What Are Common Causes of Congenital Aplastic Anemia?

Patient Presentation
A 15-month-old female had previously come to clinic for her health maintenance examination and the resident was reviewing the patient’s screening laboratories with her attending physician. The hemoglobin was 10.3 mg/dL and hematocrit was 31% with a normal lead level. “I’m going to start her on some iron for probable iron deficiency anemia and follow her up in a month,” the resident said. “I know that iron deficiency anemia is the most common cause of anemia in children, but I was doing some board review questions last night and I got the question wrong about the most common cause of congenital aplastic anemia. I thought it was Shwachman-Diamond syndrome and its really Fanconi anemia,” she continued. The attending said, “It’s been a long time since I reviewed any of those myself. I know there are congenital anomalies associated with them, but I can’t remember them exactly. Drugs, viruses and of course leukemia cause pancytopenia more often than congenital problems.”

Discussion
Aplastic anemia are disorders where there is inadequate production of erythrocytes, granulocytes and platelets caused by decreased bone marrow production leading to a peripheral blood pancytopenia. Most often it is acquired because of exposures to infections (especially viruses such as Epstein-Barr virus, rubella, herpes, etc.), drugs (e.g. chloramphenicol, chemotherapeutic agents, etc.), toxins or radiation.

Learning Point
The most common congenital bone marrow failure syndromes causing pancytopenia are (in this order) Fanconi anemia, Diamond-Blackfan anemia, and Shwachman-Diamond anemia. Most have a variety of congenital abnormalities. They usually have an increased risk of malignancies. Treatment is usually monitoring, supportive (including colony stimulating factors, transfusions, etc.) and bone marrow and other transplantations.

  • Fanconi anemia
    • Cause is chromosome breakage and defective repair
    • Autosome recessive, few X-linked recessive
    • Pancytopenia is seen first decade of life
    • Congenital abnormalities – cafe-au-lait spots, short stature, abnormal radii and thumbs, microcephaly, renal abnormalities
    • Increased risk of malignancies is 50x general population – leukemia and squamous cell carcinoma
  • Diamond-Blackfan anemia
    • Caused by ribosomal protein mutations
    • Genetics is heterogeneous
    • This is a mainly a congenital red cell aplasia, but often has neutropenia and thrombocytenia. Diagnosed usually in first year of life.
    • Congenital abnormalities – short stature, midline facial defects, renal, thumb abnormalities and cardiac defects
    • Increased risk of malignancy – leukemia, myelodysplastic syndrome, solid tumors
    • Treatment also includes corticosteroids
  • Dyskeratosis congenita
    • Cause is degradation of the telomeres (ends of chromosomes) over replication cycles causing cell death
    • X-linked, autosomal dominant, autosomal recessive
    • Pancytopenia – 50% of individuals have failure by age 50, but often first signs in childhood with death in early adulthood.
    • Congenital abnormalities – nail dystrophy, reticular skin pigmentation, leukoplakia, pulmonary fibrosis, eye abnormalities
    • Increased risk of malignancy is 20-30% by age 50 – squamous cell carcinoma, female genital tract, gastrointestinal tract
  • Shwachman-Diamond Syndrome
    • Cause is ribosomal maturation problem
    • Genetics are heterogeneous
    • Pancytopenia – mainly neutropenia, but also anemia, thrombocytopenia
    • Congenital abnormalities – exocrine pancreatic insufficiency, skeletal abnormalities such as osteoporosis, rib cage dysplasia and metaphyseal dysplasia
    • Increased risk of malignancy is up to 35% – leukemia, myelodysplastic syndrome
  • Congenital amegakaryocytic thrombocytopenia
    • Cause is not completely understood but there is an abnormality in an oncogene on chromosome 1
    • Genetics is autosomal recessive
    • Pancytopenia – mainly thrombocytopenia in infancy and then progression over next 3-5 years of aplastic anemia
    • Congenital abnormalities – does not have them
    • Early death is common

