Author: Portable Peds

13. Metabolic- Glycogen Storage Disorders

Posted on by Portable Peds

A 2 month old male infant born at 39 weeks gestation via SVD as a home birth presents to the ED for respiratory distress. Pt is tachypneic and tachycardic with global retractions, head bobbing, and grunting. Pt was placed on BiPAP, and a chest X-ray was then obtained, which showed marked cardiomegaly. Subsequent EKG showed left ventricular hypertrophy. On further examination, pt was also noted to have hepatomegaly, macroglossia, and hypotonia. What enzyme is likely deficient in this patient?

A. Glucose-6-Phosphatase 

B. Acid Alpha-Glucosidase

C. Glycogen Debranching Enzyme

D. Myophosphorylase

E. Phosphofructokinase

The correct answer is B, Acid Alpha-Glucosidase.

 

Answer Choice A: Glucose-6-Phosphatase 

Glycogen Storage Disease Type IA (Von Gierke Disease) is caused by a deficiency of Glucose-6-Phosphatase activity, whereas Type IB is caused by a defect in the transport of Glucose-6-Phosphate. This causes glycogen and fat to build up in the liver, kidneys, and intestines, leading to dysfunction in those organs.

Type 1A presents with hypoglycemia, hepatomegaly, lactic acidemia, hyperuricemia, nephromegaly, hyperlipidemia (both total lipids and triglycerides), and growth retardation/short stature. Hypoglycemia tends to be the major presenting symptom in infancy, especially when feeds start being spaced to every 3-4 hours, and this may present as seizures due to severe hypoglycemia (<40mg/dL after 3-4 hours since the last feed). If they do not present for hypoglycemia, they are often diagnosed within the first few months of life when they develop a Cushingoid face (doll-like facies with fat cheeks) and protuberant abdomen (due to hepatomegaly and nephromegaly).

Type 1B additionally presents with neutropenia, impaired neutrophil function, and inflammatory bowel disease. These defects lead to frequent bacterial infections and oral and intestinal mucosal ulcers.

For more information on management of GSD I, the American College of Medical Genetics and Genomics (ACMG) has great, thorough guidelines posted in 2014, linked in the references.

 

Answer Choice C: Glycogen Debranching Enzyme

Deficiency in this enzyme causes Glycogen Storage Disease Type III (Cori Disease or Forbes Disease). This disease is inherited as an autosomal recessive trait. This disease presents similarly to GSD IA, but less severe, with hypoglycemia, hyperlipidemia, hepatomegaly, hypotonia, immunodeficiency, and mild intellectual disability. Patients also present with myopathy that begins mildly in childhood and worsens throughout early-adulthood. These patients are treated with a high-protein diet and cornstarch to maintain a consistent, normal blood glucose.

 

Answer Choice B: Acid Alpha-Glucosidase

This enzyme deficiency, also known as Acid Maltase, causes Glycogen Storage Disease Type II (Pompe Disease), which is the correct answer. This disease has an autosomal recessive inheritance pattern.

The “Classic Infantile” form of Pompe Disease causes more severe disease, where infants present within the first 3 months of life with feeding difficulties, poor weight gain, cardiomyopathy, hepatomegaly, macroglossia, and progressively worsening proximal muscle weakness leading to hypotonia and respiratory insufficiency. The cardiomyopathy is due to deposition of glycogen in the cardiac muscle, often causing a hypertrophic cardiomyopathy. Median age at symptom onset is 1.6 months, with median age at diagnosis of about 5 months of age. These patients often need positive pressure support or mechanical ventilation by 4-5 months of age, and they typically die of cardiorespiratory failure by 2 years of age.

The “Late-onset” form of Pompe Disease can develop at any age, and this is due to a deficiency of the acid alpha-glucosidase enzyme, as opposed to the absence of this enzyme in the infantile form. Because of this, these patients often live past 2 years of life. Typically if you present with symptoms earlier in life, it tends to be more aggressive with a faster progression and higher severity. These patients also have progressive muscle weakness and eventually become wheelchair and/or ventilator dependent before dying of respiratory failure due to diaphragmatic weakness.

In Ohio, every child is screened for Pompe Disease at birth as part of their newborn screen. This patient was born at home, so they did not likely have newborn screening done and therefore went undiagnosed. On the Ohio Department Health website, they make this disclaimer,

“The test for Lysosomal Storage Diseases has not been cleared or approved by the FDA but the performance characteristics have been validated by the Ohio Department of Health Laboratory.”

On a positive note, Pompe Disease can be treated by enzyme replacement therapy with Alglucosidase alfa! Myozyme was the first brand name drug approved by the United States FDA for use in 2006 for infantile Pompe, and Lumizyme was approved for use in 2010 for patients aged 8 years or older with non-infantile Pompe. These drugs have been shown to decrease heart size, maintain normal heart function, improve muscle function, tone, and strength, and reduce glycogen build-up in organs. Patients receive this medication as a 4-hour infusion every 2 weeks. On the downside, these medications are incredibly expensive.

 

Answer Choice D: Myophosphorylase

Glycogen Storage Disease Type V (McArdle’s Disease) is caused by a deficiency in this enzyme. Patients tend to develop symptoms within the first decade of life with primarily skeletal muscular involvement, such as exercise intolerance, myalgias, and rapid fatigue with exertion. Patients also may develop muscle stiffness and contractures during exercise, especially towards the beginning of exercise, which resolves or decreases upon cessation of activity. Labs typically reveal an elevated creatinine kinase (CK) and myoglobinuria. Symptoms tend to worsen with sustained, intense aerobic exercise, so management of these patients consists of leading a fairly sedentary lifestyle with mild, regular aerobic exercise.

 

Answer Choice E: Phosphofructokinase

Glycogen Storage Disease Type VII (Tarui’s Disease) is another glycogen storage disorder, passed in an autosomal recessive pattern as well, that primarily affects skeletal muscles. However, this disease has 4 forms, and depending on the form, the patient may have additional symptoms, such as nausea/vomiting, hyperuricemia, curvature of the joints (arthrogryposis), and jaundice due to hemolytic anemia. Diagnosis can be made by muscle biopsy, which would show an elevated ammonia and decreased lactate.

 

If asked about other GSD, remember:

  • GSD-IA is similar to GSD Types 0, 3, and 4
  • GSD 5 is similar to GSD Type 7 and primarily involves the skeletal muscles
  • And if the child has cardiomyopathy, it is likely GSD 2

 

