Pediatric HCV Guidelines

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A useful recent article, ‘NASPGHAN Practice Guidelines for pediatric HCV’ (JPGN 2012; 54: 838-55) needs to be a handy reference.  However, given the rapid changes in the HCV field, it is likely that this reference will need to be updated soon to incorporate new information (eg. IL28b) as well as emerging therapies.

Highlights:

Epidemiology: 0.2% of children & 0.4% of adolescents are HCV-infected; primary mode is mother to child (vertical) transmission which occurs in 5-7% if mother not coinfected with HIV

Testing: For infants of HCV-infected mothers, check HCV antibody after 18 months or HCV RNA at younger ages.  Need two negative HCV RNAs to exclude infection (guidelines suggest checking 6 months apart).  Most individuals should be screened with antibody testing and confirmed with RNA test.

Screening for HCC (U/S, AFP): suggested only “for those with significant liver disease (ie. cirrhosis)” due to rarity of HCC in pediatric HCC.

Treatment:

  • Not if patient younger than 3 years
  • Probably Pegylated-interferon with ribavirin –references for pediatric studies indicate response rates of about 50% for genotype 1 and about 80% for types 2 & 3.
  • Who should be treated? Not always clear.  Probably those with elevated aminotransferases or progressive disease based on liver biopsy.  Possibly those with mild disease to eradicate virus.
  • Dosing: ribavirin  15/kg/day divided twice daily; weekly PEG-IFN-α-2a 180 microgram/1.73 m2 or weekly PEG-IFN-α-2b 60 microgram*m2

Treatment monitoring (Table 8):

  • CBC/diff, Hepatic panel, glucose 0, 1, 2, 4, 8, 12 weeks, then every  4-8 weeks
  • T4/TSH 0, 12, 24, 36, 48 weeks
  • Urine HCG 0, 24 weeks (if female >12 years)
  • Prothrombin, Urinalysis at week 0
  • HCV RNA 0, 24, 48, 72 weeks

Anticipatory Guidance: “no legal requirement” to disclose HCV infection in U.S.; however, CDC suggests revealing this information to sexual partners (http://www.cdc.gov/hepatitis/hcv/)

  • Avoid sharing toothbrush, shaving equipment with household contacts, unprotected sexual activity with multiple partners, tattooing/piercing
  • Do not need to screen household or casual contacts

Special issues:

  • Vaccines: HCV patients should receive all standard vaccines
  • Obesity and alcohol both can worsen the outcome
  • Fetal scalp probes and prolonged rupture of membranes but not route of delivery may increase risk of HCV transmission
  • Breastfeeding is not contraindicated but should be avoided during mastitis/bleeding

Additional related blog links:

HCV now more deadly than HIV

The cost of progress in treating Hepatitis C

Increased ferritin predicts poor response in Hepatitis C

Curing Hepatitis C without interferon

Looking for trouble

Additional references:

  • –Hepatology 2011; 54: 1433. AASLD guidelines.  See teleprevir & boceprevir as well.-http://www.aasld.org/eweb/docs/hepatitisc
  • -Hepatology 2011; 53: 1468. PEG/RBV have minimal effect on QOL/cognitive/emotional outcomes, n=114.
  • -Gastroenterology 2011; 140: 389, 450-58. HEP-C STUDY. Comb RBV (15mg/kg div BID) & PEG-2a (180mcg/1.73m2 body surface q week) is better than PEG monotherapy. 53% SVR in combo group. Neutropenia in 40% –needed to reduce dose see below). “The Combination of Ribavirin and Peginterferon Is Superior to Peginterferon and Placebo for Children and Adolescents With Chronic Hepatitis C.”
  • -Hepatology 2009; 49: 1335. Comprehensive review and guidelines
  • -J Hepatology 2010; 52: 501-07. n=107. Pediatric study. Wirth et al. Efficacy of PEG alfa-2b (1.5/g/d) & RBV (15/kg/day): Genotypes 2/3 96% SVR, genotype 1 55%.
  • -JPGN 2006; 43: 499.  Study of PEG-IFN-α-2a in children.  dose BSA m2/1.73 x 180microgm weekly x 48 weeks.  6/14 (43%) had sustained response.  all genotype 1.  Article states that IFN (3/week) + RBV has now been approved by FDA for those over 3 years