Other bone marrow failures syndromes that have similar features

  • TAR (thrombocytopenia with absent radii)
    • Cause is mRNA processing
    • Genetics is deletion in chromosome 1
    • Hematological problem – severe thrombocytopenia at birth often with megakaryocytes
    • Congenital abnormalities – bilateral absent radii, facial, cardiac and genitorurinary defects, short stature
    • Increased risk of malignancy – leukemias
  • Severe congenital neutropenias
    • A group of disorders
    • Cause is problem with protein folding
    • Genetics is heterogeneous
    • Hematological problem – neutropenia allowing overwhelming bacterial infections to occur.
    • Congenital abnormalities – does not have them
    • Increased risk of malignancy – leukemia, myelodysplastic syndrome
    • Treatment with colony stimulating factors is needed

Questions for Further Discussion
1. What causes increased production of erythrocytes, granulocytes or platelets?
2. What causes increased production of granulocytes?
3. What causes increased production of platelets? (a review can be found here)

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Aplastic Anemia and Bone Marrow Diseases.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Federman N, Sakamoto KM. The genetic basis of bone marrow failure syndromes in children. Mol Genet Metab. 2005 Sep-Oct;86(1-2):100-9.

Leguit RJ, van den Tweel JG. The pathology of bone marrow failure. Histopathology. 2010 Nov;57(5):655-70.

Wilson DB, Link DC, Mason PJ, Bessler M. Inherited bone marrow failure syndromes in adolescents and young adults. Ann Med. 2014 Sep;46(6):353-63.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

At What Age Can Children Have Their Teeth Whitened?

Patient Presentation
A 10-year-old female came to clinic for her health supervision visit. She previously had some body image problems because she was overweight and when the nurse checked her in, she had told her that she doing “…lots of things to make me pretty” and had mentioned using dental whitening strips on her teeth. She was excited to discuss self-grooming activities including manicures, pedicures and coloring her hair, and said that she had started to do these things for about 6 months. During the physician interview she noted that she was exercising more, not drinking soda pop and trying to eat more fruits and vegetables. The physician determined that she did have a primary care dentist but had not seen her for more than 2 years. The patient denied any active bullying at school or elsewhere. The past medical history showed her being overweight or obese since age 3 years. The family history was positive for obesity and type II diabetes in the family. The review of systems was negative.

The pertinent physical exam showed her vital signs were normal and her BMI for age was >>95% but her weight gain had been less over the past year than previous years. HEENT showed slightly mid-aligned teeth that did not appear to be overly discolored. She had some intact dental restorations but no obvious active caries. She had a normal thyroid and no acanthosis nigricans on examination. The laboratory evaluation for obesity screening was normal including lipids, hemoglobin A1c, glucose, liver enzymes and thyroid testing. She had a normal hemoglobin also.

The diagnosis of an obese female who was making some lifestyle changes was made. The physician encouraged the lifestyle changes especially the increased exercise and changes in food intake. He encouraged her to not use carbonated beverages, teas and coffee that could potentially stain her teeth. “If your parents let you, I think doing the manicures and pedicures are just fine. Just don’t do real false nails because that can cause other problems like fungus infection or burns because of the nail products. The teeth whiteners I don’t think are a good thing for you too at your age. I don’t know that there is a specific age that is safe but your dentist could tell you and you are overdue see him or her now. Why don’t you stop using the whitening strips until you can talk with the dentist and then do what he or she says. Taking care of your teeth and your body are the best things you can do to keep your body healthy and your smile pretty. Just remember that its okay to want to look nice on the outside but what really counts is what is inside you. Your inner beauty is what really counts.”

Discussion
The appearance of the teeth and mouth is part of what determines facial attractiveness which plays an important part in social interactions. It has been found that “…an aesthetically pleasing smile…depend[s] on tooth color, size, shape, and position, upper lip position, visibility of the teeth and amount of gingival display.” The attractiveness is obviously complex, but tooth color is one of the most important factors and most people would like pearly white teeth.

Dental “…”whitening” is any process that will make teeth appear whiter.”
Non-bleaching products work to remove surface stains by physical or chemical action (usually dentifrices), and bleaching products which contain peroxide to remove surface or deep tooth stains. The bleaching products come in different forms including those placed into a tray around the teeth, painted on, or bleaching strips. The main bleaching products are hydrogen peroxide or carbamide peroxide (which breaks down into hydrogen peroxide and urea). Over the counter (OTC) bleaching agents often contain approximately 10% carbamide peroxide which is equivalent to ~3% hydrogen peroxide. OTC bleaching agents are intended to be used over 2-4 weeks for results and have a lower cost. There are professional products that are designed for home use with a dentist’s oversight with higher concentrations of bleaching agents. Professional products used in the dental office often have higher concentrations of hydrogen peroxide (25-40%) and can be completed in much less time (often 1 visit) but have a higher cost.