Resources

  1. Leslie N, Bailey L. Pompe Disease. 2007 Aug 31 [Updated 2017 May 11]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1261/
  2. Pompe Disease Diagnostic Working Group; B Winchester, D Bali, O A Bodamer, C Caillaud, E Christensen, A Cooper, E Cupler, M Deschauer, K Fumić, M Jackson, P Kishnani, L Lacerda, J Ledvinová, A Lugowska, Z Lukacs, I Maire, H Mandel, E Mengel, W Müller-Felber, M Piraud, A Reuser, T Rupar, I Sinigerska, M Szlago, F Verheijen, O P van Diggelen, B Wuyts, E Zakharova, J Keutzer. Methods for a prompt and reliable laboratory diagnosis of Pompe disease: report from an international consensus meeting. Mol Genet Metab. 2008;93:275-281. PMID: 18078773 Epub 2007 Dec 19.
  3. Kishnani PS, Steiner RD, Bali D, Berger K, Byrne BJ, Case LE, Crowley JF, Downs S, Howell RR, Kravitz RM, Mackey J, Marsden D, Martins AM, Millington DS, Nicolino M, O’Grady G, Patterson MC, Rapoport DM, Slonim A, Spencer CT, Tifft CJ, Watson MS. Pompe disease diagnosis and management guideline. Genet Med. 2006;8:267-288. PMID: 16702877 PMC3110959
  4. Chou JY, Mansfield BC. Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease. Hum Mutat. 2008;29:921-30.
  5. Rake JP Visser G, Labrune P, et al. Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European study on glycogen storage disease type I (EGGSD I). Eur J Pediat. 2002a;161:20-34.
  6. Visser G, Rake JP, Labrune P, et al. Consensus guidelines for management of glycogen storage disease type 1b. Results of the European study on glycogen storage disease type I. Eur J Pediatr. 2002;161:120-3.
  7. Chen Y, & Kishnani P.S., & Koeberl D Chen, Yuan-Tsong, et al. (2019). Glycogen storage diseases. Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. Valle D.L., & Antonarakis S, & Ballabio A, & Beaudet A.L., & Mitchell G.A.(Eds.),Eds. David L. Valle, et al. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill. https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225080698
  8. Kishnani, P., Austin, S., Abdenur, J. et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med 16, e1 (2014). https://doi.org/10.1038/gim.2014.128 
  9. Kishnani PS, Steiner RD, Bali D, Berger K, Byrne BJ, Case LE, Crowley JF, Downs S, Howell RR, Kravitz RM, Mackey J, Marsden D, Martins AM, Millington DS, Nicolino M, O’Grady G, Patterson MC, Rapoport DM, Slonim A, Spencer CT, Tifft CJ, Watson MS. Pompe disease diagnosis and management guideline. Genet Med. 2006 May;8(5):267-88. doi: 10.1097/01.gim.0000218152.87434.f3. Erratum in: Genet Med. 2006 Jun;8(6):382. ACMG Work Group on Management of Pompe Disease [removed]; Case, Laura [corrected to Case, Laura E]. PMID: 16702877; PMCID: PMC3110959.
  10. Chen Y, & Kishnani P.S., & Koeberl D Chen, Yuan-Tsong, et al. (2019). Glycogen storage diseases. Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. Valle D.L., & Antonarakis S, & Ballabio A, & Beaudet A.L., & Mitchell G.A.(Eds.),Eds. David L. Valle, et al. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill. https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225080698
  11. Newborn Screening Panel. Ohio Department of Health website. Updated 4 February 2020. Accessed 16 January 2021. https://odh.ohio.gov/wps/portal/gov/odh/know-our-programs/Newborn-Screening/Newborn-Screening-Panel

11. Newborn- Respiratory Distress

Posted on by Portable Peds

A female infant is born at 38 weeks gestation to a G2P1 mother with known gestational diabetes via scheduled, repeat C-section. Initial Apgar scores are 8 and 9 at 1 and 5 minutes, respectively. About an hour later, the child begins to develop tachypnea (RR 70), nasal flaring, and grunting, which improves with supplemental oxygen via nasal cannula. A chest X-ray is obtained, which showed findings consistent with the diagnosis of Transient Tachypnea of the Newborn. What findings would be expected on chest X-ray for this patient?

A. Diffuse parenchymal infiltrates with fluid in the interlobar fissure

B. Diffuse parenchymal infiltrates with air bronchograms or lobar consolidation

C. Diffuse, bilateral ground-glass opacities with air bronchograms

D. Diffuse, patchy infiltrates with areas of hyperinflation

E. Left-sided intrathoracic stomach bubble with shift of the mediastinum and cardiac silhouette to the right

The correct answer is A, Diffuse parenchymal infiltrates with fluid in the interlobar fissure. There is a great Pediatrics in Review article from 2014 titled Respiratory Distress in the Newborn that discusses the majority of these disease processes, linked below in the references.

 

Answer Choice A: Diffuse parenchymal infiltrates with fluid in the interlobar fissure

This is the correct answer! Transient Tachypnea of the Newborn (TTN) is a common newborn cause of respiratory distress due to retained fetal lung fluid in term and late pre-term infants. During fetal development, the lung alveoli are fluid-filled, and towards the end of pregnancy, the fetus starts removing this alveolar fluid to allow for effective gas exchange. This process is enhanced by labor, so naturally, TTN tends to occur more often in neonates who do not undergo labor (i.e. precipitous labor and scheduled C-sections). Other risk factors include gestational age <39 weeks, fetal distress, maternal sedation, and maternal diabetes. This disease process is usually self-limited and normally does not require use of mechanical ventilation. However, use of antenatal corticosteroids (such as 2 doses of Betamethasone) given at least 48 hours prior to C-section can help decrease respiratory morbidity in these infants.

 

Answer Choice B: Diffuse parenchymal infiltrates with air bronchograms or lobar consolidation

Neonatal Pneumonia can be acquired at birth or during pregnancy (perinatal vs congenital pneumonia). Perinatal pneumonia is the most common cause of neonatal pneumonia, with the common causative organism being Group B Streptococcus (GBS). Congenital pneumonia, however, can be passed transplacentally from the mother and can be caused by a myriad of organisms, such as Rubella, Cytomegalovirus, Adenovirus, Enteroviruses, Mumps, Toxoplasma gondii, Treponema pallidum, Mycobacterium tuberculosis, Listeria monocytogenes, Varicella Zoster virus, and HIV. Risk factors for developing this infection include prolonged rupture of membranes (PROM), maternal infection, and prematurity.

This infectious process often presents as part of a generalized septic illness, requiring blood and CSF cultures and empiric antibiotics (see our previous episode on Management of the Febrile Neonate for further discussion). There is also a great neonatal early-onset sepsis calculator published by Kaiser Permanente if you need further guidance on obtaining a blood culture and starting empiric antibiotics in infants at least 34 weeks gestation. It calculates your patient’s septic risk based on gestational age, maternal temperature, ROM duration, maternal GBS status, and use of intrapartum antibiotics. The higher the maternal temperature and longer the ROM, the more likely it will recommend considering a blood culture and starting empiric antibiotics.

 

Answer Choice C: Diffuse, bilateral ground-glass opacities with air bronchograms

Respiratory Distress Syndrome (RDS) is incredibly common in premature infants due to alveolar surfactant deficiency. But before we can talk about how infants get surfactant, we should take a step back and talk globally about the 5 embryonal stages of lung development.

  1. The first stage, Embryonic, is the first 6 weeks of development where the trachea and bronchi are formed. If this stage has defective growth, infants can develop tracheoesophageal fistulas (TEF) or pulmonary sequestration.
  2. The second stage, Pseudoglandular, lasts from weeks 7-16, and this is where the bronchioles, terminal bronchioles, and lung circulation develop. This is also where infants can develop defects such as bronchogenic cysts, congenital diaphragmatic hernias (talked about in detail in a minute), and congenital cystic adenomatoid malformations.
  3. The third stage, Canalicular, is from weeks 17-24, and now the respiratory bronchioles and primitive alveoli develop. If these grow incorrectly, infants can develop pulmonary hypoplasia, RDS, BPD, and alveolar capillary dysplasia.
  4. The fourth stage, Terminal Sac, lasts from weeks 25-36 weeks gestation. This is when the fetus develops alveolar ducts, thin-walled alveolar sacs, and throughout this stage, they increasingly gain function in Type 2 pneumocytes. These Type 2 pneumocytes are the surfactant-producing cells in the lungs. If children are born during this stage, they are at risk for developing RDS and Bronchopulmonary Dysplasia (BPD).
  5. The fifth and final stage is the Alveolar stage and goes from week 37 until the infant is born. This is when the lungs develop definitive alveoli and mature Type 2 pneumocytes. Infants born during this stage are at risk for developing TTN, MAS, neonatal pneumonia, and Persistent Pulmonary Hypertension (PPHN).

So back to RDS, these kids are typically born before 36 weeks and have not yet developed enough surfactant. Surfactant decreases the surface tension in the alveoli and prevents microatelectasis and low lung volumes and instead allows the alveoli to remain open and allow for gas exchange.

