videoconference on Pediatric Hemangiomas on August 10^th, 2012. **

Etiologies of Bacterial Infections in Infants: A Retrospective Analysis

Link to article: 

http://pediatrics.aappublications.org/content/early/2012/02/22/peds.2011-1546

Article Review:

Pediatric Infectious Disease specialists from Kaiser Permanente reviewed medical records on 160,818 term infants to determine the microbiologic etiology of bacterial infection.  Ages of the infants studied ranged from 7 to 90 days of life.   From 2005-2009, all blood cultures drawn from these infants from the Emergency Room and upon admission were reviewed.  Infants with other known medical problems including prematurity were excluded from this study. 

A total of 4,255 blood cultures were taken from these infants over 5 years.  93 blood cultures (2%) of these were true pathogens and 6% were considered contaminants.  The overall incidence of bacteremia was 0.57/1,000 live births.  Of the 93 positive blood cultures, E. Coli was found in 56% of the cases, Group B Streptococcus 21%, Staphylococcus aureus (8%), and Streptococcus pneumoniae (3%).

Of the 48 infants whose blood cultures were positive for E. Coli, all but one had a positive urine culture with E. Coli.  In addition, of these 48 infants, 38 had a lumbar puncture performed of which 4 infants (11%) had a positive CSF culture for E. Coli.

Of the infants who were positive for Group B Streptococcus, 17 had a lumbar puncture performed and 5 of these (29%) had a positive CSF culture for Group B Streptococcus.

The authors also note that 36% of all pathogens identified were ampicillin resistant. 

Listeria infection was not found in this study group, and thus the authors conclude that ampicillin may no longer be necessary when empirically treating these infants, while awaiting culture results.

COMMENTARY From Arnd Herz, MD, co-author and Pediatric Infectious Disease Specialist:

In our study, the majority (72%) of “positive blood cultures” represent a blood culture contamination, rather than true infection.  This allows us to put things into perspective as we council parents when we re-evaluate the infant.  However, an initial positive blood culture result (before further details are available) increases the likelihood of the infant being truly bacteremic, compared to the a priori  risk for the same age febrile infant, by 14-fold (from 2% to 28%).  Thus all infants with a first report for a positive blood culture deserve an immediate re-assessment.   Repeating a blood culture is rarely helpful to distinguish a blood culture contamination from a clinical significant pathogen, as that distinction is made solely on clinical grounds and the ultimate identification of the organism growing in the initial blood culture bottle.

Knowing the most common causes of bacteremia should help in directing our care.  All febrile infants need an examination of their urine, as a urinary E. Coli is the most likely source of any bacteremia.  Early-onset Group B Streptococcal disease has been reduced by maternal antibiotic treatment intrapartum, but late-onset disease is still present. Maternal GBS status or treatment is not predictive for late-onset disease.  Given the relatively high rates of meningitis for bacteremic infants, all infants deserve a lumbar puncture prior to initiation of antibiotics.  

Finally, it is helpful to remember that Listeria and Enterococcus are exceedingly rare in our population and therefore antibiotic choices can be tailored to commonly encountered bacteria.  Ampicillin (or Penicillin) or a Cephalosporin treat Group B Streptococcus effectively.  An aminoglycoside or a higher-level Cephalosporin will treat E. coli and most other Gram-negative organisms.  However, we should not forget that 8% of pathogens were S. aureus, and while we presently did not have a single case of MRSA, this is a real concern for the future,  as  routine choices of antibiotics do not usually cover this organism well. 

In summary, Ampicillin and Gentamicin still cover all commonly encountered bacteria in this age group.  A third generation Cephalosporin alone would be equally efficacious, as would an aminoglycoside alone for a Gram-negative organism.  A gram-positive organism very frequently represents a contaminant; however, in a sick child it may also be the first case of MRSA and may need empiric coverage with Vancomycin and Gentamicin.
  
http://pediatrics.aappublications.org/content/early/2012/02/22/peds.2011-1546