Peroxide is considered safe and effective in adults for tooth whitening but there is less data for children and adolescents.
There is at least 1 on-going, randomized clinical trial of dental bleaching in adolescents as of this writing. The most common side effects of dental bleaching are tooth sensitivity and tissue irritation especially in early treatment stages. These problems usually resolve with discontinuation of the product, often within 24 hours. Ill-fitting trays also can cause tissue irritation. Leakage around dental restorations or root problems (ankylosis and resorption) have also been noted. Use of at home products have the potential for abuse (used longer or more frequently than recommended) especially as it can be difficult for a parent to oversee the application.

Regularly scheduled dental examinations are always recommended as part of overall health. A dentist can help to evaluate any dental clinical concerns such as existing restorations, braces/appliances, and reasons for tooth discoloration. A dentist can provide the whitening treatment if recommended, or help to oversee a home treatment plan.

According to Lee et.al. in a 2005 review, conditions that should be resolved or considered before dental bleaching include:

“1. dry mouth;
2. enzymatic disorders;
3. respiratory or digestive tract disorders;
4. asthma;
5. allergy to vinyl;
6. hypersensitivity to hydrogen compounds;
7. mouth breathing;
8. unrestored tooth decay;
9. frankly exposed root surfaces;
10. broken teeth;
11. severe enamel erosion due to acidic or carbonated drink intake or gastric regurgitation (eg, bulimia);
12. parafunctional grinding;
13. poor oral hygiene.”

Learning Point
Tooth coloration is different in primary and permanent teeth because the dental enamel thickness is different.
The American Academy of Pediatric Dentistry says that full arch bleaching when a child has mixed dentitia is not recommended as this “…would result in mismatched dental appearance once the child is in the permanent dentitia.”

According to the 2005 Lee et.al. review, the authors recommend to avoid using home whitening treatment until patients are 14-15 years of age to avoid possible abuse of the products and potential toxicity. They recommend to use custom-fabricated dental trays to decrease the overall amount of product needed, and use < 0.5 gm of a 10% carbamide peroxide whitening gel for ~10 teeth.

Questions for Further Discussion
1. What causes tooth discoloration?
2. What are indications for dental consultation?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Cosmetic Dentistry

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Lee SS, Zhang W, Lee DH, Li Y. Tooth whitening in children and adolescents: a literature review. Pediatr Dent. 2005 Sep-Oct;27(5):362-8.

Donly KJ, Segura A, Sasa I, Perez E, Anastasia MK, Farrell S. A controlled clinical trial to evaluate the safety and whitening efficacy of a 9.5% hydrogen peroxide high-adhesion whitening strip in a teen population. Am J Dent. 2010 Oct;23(5):292-6.

Tin-Oo MM, Saddki N, Hassan N. Factors influencing patient satisfaction with dental appearance and treatments they desire to improve aesthetics. BMC Oral Health. 2011 Feb 23;11:6.

American Dental Association. Statement on the Safety and Effectiveness of Tooth Whitening Products. April 2012. Cited 1/19/16

Pinto MM, et.al.. Tooth whitening with hydrogen peroxide in adolescents: study protocol for a randomized controlled trial.
Trials. 2014 Oct 14;15:395.

American Academy of Pediatric Dentists. Policy on the Use of Dental Bleaching For Child and Adolescent Patients. Available from the Internet at http://www.aapd.org/media/Policies_Guidelines/P_Bleaching.pdf (rev. 2014, cited 1/19/16).

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

What Genetics are Associated with Multiple Sclerosis?

Patient Presentation
A 5-year-old female came to clinic for her health supervision visit. She was well and her mother had no concerns. During the interview the mother offered that she had been diagnosed with multiple sclerosis after having some fatigue and numbness with problems walking and some visual changes. She was taking medication and was in remission. The family history was positive for thyroid disease, diabetes, and stroke. There were no other neurological problems.