Risk factors for RDS include prematurity, gestational diabetes, multiple gestation, and male infants. Infants of a diabetic mother are at increased risk because hyperinsulinemia has been shown to delay fetal lung development. However, administration of corticosteroids 48 hours prior to delivery (2 doses of Betamethasone) has been shown to stimulate surfactant production and decrease the rate of RDS in premature infants.  

 

Answer Choice D: Diffuse, patchy infiltrates with areas of hyperinflation

Meconium Aspiration Syndrome (MAS) is due to neonates aspirating meconium, which causes a chemical pneumonitis and partial obstruction, leading to air trapping and hyperaeration. Additionally, meconium has many components, one of which is bile acids. These bile acids locally inactivate pulmonary surfactant, causing atelectasis.

Meconium is present in the fetal GI tract as early as 16 weeks, but it does not move into the descending colon until about 34 weeks gestation. Therefore, it is uncommon to see MAS prior to 37 weeks gestation.

Risk factors include meconium stained amniotic fluids, post-term gestation (>40 weeks gestation), fetal stress, and African American ethnicity.

 

Answer Choice E: Left-sided intrathoracic stomach bubble with shift of the mediastinum and cardiac silhouette to the right

These findings would be suggestive of Congenital Diaphragmatic Hernia (CDH). Due to a defect in the diaphragm, abdominal organs are able to migrate into the chest during embryonic development, leading to pulmonary hypoplasia on the affected side(s). Per a Pediatrics in Review article from 1999, about 85% of the diaphragmatic defects are left-sided, 13% right-sided, and 2% bilateral. CDH can be a solitary defect, combined with multiple other defects, or due to chromosomal abnormalities (i.e. Trisomies 18 and 21). This defect might be noted prenatally with low maternal serum alpha-fetoprotein (MS-AFP) and ultrasonographic findings of polyhydramnios and an intrathoracic gastric bubble. If you’re interested in reading more about management of CDH, there’s a great NeoReviews article from the AAP in 2016 listed in the references.

 

Resources

  1. Reuter S, Moser C, Baack M. Respiratory distress in the newborn. Pediatr Rev. 2014 Oct;35(10):417-28; quiz 429. doi: 10.1542/pir.35-10-417. PMID: 25274969; PMCID: PMC4533247.
  2. Hermansen CL, Mahajan A. Newborn Respiratory Distress. Am Fam Physician. 2015 Dec 1;92(11):994-1002. PMID: 26760414.
  3. Kuzniewicz MW, Puopolo KM, Fischer A, Walsh EM, Li S, Newman TB, Kipnis P, Escobar GJ. A Quantitative, Risk-Based Approach to the Management of Neonatal Early-Onset Sepsis. JAMA Pediatr. 2017 Apr 1;171(4):365-371. doi: 10.1001/jamapediatrics.2016.4678. PMID: 28241253 
  4. Escobar GJ, Puopolo KM, Wi S, Turk BJ, Kuzniewicz MW, Walsh EM, Newman TB, Zupancic J, Lieberman E, Draper D. Stratification of risk of early-onset sepsis in newborns > 34 weeks’ gestation. Pediatrics. 2014 Jan;133(1):30-6. doi: 10.1542/peds.2013-1689. Epub 2013 Dec 23. PMID: 24366992
  5. Kuzniewicz MW, Walsh EM, Li S, Fischer A, Escobar GJ. Development and Implementation of an Early-Onset Sepsis Calculator to Guide Antibiotic Management in Late Preterm and Term Neonates. Jt Comm J Qual Patient Saf. 2016 May;42(5):232-9. doi: 10.1016/s1553-7250(16)42030-1. PMID: 27066927.
  6. Van Meurs K, Lou Short B. Congenital diaphragmatic hernia: the neonatologist’s perspective. Pediatr Rev. 1999 Oct;20(10):e79-87. doi: 10.1542/pir.20-10-e79. PMID: 10512896.

10. Newborn- Necrotizing Enterocolitis (NEC)

Posted on by Portable Peds

An infant was born weighing 1,250g at 30 weeks gestation due to premature rupture of membranes.  Pregnancy complications included maternal cocaine use and intrauterine growth restriction.  As feeds were introduced with donor breast milk, the infant appeared to have increased discomfort with feeds.  The baby went on to develop necrotizing enterocolitis, also known as NEC, at 20 days of life.  Which of the following is NOT a risk factor for the development of NEC?

A. Pre-term birth

B. Very low birth weight (defined as < 1,500g)

C. Intrauterine growth restriction

D. Maternal cocaine use

E. Feeding with donor breast milk

 

The correct answer is E, Feeding with donor breast milk is NOT a risk factor for the development of Necrotizing Enterocolitis (NEC).

 

Before we get into the risk factors, let’s learn a little more about NEC.  Infants present with poor feeding tolerance, increasing gastric residuals, increasing abdominal distension, and blood bowel movements.  The pathognomonic finding on abdominal X-ray is pneumatosis intestinalis which has been described as a “bubbly appearance” throughout the bowel.  Pneumatosis intestinalis results from intramural gas generated from anaerobic bacteria becoming trapped in the submucosal layer of the bowel wall.  Serial abdominal x-rays are the current gold standard to evaluate for disease progression.  Treatment includes making the infant NPO, placing a gastric tube for decompression, empiric antibiotics, and providing nutrition via TPN.  A surgical consult is also appropriate as approximately 30% of infants will progress to surgical disease. 

Now you may be wondering what antibiotics you should start… unfortunately there is no consensus recommendation on empiric antibiotics.  What the experts do agree on is that coverage should be broad and should target gram negative and anaerobic bacteria.  Typically, empiric coverage should last somewhere between 7-14 days.  A Cochrane systematic review completed in 2012 looked at various antibiotic regimens and concluded that there was insufficient evidence to recommend a particular antibiotic regimen for the treatment of NEC.  A randomized control trial would be needed to address this issue.  Most NICU’s will have standard empiric antibiotics based on provider preference and the local antibiogram.  Complications include intestinal perforation, intestinal stricture formation, intestinal malabsorption and short bowel syndrome, cholestatic liver disease, and neurodevelopmental delay.

 

So now that we have heard about a quick overview, let’s get back to our question. Feeding with breast milk, including donor breast milk, has been identified as the only consistent intervention for the prevention of NEC.  It is currently recommended that infants at risk for NEC, specifically those born with very low birth weight and born premature, receive feeds with breast milk or with donor breast milk if their own mother’s milk is not available.  Additionally, if fortification is needed, human milk derived fortifiers decrease the rate of NEC, specifically NEC which requires surgical treatment.  Formula feeding is a known risk factor for the development of NEC in both preterm and term infants.

 

The biggest risk factors for the development of NEC are prematurity and low birthweight.  Most NEC occurs in infants born at less than 32 weeks gestational age, and NEC affects 5-9% of all very low birth weight infants. About 90% of all NEC cases occur in pre-term infants.

 

Some additional risk factors to keep in mind are the need for packed red blood cell transfusion, a patent ductus arteriosus or other congenital heart disease, birth asphyxia or hypoxia, intrauterine growth restriction, polycythemia, chorioamnionitis, premature rupture of membranes, maternal cocaine use, chromosomal abnormalities, sepsis, gastroschisis, hypothyroidism, maternal pre- eclampsia, and maternal gestational diabetes.

 

The onset of NEC is inversely related to gestational age, the earlier the baby is born, the later the onset of NEC.  This is believed to be due to the fact that the timing of the onset of NEC often correlates with the initiation or advancement of feeds.  Typically, infants born near or at term are introduced to feeds sooner than their preterm counterparts therefore the onset of NEC is typically seen at an earlier post gestational age.

 

Again, the biggest risk factors to keep in mind are prematurity and low birth weight.  NEC onset is usually associated with the initiation or advancement of feeds.  While formula feeding is a known risk factor for the development of NEC, breast milk is protective.