PEG-Interferon Dosing:

Dosing adjustment from hep C study in children –needed in ~40%

PEG -2a
original: 180mcg/1.73m2
1. level 1: 135 mcg, level 2: 90mcg, level 3: 45 mcg

If ANC 750-999 week 1-2: level 1 adjustment, weeks >3: no adjustment
If ANC 500-749: week 1-2: hold dose ’til >750, then level 1; weeks >3, level 1 adjustment
If ANC 250-499: week 1-2, hold until >750, then level 2 adjustment, weeks >3, then hold ’til 750, then level 1 adjustment
If ANC <250, stop drug

If PLTs 35-49K, hold til >50, then level 1
If PLTs 25-34, hold til >50, then level 2
If PLTs <25, stop drug

If Hgb <10, reduce RIBA dose by 1/2 & increase dose when hgb>10
If hgb <8.5, stop RIBA

If indirect bili >5, stop drug.  If <2.5, restart dose at one-half and if remains less than 2.5, can resume full dose after 4 weeks.

IF ALT 5-10 ULN, recheck in 1 week.  If stays high, level 1 adjustment.
IF ALT10 ULN for more than 1 week, then if drops to 5-10, level 1 but if remains >10 ULN, then stop drug.

Side effect frequency:
flu symptoms: 91%, h/a, 62%, GI symptoms 56%, injection pain 45%, muscle aches 36%, irritable 31%, fatigue 27%, rash 20%, itching 15%, anorexia 13%, trouble sleeping 11%, depression 4-12%

TNF-α antagonists and infections

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In our pediatric patients who receive tumor necrosis factor-α (TNF-α) antagonists, fortunately we see few infectious complications.  In older patients, infections are much more important source of morbidity.  The main TNF-α inhibitors in clinical use include infliximab, etanercept, adalimumab, and certolizumab. Two large studies help quantify this risk:

  • Grijalva CG et al. JAMA 2011; 306: 2331-39.
  • Strangeld A et al. Ann Rheum Dis 2011; 70: 1914-20.

The first study assembled retrospective cohorts between 1998-2007 with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis/psoriatic arthritis or ankylosing spondylitis (group 3).  This study’s acronym is SABER: Safety Assessment of Biologic Therapy. This data was compiled from 4 large US automated databases.  In total, there were 10,484 RA, 2323 IBD, and 3215 group 3 patients.  1172 serious infections were identified, mostly (53%) pneumonia or skin/soft tissue infections.  Among IBD patients, hospitalization rates were 10.91 (per 100 person-years) for TNF-α antagonists and 9.6 for comparison group.  The rates of hospitalization were similar in RA (8.16 with TNF-α antagonists) and lower in the group 3 patients (5.41 with TNF-α antagonists).   In all groups, baseline glucocorticoid use was associated with a dose-dependent increase in infections.  Overall, there was not an increase risk of hospitalizations with TNF-α antagonists compared with nonbiologic treatments.

The second cited reference examined patients from Germany with RA, enrolled in the RABBIT registry.  Data was available for 5044 patients.  There were 392 serious infections in this cohort with fewer infections noted after 3 years.  Risks for infection included age (>60), chronic lung or renal disease, history of serious infections, and treatment with glucocorticoids.  Treatment with 7.5-14mg conferred at relative risk (RR) of 2.1; treatment with ≥15mg conferred a RR of 4.7.  The rates of serious infections has an exponential change when risk factors are added together.  In Figure 3, estimated risk of serious infections for patients receiving ≥15mg  glucocorticoids along with three additional risk factors was 45% per year; with two risk factors the risk was approximately 20% and with one additional risk factor approximately 10%.

While these studies confirm significant risks of infections with biologic agents, the absolute risk is low particularly when other risk factors are not present.  In pediatric populations, glucocorticoids are the most prominent risk factor.  In addition, the risk of serious infections may be reduced by effective therapy.  In the SONIC study, serious infectious complications were less frequent in patients on combination therapy (infliximab and azathioprine) than with either monotherapy.  This result was likely due to the decreased need for glucocorticoids.