 

Resources

  1. Samuels N, van de Graaf RA, de Jonge RCJ, Reiss IKM, Vermeulen MJ. Risk factors for necrotizing enterocolitis in neonates: a systematic review of prognostic studies. BMC Pediatr. 2017 Apr 14;17(1):105. doi: 10.1186/s12887-017-0847-3. PMID: 28410573; PMCID: PMC5391569.
  2. Chu A, Hageman JR, Caplan MS. Necrotizing Enterocolitis. NeoReviews Mar 2013, 14 (3) e113-e120; DOI: 10.1542/neo.14-3-e113.
  3. Rich BS, Dolgin SE. Necrotizing Enterocolitis. Pediatrics in Review Dec 2017, 38 (12) 552-559; DOI: 10.1542/pir.2017-0002.
  4. Wertheimer F, Arcinue R, Niklas V. Necrotizing Enterocolitis: Enhancing Awareness for the General Practitioner. Pediatr Rev. 2019 Oct;40(10):517-527. doi: 10.1542/pir.2017-0338. PMID: 31575803.
  5. Ross A, LeLeiko NS. Pediatrics in Review Apr 2010, 31 (4) 135-144; DOI: 10.1542/pir.31-4-135.
  6. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med. 2011;364(3):255-264. doi:10.1056/NEJMra1005408.
  7. Kim SS, Albanese CT. Necrotizing Enterocolitis. Pediatric Surgery. 2006;1427-1452. doi:10.1016/B978-0-323-02842-4.50095-4.
  8. Gregory KE, Deforge CE, Natale KM, Phillips M, Van Marter LJ. Necrotizing enterocolitis in the premature infant: neonatal nursing assessment, disease pathogenesis, and clinical presentation. Adv Neonatal Care. 2011;11(3):155-166. doi:10.1097/ANC.0b013e31821baaf.
  9. Shah D, Sinn JK. Antibiotic regimens for the empirical treatment of newborn infants with necrotising enterocolitis. Cochrane Database Syst Rev. 2012 Aug 15;(8):CD007448. doi: 10.1002/14651858.CD007448.pub2. PMID: 22895960.

9. Newborn- Indirect Hyperbilirubinemia

Posted on by Portable Peds

A child presents to your primary care clinic, who is a three-day old exclusively breast-fed female of European descent born at 36 weeks gestation.  Pregnancy, labor, delivery, and post-natal course were uncomplicated.  Mom’s blood type was A+, and this is her first child.  The infant was discharged at 24 hours of life, and her bilirubin level at that time was 6mg/dL, all indirect, which corresponded to a low intermediate risk level for developing severe hyperbilirubinemia.  She appears jaundiced on exam, and you note that she has lost approximately 8% of her birth weight.  Her current total serum bilirubin is 12mg/dL, all indirect.  You continue to trend bilirubin levels in your office throughout the week.  Her total bilirubin level peaks on day of life four and is down-trending by day of life six. What is the most likely etiology of her jaundice?

A. Breast milk jaundice

B. Breastfeeding jaundice

C. ABO incompatibility

D. Biliary atresia

E. G6PD deficiency

 

The correct answer is B, Breastfeeding jaundice.

 

Answer Choice B: Breastfeeding Jaundice

Over 60% of healthy newborns will develop jaundice.  The first step in any question about jaundice is to determine if the bilirubin is direct or indirect.  Breastfeeding jaundice is a form of indirect hyperbilirubinemia which develops between day of life two to four, peaks between day of life four to five, and typically resolves by two weeks of life.  Breastfeeding jaundice is mainly caused by inadequate milk intake.

 

Answer Choice A: Breast Milk Jaundice

This answer is easy to mix up with breast milk jaundice, which was answer A.  Breast milk jaundice develops later in life.  Breast milk jaundice is also a cause of indirect hyperbilirubinemia and peaks on day of life five to fifteen and can take up to 12 weeks to resolve.  In contrast to breast feeding jaundice, these infants are usually feeding well with good weight gain.

 

Answer Choice C: ABO Incompatibility

While ABO incompatibility is another cause of indirect hyperbilirubinemia, it is essentially ruled out in this situation as mom’s blood type is A+.  ABO incompatibility should primarily be considered in infants born to mothers whose blood is type O.

 

Answer Choice D: Biliary Atresia

This is incorrect as it is a cause of direct hyperbilirubinemia as compared to indirect hyperbilirubinemia.  To learn more about this, feel free to look at our episode on direct hyperbilirubinemia.

 

Answer Choice E: Glucose-6-Phosphate Dehydrogenase Deficiency

Finally, G6PD, or glucose-6-phosphate dehydrogenase, deficiency, is another cause of indirect hyperbilirubinemia which is unlikely in this infant.  G6PD deficiency is an X-linked recessive genetic condition that is most common in males of African, Asian, Middle Eastern, and Mediterranean descent.  In the United States, African American males are the most commonly affected.  G6PD deficiency increases the vulnerability of erythrocytes to oxidative stress.  Fava beans and oxidative medications, including many sulfa medications and nitrofurantoin, should be avoided in G6PD deficiency as these may trigger an acute hemolytic reaction.  Fava beans and oxidative medications must also be avoided in breastfeeding mothers as they may be transmitted through breast milk and lead to a hemolytic reaction in the infant.

 

Here are some additional points about hyperbilirubinemia:

  1. The AAP recommends that any infant discharged at 24 hours of life or younger should be seen by their PCP by 72 hours of life.  
  2. Major risk factors for the development of severe hyperbilirubinemia include:
  • Jaundice in the first 24 hours of life
  • Blood group incompatibility with a positive direct Coomb’s test
  • Prematurity
  • Previous siblings requiring phototherapy
  • Cephalohematomas or other bruising
  • Exclusive breastfeeding
  • Infants of East Asian descent

 

Resources

  1. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004 Jul;114(1):297-316. doi: 10.1542/peds.114.1.297. Erratum in: Pediatrics. 2004 Oct;114(4):1138. PMID: 15231951.
  2. Maisels, MJ. Neonatal Jaundice. Pediatrics in Review Dec 2006, 27 (12) 443-454; DOI: 10.1542/pir.27-12-443.
  3. Anderson, NB, Calkins, KL. Neonatal Indirect Hyperbilirubinemia. NeoReviews Nov 2020, 21 (11) e749-e760; DOI: 10.1542/neo.21-11-e749.
  4. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006-. Fava Beans. [Updated 2018 Dec 3]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532498/.
  5. Frank JE. Diagnosis and management of G6PD deficiency. Am Fam Physician. 2005 Oct 1;72(7):1277-82. PMID: 16225031.
  6. Kaplan M, Hammerman C. Glucose-6-Phosphate Dehydrogenase Deficiency: A Worldwide Potential Cause of Severe Neonatal Hyperbilirubinemia. NeoReviews Feb 2000, 1 (2) e32-e39; DOI: 10.1542/neo.1-2-e32.
  7. Koosha A, Rafizadeh B. Evaluation of neonatal indirect hyperbilirubinaemia at Zanjan Province of Iran in 2001-2003: prevalence of glucose-6-phosphate dehydrogenase deficiency. Singapore Med J. 2007 May;48(5):424-8. PMID: 17453100.

8. Newborn- Direct Hyperbilirubinemia

Posted on by Portable Peds

A four week old infant is brought into your primary care office.  She was born at 39w6d via uncomplicated home delivery and missed her newborn appointment.  Mom received appropriate prenatal care, and the pregnancy was uncomplicated.  The child’s birth weight was appropriate for age.  She has been breast feeding well and has continued to gain weight along the 30th percentile.  She has had no fevers or other signs of illness. On exam the child is markedly jaundiced with prominent icteric sclera.  You note that she has a firm, palpable liver edge.  She has no dysmorphic features or murmurs on exam.  She has a stool in the office which is a pasty white color.  You check a total serum bilirubin which is notable for direct hyperbilirubinemia.  You also obtain an abdominal ultrasound, which is notable for a triangular fibrous mass at the porta hepatis.  What is the most likely diagnosis?  

A. Choledochal cyst 

B. Physiologic jaundice

C. Alagille syndrome

D. Biliary atresia

E. Galactosemia

 

The correct answer is D, Biliary atresia.

 

Answer Choice D: Biliary Atresia

Biliary atresia is a form of direct hyperbilirubinemia.  The definition of direct hyperbilirubinemia can vary depending on laboratory systems.  In some systems, a direct bilirubin of more than 20% the total serum bilirubin is considered abnormal.  In other systems, any direct bilirubin greater than 1mg/dL is considered abnormal.  Due to variability in lab systems, the North American and Europeans Societies for Pediatric Gastroenterology, Hepatology and Nutrition recommend that any infant with a direct bilirubin > 1mg/dL are referred for further evaluation.   

Extrahepatic biliary atresia is the most common cause of neonatal cholestasis.  It typically presents with jaundice between 3-6 weeks of age.  These patients frequently have pasty white or acholic stools. Early referral to a pediatric gastroenterologist is key.  The ultrasound finding described in the question is suggestive of biliary atresia, but not diagnostic. The primary purpose of the ultrasound is to rule out a choledochal cyst, which was answer choice A.  A normal ultrasound does not rule out biliary atresia. Liver biopsy is diagnostic in 90-95% of cases and will demonstrate large duct obstruction, portal tract edema, bile ductular proliferation and the presence of bile plugs in bile ductules.  Patient’s then undergo intraoperative cholangiogram followed by a hepato-porto-enterostomy Kasai procedure which allows bile to drain into the intestine.  The younger the patient is at the time of the procedure the higher the success rate.  If these patients are not treated, they will most likely die from liver failure by 2 years of age. 

 

Answer Choice A: Choledochal Cyst

Choledochal cysts are cystic dilations of the bile duct which lead to obstruction and bile retention, which in turn leads to jaundice and liver enlargement.  There are five different types based on the site of the cyst or dilation.  They can be identified on ultrasound, and treatment is surgical.

 

Answer Choice B: Physiologic Jaundice

Physiologic jaundice is incorrect for several reasons.  First, all jaundice that persists past two weeks of life requires further investigation. Second, physiologic jaundice results in indirect hyperbilirubinemia.  In this case, the patient had direct hyperbilirubinemia which ALWAYS requires further investigation.  This is why it is essential to always obtain a fractionated serum total bilirubin; you cannot rely solely on transcutaneous bilirubin monitoring.  

 

Answer Choice C: Alagille Syndrome

Alagille syndrome is less likely in this patient.  While these patients do present with jaundice and acholic stools there are several other features to look for including

  1. Dysmorphic facies: prominent broad forehead, deep set eyes and a triangular chin
  2. Congenital heart disease, most commonly pulmonary stenosis
  3. Short stature and hypogonadism 
  4. Abnormalities of the eyes, kidneys, and butterfly vertebra 

This syndrome is inherited in an autosomal dominant fashion with variable penetrance and expressivity.  In contrast to biliary atresia, their liver size is normally normal in the neonatal period.  Histology demonstrates a paucity of normal intralobular bile ducts which are progressively lost with age.

 

We discuss more about galactosemia in our episode related to inborn errors of metabolism (Episode 15), but this is an unlikely etiology in this patient given the fact that they are overall clinically well appearing.  Children with biliary atresia are initially well appearing and are growing well, while infants with metabolic disorders or infections as the cause of their cholestatic jaundice are typically ill appearing and slow to gain weight.

 

References

1. Zallen GS, Bliss DW, Curran TJ, Marvin WH, silen, ML.  Biliary Atresia.  Pediatrics in Review Jul 2006, 27 (7) 243-248; DOI: 10.1542/pir.27-7-243.

2. Wang KS; Section on Surgery; Committee on Fetus and Newborn; Childhood Liver Disease Research Network. Newborn Screening for Biliary Atresia. Pediatrics. 2015 Dec;136(6):e1663-9. doi: 10.1542/peds.2015-3570. PMID: 26620065; PMCID: PMC4920543.

3. Suchy FJ. Neonatal Cholestasis.  Pediatrics in Review Nov 2004, 25 (11) 388-396; DOI: 10.1542/pir.25-11-388.

4. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004 Jul;114(1):297-316. doi: 10.1542/peds.114.1.297. Erratum in: Pediatrics. 2004 Oct;114(4):1138. PMID: 15231951.

5. Fawaz R, Baumann U, Ekong U, Fischler B, Hadzic N, Mack CL, McLin VA, Molleston JP, Neimark E, Ng VL, Karpen SJ. Guideline for the Evaluation of Cholestatic Jaundice in Infants: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2017 Jan;64(1):154-168. doi: 10.1097/MPG.0000000000001334. PMID: 27429428.

6. Infectious Disease- Meningitis

Posted on by Portable Peds

A 10 year old previously healthy male presents after 24 hours of non-remitting headache, intractable vomiting, and fevers to 104.1F at home. Mother brought the patient to the ED after symptoms continued to worsen, and she noticed him moving his neck less. No recent travel, but he did go to a sleepover recently and notes that one of the friends there had a “GI bug.” Given his symptoms, a lumbar puncture is performed, and the fluid obtained is noted to be clear and colorless with an opening pressure of 30 mmH20, WBC of 200, predominantly lymphocytes, protein low at 80 mg/dl, and glucose slightly elevated to 60 mg/dl. Serum glucose was 85. Given these results, what is the most likely etiology of this child’s symptomatology?

A. Bacterial meningitis

B. Subarachnoid hemorrhage

C. Fungal meningitis

D. Viral meningitis

E. Tuberculous meningitis

 

The correct answer is D, Viral Meningitis.

 

Answer Choice A: Bacterial Meningitis

This answer is incorrect given the CSF profile. The opening pressure in cases of bacterial meningitis is typically much higher than viral with a turbid appearance of the fluid and high protein count with low glucose and leukocytosis with neutrophilic predominance. It is important to note that a viral meningitis may have a neutrophilic predominance if caught very early in the disease course. The CSF to serum glucose ratio can be calculated from the question stem and is typically <0.4 in bacterial, fungal, and tubercular meningitis compared to a typical ratio of >0.6 with viral meningitis. The most common causes of meningitis vary by age group:

-Newborns are at the highest risk for Group B Streptococcus (Streptococcus agalactiae), Listeria monocytogenes, E. coli, and Klebsiella.

-The most common pathogens seen in toddlers and children are Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae Type B (although this is significantly decreased with vaccinations).

-Teens most commonly are affected by Neisseria meningitidis and Streptococcus pneumoniae.

 

Answer Choice B: Subarachnoid Hemorrhage

This answer is incorrect. The signs of an acute subarachnoid hemorrhage can include sudden and severe headache, vomiting, lethargy, weakness or paralysis, new-onset seizure, loss of consciousness, or altered mental status. Keys in the question stem that lead away from this as the correct answer are notably the fever and viral prodrome. Additionally, the lumbar puncture would likely be grossly bloody or xanthochromic but may otherwise have normal indices.

 

Answer Choice C: Fungal Meningitis

This answer choice is also incorrect given the CSF profile and the presenting fact that this patient was overall healthy prior to sudden disease onset. Fungal meningitis is more likely to occur in immunocompromised patients. CSF profile in a patient with fungal meningitis will have a slightly elevated protein count, slightly decreased glucose (similar to bacterial meningitis) and a mild leukocytosis made up of predominantly monocytes (similar to viral meningitis). Fungal and tuberculous meningitis are essentially indistinguishable at this level. Because of this, you can essentially eliminate both answer choices C and E!