Additional references/relevant previous blogs:

  • NEJM 2010; 362: 1383. Sonic study. Combination AZA/IFX with greater efficacy. 56.8% remission in combo Rx.
  • -IBD 2008; 14: 721.  Pneumocystis jiroveci (carinii) w infliximab -review of 84 cases.  Dig Dis Sci 2007; 52: 1481-84.  PCP most likely to occur on average 3 weeks after 2nd infusion (possibly due to concommitant drug use)
  • -Gastroenterology 2008; 134: 929.  n=100 consecutive IBD patients with opportunistic infections.  Any of drugs associated w ~2.9 OR in adutls (greatest in >50yrs).  OR 14.5 when multiple immune drugs. Steroids more associated with Candida. AZA/6MP more with viral: HSV, VZV (shingles), CMV.  IFX less commonly with infections -though increased histoplasma and atypical mycobacterium
  • -Gastroenterology 2009; 136: 1182.  Review of biologics.
  • -IBD 2007; 13: 769.  Review of safety of wide range of biologics
  • –Clin Gastroenterol Hepatol. 2006; 5:621-30.  TREAT registry.  Steroids but not biologics associated with increased mortality risk.
  • Only one chance to make first impression

Look of improvement on an EoE diet

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In this month’s Gastroenterology, 50 adults with Eosinophilic esophagitis (EoE) were treated with a 6-food elimination diet (SFED) (Gastroenterology 2012; 142: 1451-1459).  Repeat endoscopy after 6 weeks determined responsiveness.  Histologic response was defined by having <5 eosinophils/high power fields (eos/hpf).  In 20 patients, reintroduction of foods followed by repeat endoscopy was undertaken.

After SFED, 32 (64%) had peak eosinophil counts <5 eos/hpf.  Symptom scores decreased in 94%.  After trigger food reintroduction, eosinophil counts returned to pretreatment values.  The changes are clearly visible in Figure 5.  The pictures are almost like the weight loss commercials on TV –striking improvement.  I contemplated putting in a scan of the Gastroenterology cover, but have not received permission from the publisher.  Check out this link to view it yourself:

http://download.journals.elsevierhealth.com/pdfs/journals/0016-5085/PIIS0016508512006257.pdf

Based on reintroduction, the foods most commonly associated with EoE were wheat (60%), and milk (50%).  Skin-prick testing predicted only 13% of foods associated with EoE.  In general, these study results mirror results from pediatric studies, with the exception that milk allergy has been found to be more common in some pediatric studies.

Only 20 patients completed the reintroduction process.  This process involved adding 1 food group every 2 weeks.  If the patient had symptoms during reintroduction or remained on regimen for 4 weeks, then  endoscopy with biopsies was performed.  If recurrence noted based on symptoms or histology, this required a 6 week washout before additional food reintroduction.  Of note, median time for recurrence of symptoms was 3 days after reintroduction.

Six foods: milk, wheat, eggs, soy, shellfish/fish, nuts.

This study shows that, as in children, adult EoE is predominantly a food-allergy disease

Related blog entries:

Eosinophilic Esophagitis -Six Food Group Diet

Guidelines for Eosinophilic Esophagitis

MicroRNA signature for eosinophilic esophagitis

The undiscovered country

Upper endoscopy useful for identifying Crohn’s disease

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In a large pediatric study, the value of upper endoscopy in detecting Crohn’s disease (CD) is evident (JPGN 2012: 54: 753-57).

While the majority of pediatric patients with suspected inflammatory bowel disease probably undergo both upper endoscopy and colonoscopy, the added value of upper endoscopy remains unclear.  In this retrospective study with 171 pediatric patients (70 with CD, 33 with UC, 68 Non-IBD), 11% of children with CD had the diagnosis established based “solely” on the finding of granulomatous inflammation in upper intestinal tract (along with clinical symptoms).