 

Answer Choice D: Viral Meningitis

If you guessed this answer choice, you are correct! Overall, viral meningitis is the most common cause of meningitis and the clinical presentation as well as the lab findings of CSF analysis are consistent with this picture. Of all of the viruses, Enteroviruses are the most common cause of viral meningitis across all age groups with Parechoviruses being the next most common in children. Herpesviruses that cause meningitis include Herpes simplex virus (HSV) types 1 and 2, Varicella-zoster virus (VZV), Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Human herpesvirus 6 (HHV6). Other viral causes include Adenovirus, Lymphocytic Choriomeningitis virus (LCMV), Influenza, Parainfluenza, and Mumps. There are more than 100 arthropod-borne viruses (commonly known as Arboviruses) that cause disease. The most common of these that can cause viral meningitis, encephalitis, or a combination of the two include West Nile virus, LaCrosse virus, and Saint Louis virus. These will typically present with a viral prodromal period of headaches, arthralgias, myalgias, and rash, followed by neurologic symptoms of vomiting, stiff neck, or even mental status changes and seizures.

Answer Choice E: Tuberculous Meningitis

As mentioned previously, this answer choice is also incorrect and would be very difficult to distinguish from fungal meningitis. Tuberculous meningitis may also have a xanthochromic, fibrinous, or opaque color to the fluid whereas fungal can have the fibrin appearance but is more likely to appear clear like viral meningitis. Tuberculous meningitis is most commonly found in children 1-5 years old. There are very few bacteria that cause an aseptic meningitis, and they include Mycobacterium tuberculosis (TB), Borrelia burgdorferi (Lyme disease), and Treponema pallidum (Syphilis). The classic “RIPES” regimen with rifampin, isoniazid, pyrazinamide, ethambutol, and streptomycin would be the standard therapy for at least 9 months for these patients. 

 

Resources

  1. Cantu RM, M Das J. Viral Meningitis. [Updated 2020 Oct 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK545217/
  2. Engorn, B. & Flerage, J. (2015). The Harriet Lane handbook: a manual for pediatric house officers. 20th ed. Philadelphia, PA: Mosby Elsevier.
  3. Koskiniemi M, Vaheri A, Taskinen E. Cerebrospinal fluid alterations in herpes simplex virus encephalitis. Rev Infect Dis. 1984 Sep-Oct;6(5):608-18. doi: 10.1093/clinids/6.5.608. PMID: 6095403.
  4. Park HZ, Lee SP, Schy AL. Ceftriaxone-associated gallbladder sludge. Identification of calcium-ceftriaxone salt as a major component of gallbladder precipitate. Gastroenterology. 1991;100:1665–70.

5. Infectious Disease- TORCH Infections

Posted on by Portable Peds

A 2 week old neonate presents to the outpatient office for a weight check after recently moving from out-of-state. No newborn records have been sent from the previous hospital, and the mother is unsure of her prenatal testing, although she states delivery was uneventful. She is concerned because of a rash that has developed over the past day, and he seems smaller compared to his older brother when he was the same age. On exam, you note a murmur, a petechial rash over his entire body, and his weight is below the first percentile. What is the most likely cause of this infant’s symptoms?

A. Congenital Parvovirus B19

B. Congenital Cytomegalovirus

C. Congenital Rubella

D. Congenital Syphilis

E. Congenital Toxoplasmosis

The correct answer is C, Congenital Rubella. We will need to dive into the specifics of each disease given that they all lead to overlapping features of IUGR (or SGA post-natally) and multi-organ system involvement.  

 

Answer Choice A: Congenital Parvovirus B-19

This is not the correct answer due to the clinical presentation. The typical presentation of parvovirus B-19 in the neonatal period is extremely severe with isolated pleural and pericardial effusions, fetal hydrops, and a high risk of fetal death. The greatest risk of mortality is present if transmission occurs in the first half of pregnancy with the overall risk being between 2-6%. The diagnosis is made with a positive serum IgM specific for Parvovirus, indicating that the infection occurred 2-4 months prior. Being a virally-mediated disease process, the treatment is typically limited to supportive care. 

 

Answer Choice B: Congenital Cytomegalovirus

The presentation of this patient is not consistent with Congenital Cytomegalovirus, commonly known as CMV. The vast majority of infants with congenital CMV are asymptomatic at birth but if symptoms are present they will most likely include IUGR, jaundice, hepatosplenomegaly, microcephaly, thrombocytopenia, intracranial calcifications, and hearing loss. The easiest way to remember congenital CMV is with the 4 C’s of CMV:

– Chorioretinitis

– Central cerebral calcifications (Periventricular)

– Potential for “C”ensorineural hearing loss (Sensorineural)

These babies can also have thrombocytopenia with subsequent petechiae and purpura (blueberry muffin rash) but will typically NOT have cardiac involvement and will NOT have an audible heart murmur. The diagnosis is made by CMV-specific PCR, which can be run on urine, stool, saliva, CSF, or blood, and IgM can be tested within 3 weeks of birth. The treatment is Ganciclovir 6mg/kg/dose IV BID for 6 weeks OR Valganciclovir 16mg/kg/dose PO BID. 

 

Answer Choice C: Congenital Rubella

The history and exam findings in this patient are consistent with Congenital Rubella. Infants present with IUGR (then SGA) cataracts, cardiac anomalies, deafness, and the classic blueberry muffin rash. If suspecting this diagnosis, it is important to obtain an IgM level, which will be positive between 0-3 months of age. Early eye exam and echocardiogram are important for initial diagnosis and to continue to closely monitor and intervene as necessary. Patent Ductus Arteriosus and Pulmonary Valve Stenosis are the two most common cardiac anomalies associated with congenital rubella. White matter anomalies and periventricular calcifications are often present, as are calcifications in the basal ganglia. Given this is a virally mediated process, the treatment remains largely supportive, and it is incredibly important to vaccinate mom! It is important to note that the risk of congenital infection and defects resulting from such is highest during the first 12 weeks of gestation and decreases thereafter; defects are rare after infection in the 20th week (or later) of gestation. This presents a substantial problem due to the fact that a significant portion of mothers may present for prenatal care after this time period. In similar fashion to CMV, these infants need to be followed well into childhood due to the high rate of hearing dysfunctions associated with this congenital infection. 

 

Answer Choice D: Congenital Syphilis

The presentation of this patient is not consistent with Congenital Syphilis, which is likely to present with more mucocutaneous lesions, hepatosplenomegaly, snuffles, lymphadenopathy, osteochondritis, hemolytic anemia, or thrombocytopenia. Of note, the skin and all secretions are highly contagious! If the mother has adequate prenatal care, this is something that is routinely tested for. However, depending on timing of testing and contraction of illness, it does have potential to be missed. Of note, if maternal serology is positive, the infant should be screened with a VDRL test or RPR (more common) and confirmed with Fluorescent treponemal antibody absorption test (FTA-ABS) or microhemagglutination assay for treponema pallidum antibodies (MHA-TP). If the infant is positive on confirmatory testing, treatment should be initiated with penicillin G. 

 

Answer Choice E: Congenital Toxoplasmosis

Lastly, this patient does not fit the picture of Congenital Toxoplasmosis given the clinical history and physical exam. The vast majority of infants affected by Congenital Toxoplasmosis are asymptomatic at birth. If there are symptoms present, they typically include a maculopapular rash (as opposed to the purpuric one seen with Congenital Rubella), generalized lymphadenopathy, hepatosplenomegaly, jaundice, pneumonitis, petechiae, and thrombocytopenia. Similar to other congenital infections, microcephaly, chorioretinitis, seizures, and hearing loss are common manifestations of infection. It is even more common for this disease process to not present until later in life with seizures, developmental delay, learning disabilities, and cognitive deficits. It is interesting to note that when Toxoplasmosis occurs early in pregnancy, there is a lower chance of fetal infection, but when infection does occur, the consequences are more severe with the opposite holding true later in pregnancy with a greater chance of infection but less severe sequela. Diagnosis is made by the presence of IgM or IgA immediately or by IgG  if testing after 1 year of age. Treatment is with pyrimethamine, sulfadiazine, and folinic acid for at least 1 year. 

Resources

  1. Engorn, B. & Flerage, J. (2015). The Harriet Lane handbook: a manual for pediatric house officers. 20th ed. Philadelphia, PA: Mosby Elsevier.
  2. Coller RJ. (2018). Board Review Series: Pediatrics. 2nd ed. Lippincott Williams & Wilkins.
    American Academy of Pediatrics. Kimberlin DW, Brady, MT, Jackson MA, Long SS. Red Book: 2018 Report of the Committee on Infectious Diseases, 31st ed. American Academy of Pediatrics, Itasca, IL 2018.
  3. Rowe RD. Maternal rubella and pulmonary artery stenoses: report of eleven cases. Pediatrics. 1963 Aug;32:180-5. PMID: 14044445.

4. Infectious Disease- Febrile Neonate

Posted on by Portable Peds

A 9 day old male, born at 36 weeks gestation via normal spontaneous vaginal delivery presents to a pediatric emergency room due to increased fussiness, fever, and decreased oral intake. Maternal perinatal history is unremarkable aside from a mild flu-like illness in her first trimester and pre-term labor. Mother had negative serologies at delivery and no history of sexually transmitted infections. Delivery was uncomplicated, although placenta was noted to have presence of white nodules, and the infant did not require NICU admission. A full septic evaluation was performed with serum glucose 80, serum WBC 18.1 with neutrophilic predominance, and CSF analysis showing WBC 20,000, glucose 25, and protein 125. Blood, CSF, and urine cultures pending. What is the most likely diagnosis and the recommended empiric treatment?

 

A. Herpes simplex meningitis; acyclovir, ampicillin, and gentamicin

B. Group B strep meningitis; ampicillin, ceftriaxone, and gentamicin

C. Listeria monocytogenes meningitis; ampicillin and gentamicin

D. Escherichia coli meningitis; ampicillin and gentamicin

E. Neisseria meningitidis meningitis; ampicillin, ceftriaxone, and gentamicin

 

The correct answer is C.

Answer choice A: Herpes simplex meningitis; acyclovir, ampicillin, and gentamicin

This answer is incorrect because the CSF constituents and ratios are inconsistent with a viral illness. Typically, if a meningitis is virally mediated, the CSF will show <100 WBC per mm^3, with a predominance of lymphocytes, although if caught early, PMNs may predominate. There will also likely be normal to elevated protein, as opposed to typical mild to marked elevation in bacterial meningitis, and a normal CSF: serum glucose ratio, as opposed to being markedly decreased with bacterial meningitis.

 

HSV should be strongly considered when there is a maternal history of infection or there is visualization of cutaneous lesions – especially when they have the classic vesicular appearance. Many times these babies will present with apnea or seizures as well. It is common to obtain surface and serologic testing in addition to rapid CSF panels with HSV included, and when covering with empiric antibiotics, initiate acyclovir treatment for viral coverage,  then discontinue once there is evidence of negativity on testing. After the infant is >28 days of life, the risk of HSV drops precipitously, and acyclovir should only be used if there are specific concerns.

 

Answer choice B: Group B strep meningitis; ampicillin, ceftriaxone, and gentamicin

Empiric antibiotic therapy for a febrile neonate typically includes ampicillin, gentamicin, and acyclovir. Answer choice B is incorrect for two reasons. The first being that group B streptococcus, commonly referred to as ‘GBS’ is not the most likely etiology of meningitis given that the baby is at 9 days of life and the report of a “flu-like illness” during the pre-natal period is highly suspicious of another infection listed in the answer choices. Additionally, the treatment course of a neonatal GBS meningitis case would be with ampicillin and cefotaxime for 14 days and would not include ceftriaxone. Ceftriaxone is not used until an infant is over 1 month old. Research to date states that “Ceftriaxone is contraindicated in neonates because it displaces bilirubin from albumin binding sites, resulting in a higher free bilirubin serum concentration with subsequent accumulation of bilirubin in the tissues. Even more dangerous is ceftriaxone’s interaction with calcium. This interaction precipitates calcium, which results in serious adverse effects.” 

 

Answer choice C: Listeria Monocytogenes meningitis; ampicillin and gentamicin

This is the correct answer choice for this question! The clues in this case leading you to Listeria are the presence of “flu-like symptoms” in the pre-natal period, which is highly suspicious for this infection, and the presence of white nodules in the placenta. These are identified on pathological review as micro-abscesses and are only seen with listeria infections. These two pieces of information lead away from the most common diagnosis of GBS meningitis and instead trend toward the diagnosis of listeria as both can present similarly with pre-term labor and time to symptom onset after delivery. If the mother is described as being asymptomatic in pregnancy – think about GBS – if there is a history being symptomatic, this may lead you towards putting listeria higher on your differential in the appropriate clinical setting. 

 

The treatment for Listeria is initially with ampicillin and gentamicin for at least a 3 week course in an immunocompetent patient. If the patient is immunocompromised for any reason or has evidence of cerebritis or brain abscesses, a longer treatment duration of 6-8 weeks is warranted. In the typical 3-4 week treatment period, gentamicin may not be required for the entire duration,    and in many cases, it is only continued for the first 7-14 days until there is evidence of clinical improvement. At that point, ampicillin monotherapy is continued for the remainder of the treatment course, and gentamicin is discontinued to avoid precipitation of nephrotoxicity and ototoxicity as much as possible.

 

Answer choice D: Escherichia coli meningitis; ampicillin and gentamicin

This answer choice is unfortunately incorrect, but if I’ve learned nothing else in residency, it is to have a high respect for gram negative sepsis, especially in the neonatal population! Given the history discussed above as well as the age of the neonate presenting, E. coli is not the most likely etiology in this patient. Per the literature to date, Escherichia coli meningitis is 7 times more frequent in preterm than term infants. The median age at diagnosis is 14 days; with bimodal peaks of infection present in 70% of cases either at 0–3 days of life in pre-term neonates or 11–15 days of life in term neonates. E. coli is currently the most common cause of early-onset sepsis and meningitis among very low birth weight infants, weighing < 1500 gram.

 

In meningitis due to gram negative rods, including E. coli, the CSF may be cloudy and will very likely show a significant pleocytosis, in which case, cefotaxime should be added to the treatment regimen for its phenomenal CNS penetration and efficacy against these organisms. 

 

Answer choice E: Neisseria meningitidis meningitis; ampicillin, ceftriaxone, and gentamicin

This is an interesting answer choice as the CSF analysis still fits with a bacterial meningitis and would be consistent with a Neisseria picture given the presence of pleocytosis with a predominance of neutrophils (typically 100-50,000), hypoglycorrhachia (which means low CSF glucose) with a ratio of CSF to serum glucose <0.40. Additionally, bacterial meningitis CSF profiles will typically have significantly increased protein compared to viral and a positive gram stain and culture. This answer choice is not the most likely answer choice solely due to the age of the child in addition to the clues given for listeria monocytogenes as the most likely causative agent.  The prevalence of organisms causing bacterial meningitis significantly changes after the first month of life. After 1 month, we start worrying about Neisseria meningitidis, Strep. pneumo, and Hemophilus Influenza B (if unimmunized) much more than the bacteria previously discussed. 

 

Given this shift, empiric antibiotics additionally change with stopping the use of gentamicin and initiation of ceftriaxone and vancomycin instead. You would also consider Ampicillin if immunocompromised. It is additionally important to note that the blood brain barrier is still underdeveloped even at 1 month of age, and a blood culture can be positive in the majority of cases of bacterial meningitis, harboring the need for lumbar puncture in that population. 