Other key findings:

  • Presence of histologic gastric inflammation in CD patients compared to control patients was significantly higher (p<0.0001) but not significantly higher compared to UC patients (p=0.19).
  • Duodenal inflammation was highly suggestive of CD compared with both UC and non-IBD patients.  This occurred in 19% of CD patients compared with 0% and 1% in the other groups respectively.
  • 21 children (30%) had granulomas identified in upper GI tract (19 in stomach).  In 8 (11%), the diagnosis was changed based on this finding.  Prior to histology, the tenative diagnosis: 2 UC, 4 IC, 2 non-IBD.
One curious finding was a the presence of “perianal abscess/fistula” with similar frequency in CD patients and UC patients based on their Table 2 Patient Characteristics.
Additional references:
  • -IBD 2009; 15: 1101-4.  Presence of UGI disease in IBD.
  • -JPGN 2007; 44: 653.  NASPGHAN report on discriminating/labelling UC vs. Crohn’s.
  • -JPGN 2002; 35: 636-40. Advocates panendoscopy for all new IBD.  Granulomas in 28% of EGDs & 71% of UC pts c some abnl on EGD; 82% Crohn’s c abnl EGD.
  • -JPGN 2005; 41: abstract 181 (page 549).  UGI identified granulomas in 15% that were not identified elsewhere.
  • -JPGN 2004; 39: 257-61. Diagnostic role of EGD for pediatric IBD.
  • Magnetic resonance enterography for Crohn’s disease

HAV vaccination: how long will it take?

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Despite the availability of a safe and effective vaccine, immunization rates in the U.S. remain poor (Pediatrics 2012; 129: 213-221).

In this study which included data from the 2009 National Immunization Survey-Teen, hepatitis A virus (HAV) vaccination  coverage was examined in adolescents 13-17 years of age.  The national coverage for at least 1 dose was 42%; 70% of these vaccinees completed the 2-dose series.  For Georgia, the rates were similar to national data: the 1-dose receipt % was 42.5% and the 2-dose receipt % was 26.3%; 62% completion of 2 doses.

More specific breakdown of coverage rates:

  • 74.3% from 11 states that recommended universal HAV vaccination since 1999
  • 54% from 6 states that recommended consideration of HAV vaccination since 1999 & universal coverage since 2006
  • 27.8% for 33 states that recommended universal vaccination since 2006

While acute HAV rates have been declining, in 2009 there were 1987 reported cases; the CDC estimates that the total number of cases was 21,000 (due to underreporting and asymptomatic cases).  The highest rates of disease were in young adults between 20-29 years of age.

This data is disappointing. Yet, extrapolation from this data indicates that national coverage in seven years, when all states will have had 10 years to implement universal vaccination to young children, could be markedly better.

Additional references:

  • -NEJM 2007; 357: 1685. HAV vaccine effective in preventing cases of HAV after exposure (as good as IVIG). Low rates of HAV c postexposure prophylaxis c HAV vaccine (4.4%) or immune globulin (3.3%). n=1090.
  • -MMWR 2007; 56: 1080-84. Updated recs for IVIG -use only for exposures in infants <12months, immunocompromised persons, persons with chronic liver disease, or persons w contraindications to HAV vaccine.
  • -Pediatrics 2007; 120: 189. Recs from AAP. Recs for vaccine — all children at 1 year of age in US w 2-dose regimen; w/in 1 mo of 1st dose 97% of children & 95% of adults develop protective antibody. VAERS (adverse rxns) 800-822-7967 for forms.
  • -Pediatrics 2007; 119; e12, e22. HAV vaccine is cost-effective.
  • -MMWR 2007; 56: No. SS-3. drop in new infections by 80% compared to previous nadir; HAV 1.5/100,000 & HBV 1.8/100,000
  • -Hepatology 2006; 44: 1589. Decreasing incidence of fulminant HAV ; between 1988-2005, decrease of HAV in UNOS database from 0.7% to 0.1%. Risk factors for severe disease: creatinine >2, ALT <2600, intubation, pressors.
  • -J Pediatr 2004; 144: 327. Maternal antibody decrease HAV vaccine response when administered at 2, 4 & 6 months.
  • -Am J Gastroent 2002; 97: 721-8. ? cost-effective to vaccinate HCV pts; however, ~35% FHF risk if secondarily infected.

Test your knowledge of Clostridium difficile

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While Clostridium difficile (C diff) is a common infection, there is a lot to know.  A thorough but brief review is a good place to test your knowledge (Clin Gastroenterol Hepatol 2012; 10: 581-92).