 

Resources

  1. Bundy LM, Noor A. Neonatal Meningitis. [Updated 2020 Jun 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532264/
  2. Charlier C, Perrodeau É, Leclercq A, Cazenave B, Pilmis B, Henry B, Lopes A, Maury MM, Moura A, Goffinet F, Dieye HB, Thouvenot P, Ungeheuer MN, Tourdjman M, Goulet V, de Valk H, Lortholary O, Ravaud P, Lecuit M; MONALISA study group. Clinical features and prognostic factors of listeriosis: the MONALISA national prospective cohort study. Lancet Infect Dis. 2017 May;17(5):510-519. doi: 10.1016/S1473-3099(16)30521-7. Epub 2017 Jan 28. Erratum in: Lancet Infect Dis. 2017 Sep;17(9):897. PMID: 28139432.
  3. Mount HR, Boyle SD. Aseptic and Bacterial Meningitis: Evaluation, Treatment, and Prevention. Am Fam Physician. 2017 Sep 1;96(5):314-322. PMID: 28925647.
  4. Park HZ, Lee SP, Schy AL. Ceftriaxone-associated gallbladder sludge. Identification of calcium-ceftriaxone salt as a major component of gallbladder precipitate. Gastroenterology. 1991;100:1665–70.

3. Immunizations- Influenza Part 2

Posted on by Portable Peds

A 3 year old F with h/o asthma and cochlear implant was recently diagnosed with Kawasaki Disease and was treated appropriately at her local pediatric hospital. The patient also received a dose of Tamiflu (Oseltamivir) yesterday. The parents are requesting the patient receive a live attenuated influenza vaccine, but you counsel them that she should avoid a live influenza vaccine. Which of the following is NOT a reason to avoid the live attenuated influenza vaccine in this patient?

A. History of asthma

B. Recent administration of Tamiflu (Oseltamivir)

C. Cochlear implant

D. Age

E. Receiving aspirin or salicylate-containing medications

 

The answer is D. The CDC recommends the live attenuated influenza vaccine (LAIV) may be given starting at age 2. However, the rest of the answer choices are contraindications to receiving the LAIV.

 

Recommendations of the Advisory Committee on Immunization Practices- United States, 2020-21 Influenza Season (Published August 21, 2020)

  • Contraindications to live attenuated influenza vaccination (LAIV4) are as follows:
  • History of severe allergic reaction to a previous dose of influenza vaccine or to any vaccine component (except egg)
  • Receiving aspirin or salicylate-containing medications (Risk of Reye Syndrome)
  • Age 2-4 years with history of asthma or wheezing
  • Immunocompromised due to any cause (including medications and HIV infection)
  • Anatomic or functional asplenia (including due to Sickle Cell Anemia)
  • Close contacts or caregivers of severely immunosuppressed persons who require a protected environment
  • Cerebrospinal fluid communication with oropharynx, nasopharynx, nose, ear, or any other cranial CSF leak
  • Cochlear implant (Potential for CSF leak)
  • Pregnancy
  • Received influenza antiviral medications within the previous 48 hours for Oseltamivir (Tamiflu) and Zanamivir (Relenza), 5 days for Peramivir (Rapivab), and 17 days for Baloxavir (Xofluza). This duration may be prolonged in patients with delayed medication clearance, such as renal insufficiency.

 

Precautions for use of LAIV4 include the following:

  • Moderate or severe acute illness with or without fever
  • History of GBS within 6 weeks of receiving any influenza vaccine
  • Asthma in patients aged 5 years or older
  • “Other underlying medical condition (other than contraindications) that might predispose to complications after wild-type influenza virus infection (i.e. chronic pulmonary, cardiovascular [except isolated hypertension], renal, hepatic, neurologic, hematologic, or metabolic disorders [including diabetes mellitus])”

 

Per 2013 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for Vaccination of the Immunocompromised Host (Published December 4, 2013)

Annual inactivate influenza vaccination is recommended for immunocompromised patients aged 6 months or older, except for patients who are very unlikely to respond (although unlikely to be harmed by IIV), such as those receiving intensive chemotherapy (induction or consolidation chemotherapy for acute leukemia) or those who have received anti–B-cell antibodies within 6 months.

 

References

1. Grohskopf LA, Alyanak E, Broder KR, et al. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices — United States, 2020–21 Influenza Season. MMWR Recomm Rep 2020;69(No. RR-8):1–24. DOI: http://dx.doi.org/10.15585/mmwr.rr6908a1

2. Lorry G. Rubin, Myron J. Levin, Per Ljungman, E. Graham Davies, Robin Avery, Marcie Tomblyn, Athos Bousvaros, Shireesha Dhanireddy, Lillian Sung, Harry Keyserling, Insoo Kang, 2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host, Clinical Infectious Diseases, Volume 58, Issue 3, 1 February 2014, Pages e44–e100, https://doi.org/10.1093/cid/cit684

3. Robinson CL, Bernstein H, Poehling K, Romero JR, Szilagyi P. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Children and Adolescents Aged 18 Years or Younger — United States, 2020. MMWR Morb Mortal Wkly Rep 2020;69:130–132. DOI: http://dx.doi.org/10.15585/mmwr.mm6905a3

2. Immunizations- Influenza Part 1

Posted on by Portable Peds

A 4 month-old full term female with history of eczema and egg allergy presents for her 4 month well child visit in October. Mother is requesting an influenza vaccine be given with her scheduled 4 month vaccines. When questioned about the egg allergy, mom states that she had hives and respiratory distress after eating eggs previously. Should this patient receive the influenza vaccine at this visit?

A. No, her severe egg allergy is a contraindication to giving the vaccine.

B. No, she is not old enough to receive the vaccine at this visit.

C. Yes, she can receive the vaccine if monitored closely in clinic for signs of anaphylaxis.

D. Yes, she can receive the vaccine without additional monitoring.

E. Yes, she can receive the vaccine, but she will need a second vaccine dose.

 

The correct answer is B. The CDC recommends annual influenza vaccines be given starting at age 6 months for Inactivated Influenza Vaccine (IIV), 2 years for Live Attenuated Influenza Vaccine (LAIV), and 18 months for recombinant influenza vaccine (RIV).

 

If the patient had been 6 months of age, answer choice C would have been correct. Severe egg allergy is NOT a contraindication to receiving the influenza vaccine. However, the patient should be closely monitored by a medical provider after administration for signs of severe allergic reaction.

 

If the patient is 6 months to 8 years of age, then you should ask if the child has received 2 doses or more TOTAL. If not, then give 2 doses of influenza vaccine, given 4 weeks apart as minimum interval. It is important to note that the 2 doses of influenza vaccine do not have to have been given in the same season or consecutive seasons to count. The 2 dose series should be based on age of first vaccination. In other words, if the first dose is given at age 8, and the child turns 9 during the same season, they should still receive the second dose of the influenza vaccine.

 

A systematic review and meta-analysis posted in Vaccine journal in March 2020 showed influenza “vaccination offered high protection against influenza hospitalization in children… Effectiveness was higher against H1N1 (74%) and Influenza B (51%) and moderate against H3N2 (41%)… and significantly higher in fully vs partially vaccinated children” (62% vs 34%, respectively).

 

References

1. https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html#note-flu

2. https://www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/immunizations/Influenza-Implementation-Guidance/Pages/Annual-AAP-Influenza-Policy.aspx

3. https://www.sciencedirect.com/science/article/pii/S0264410X20302619

Influenza vaccine effectiveness against influenza-associated hospitalization in children: A systematic review and meta-analysis. Vaccine. Volume 38, Issue 14, 23 March 2020, Pages 2893-2903