  • a. When was C diff discovered?
  • b. When was C diff identified as a cause of antibiotic-associated diarrhea?
  • c. What antibiotics have been associated with a surge in severity and frequency of C diff infections?
  • d. Which C diff strains are the predominant cause of severe C diff?
  • e. How many C diff infections are occurring yearly in hospitalized patients in U.S.?
  • f. What are the most important risk factors?
  • g. How does the risk profile change for multiple antibiotics?
  • h. What time of year sees the greatest number of infections?
  • i. What does C diff smell like?
  • j. What % of antibiotic-associated diarrhea is due to C diff?
  • k. What clinical parameters may indicate severe infection and which ones indicate fulminant infection?
  • l. How much does a nucleic acid amplification test (NAAT) cost compare to enzyme immunoassay (EIA)?  How does this test work? What are the advantages/disadvantages?
  • m. How to treat severe infection?
  • n. What instructions should be given to prevent C diff in hospital?

Answers:

  • a. 1935
  • b. 1970s
  • c. Fluoroquinolones
  • d. BI/NAP1/027.  This strain has hypersecretion of toxins A & B, the presence of binary toxin, and resistance to fluoroquinolones.
  • e. CDI present in 300,000 hospitalized patients in 2005 (vs. 85,000 in 1993)
  • f. Hospitalization, older age (>65 years), and receipt of antibiotics (especially during 1st two months).
  • g. Hazard ratio 2.5 for two antibiotics, HR 9.6 for exposure to five antibiotics
  • h. Winter
  • i. “Horse stable”
  • j. 15-25%
  • k. Severe: WBC>15,000, Creatinine >1.5 fold patient’s baseline.  Also, albumin <2.5, admission to ICU, pseudomembranes on endoscopy, comorbid diseases.  Fulminant: (50% mortality) colon >6cm in diameter/toxic megacolon, WBC >50,000, lactate >5 mmol/L.
  • l. ~10 times the cost.  Works by identifying genes that encode toxins by PCR or loop-mediated amplification of DNA.  Test is very sensitive and rapid but may have false-positives.  Some recommend using a less expensive test for screening to decrease costs.
  • m. Vancomycin up to 500mg QID (NG/PO) plus metronidazole.  If complete ileus, vancomycin can be given rectally
  • n. Hand hygiene (not alcohol): either soap or chlorhexidine, contact precautions, cleaning environment –chlorine solutions effective (1000-5000 ppm), antimicrobial stewardship (especially reducing clindamycin and fluoroquinolones)

How many did you get right?

Related posts:

Clostridium difficile -Current Battlelines

Proton pump inhibitors–infection risk with cirrhosis

A cautionary vitamin D tale?

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A recent case report indicates that pharmacologic doses of vitamin D can cause hypercalcemia and hypervitaminosis D (Pediatrics 2012; 129: e1060-63).  The three cases all document good reasons for instituting therapy: craniotabes, hypocalcemic seizures, and tibial bowing.  The total dose that the patients received over 7-12 weeks ranged from 112,000 IU to 168,000 IU.  The ages of the patients ranged from 2 weeks to 33 months.   The peak abnormal calcium for all three patients was 11 mg/dL and the peak 25-hydroxy vitamin D was 102 ng/dL.  There were no clinical symptoms in these three patients due to increased calcium.  A fourth oh-by-the-way patient was described as well.  This patient was receiving vitamin D for an “inappropriate indication” (failure to thrive) and had received 3.6 million IU without monitoring.  This led to the development of a multitude of symptoms associated with a calcium level of 17.4 mg/dL.

My take-home points:

  • If giving generous doses of vitamin D, obtain a followup calcium several weeks into therapy. However, pharmacologic doses of vitamin D for valid indications pose a very low risk.
  • Excessive doses of vitamin D can be detrimental. (This last statement may be akin to the warning “hot coffee might cause a burn.”)

Related blog entries:

Common to be “D-ficient”

Vitamin D, IBD, and Causality

Colonic disease and PSC

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While primary sclerosing cholangitis (PSC) has been associated with inflammatory bowel disease, and ulcerative colitis (UC) in particular, the pathogenesis of this relationship has not been established.  A fascinating observation on this relationship is that an inflamed colon is important in PSC development (Clin Gastroenterol Hepatol 2012; 10: 439-41).

In this study which reviewed 2754 Irish patients with IBD, 59 (2.2%) had PSC.  PSC incidence correlated with increasing colonic involvement.  Among the 13 patients with Crohn’s disease, none had isolated small bowel disease.  The second part of the study involved a review of 82 separate PSC patients attending the Irish National liver transplant unit.  The majority of ulcerative colitis patients had a pancolitis; all 10 PSC patients with Crohn’s disease had colonic involvement.

Since PSC occurs without IBD, colonic inflammation is not necessary for PSC development.  However, in patients with IBD, colonic inflammation is very important.  In fact, in a previous study of 53 PSC-IBD patients, no UC patient status post a colectomy had recurrent liver disease following liver transplantation whereas seven patients with intact colons had recurrent disease following liver transplantation.

The authors speculate that bacterial translocation along with subsequent portal bacteremia may be an important step in pathogenesis among these patients.

Additional references/previous posts:

Salmonella by mail-order

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Sometimes patients are amazed that hemoccult cards can be sent by mail.  Now, I learned something new: you can mail-order live poultry and thereby spread salmonella far and wide (NEJM 2012; 366: 2065-73).  This study identified 316 cases in 43 states.

Key findings:

  • 36 hospitalized (23%)
  • 38 had chicks as pets (42%); of these, 22 (69%) said the pet owner was a child <5 years
  • Salmonella enterica serotype Montevideo subtype
  • 81% of infections identified as coming from a hatchery in Western U.S.
  • After identification of problem, owners implemented recommendations which lowered salmonella contamination.  After these measures, outbreak strain still detected in 7% of samples
  • Hatcheries mail live poultry to all 50 states –4 million birds are produced annually for this purpose. Approximately 250,000 birds are shipped each week, usually within 24 hours of hatching; each costing about $5 each.

Because only a portion of salmonella infections are identified with laboratory tests, there are likely thousands more infections associated with this outbreak.  Overall, nontyphoidal salmonella infections are estimated to cause 1 million illnesses, 19,000 hospitalizations, and 370 deaths annually.  Most infections are acquired as foodborne illnesses.  Though contact with animals, as this report indicates, is another mechanism.  These birds can appear healthy and intermittently shed salmonella.

Individuals wishing to reduce their risk of illness should practice careful hand hygiene around animals.  See link for helpful advice:

http://www.cdc.gov/healthypets/resources/salmonella-baby-poultry.pdf

The poultry business can help by adhering to sanitary practices, by avoiding artificially coloring chicks (which targets children), and by warning recipients of the danger of salmonella infection.

More on perinatal HBV

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In addition to a recent blog entry (How to stop HBV vertical transmission), several other recent articles add information about HBV vertical transmission:

  • Gastroenterology 2012; 142: 773-81.  Data from 2386 Taiwanese children born to HBsAg-positive mothers were examined.  HBeAg-positivity increased the likelihood of having an HBV-infected infant (9.26%) despite appropriate immunization & HBIG.  Since HBeAg-posiitivity is associated with higher HBV DNA levels, this is logical based on previous studies. Fulminant HBV developed in 1 of 1050 children who did not receive HBIG; in this study, the majority of mothers with HBeAg-negative HBV did not receive HBIG.
  • Pediatrics 2012; 129: 609-16.  This study examined HBV prevention in the U.S. from 1994-2008.  The CDC created the US Perinatal Hepatitis B Prevention Program (PHBPP) to accelerate progress at eliminating perinatal HBV transmission.  While the number of infants born to HBsAg-positive women with HBV increased from 19,208 to 25,600, the incidence of infants with chronic hepatitis B virus infection among tested infants decreased from 2.1% in 1999 to 0.8% in 2008.  This is due to the fact that 94.4% of PHBPP-managed infants received HBV vaccine and HBIG within 1 day of birth.  Yet, gaps remain.  The number of infants who completed the vaccine series by 12 months actually declined from 86% (1994) to 77.7% (2008). And, in 2008 only one-quarter of CDC’s 25,6000 infants born to HBsAg-positive women had known serologic outcomes.

Related previous post: Looking for trouble