The pertinent physical exam showed a healthy female with normal vital signs and growth parameters around the 15-25%. Her examination, including her neurological examination, was normal. The diagnosis of a healthy 5 year old was made. The mother remarked that she was doing well but did worry about her daughter getting multiple sclerosis. “They don’t know what causes it but they do know somethings like it can be genetic, so we’re just going to have to keep monitoring her as she grows,” her mother said.

Discussion
Multiple sclerosis (MS) is “a chronic degenerative, often episodic disease of the central nervous system marked by patchy destruction of the myelin that surrounds and insulates nerve fibers, usually appearing in young adulthood and manifested by one or more mild to severe neural and muscular impairments, as spastic weakness in one or more limbs, local sensory losses, bladder dysfunction, or visual disturbances.”

It is a chronic disease and therefore symptoms must occur more than once. The first episode is called an acute demyelinating attack. Fifteen to forty-five percent of children with their first attack will go on to have others and therefore later be diagnosed with MS. Because pediatric patients have high relapse rates, diagnosis often is within a year of the initial clinical event. Historically the diagnosis required multiple attacks or evidence of new MRI lesions in different parts of the CNS. The 2010 revised MacDonald criteria can be used to diagnose MS with the first attack if specific criteria are met. The keys to the diagnosis of MS are that there needs to be evidence of inflammatory disease that is occurring in multiple CNS brain regions and overtime is disseminated.

“About 2-10% of patients with multiple sclerosis (MS) will have their first symptom before the age of 18 years. The majority of children presenting with the acute demyelination of the central nervous system manifest with acute visual loss (optic neuritis), limb weakness and bladder impairment (transverse myelitis), brainstem symptoms, or with a syndrome characterized by polyfocal deficits associated with encephalopathy (acute disseminated encephalomyelitis[ADEM]).” Children may have a difficult time describing their symptoms including sensory or visual changes and so it can be hard to diagnosis the initial event.

MS and ADEM are not the same but have some overlapping characteristics. “[MS] is a chronic inflammatory disease of the central nervous system (CNS) characterized by immune-mediated myelin loss with variable degrees of axonal injury. It is characterized by recurrent attacks of neurological dysfunction. Acute disseminated encephalitis (ADEM) is typically known as a monophasic inflammatory demyelinating disorder of the CNS usually following a viral infection. Complete recovery from ADEM is reported at 57 to 89%.”

Pediatric patients with MS tend to have cognitive deficits at the time of diagnosis which worsens over time. They tend not to have as many physical disabilities at onset, and actually have physical disabilities that are delayed about 20 years. However, the onset of physical disabilities is ~10 years before patients who are adults at onset. Pediatric patients also have high lesion volumes and high relapse rates.

There are several options for treatment of MS. For acute attacks, some children are just monitored closely. Others may receive intravenous steroid therapy and for those that have severe impairment, plasma exchange is considered. First line therapy is usually with interferon beta or glatiramer acetate. Unfortunately both are injectable and many children will not tolerate them. If patients do not respond or do not tolerate them, natalizumab or cyclophosphamide are considered. Teriflunomide and fingolimod are oral medications that are currently in clinical trials which include pediatric patients.

For healthy children of parents who have MS, a systemic review found conflicting data but several studies showed the children exhibited negative psychosocial traits when compared to children living with healthy parents. They also found that adolescents often necessarily had increased family responsibilities which were linked to higher stress and poorer social relationships. However these children and adolescents also had higher personal competence.

Learning Point
The cause of MS is unknown but certain genetic factors appear to be related although familial aggregation is not strong. Children with at least 1 HLA-DRB15 allele (one of the major histocompatability genes) have an increased risk of being diagnosed with MS. Some single nucleotide polymorphisms (SNPs) have also been associated. Vitamin D deficiency and exposure to different viruses also have been implicated. Epstein Barr virus serology from previous remote infection is found in 85-88% of pediatric MS patients. Cytomegalovirus exposure has a negative predictive association. Herpes simplex virus exposure does not increase risk, but in patients who are the HLA-DRB15 allele positive the risk increases.

Questions for Further Discussion
1. What are criteria for an acute demyelinating attack?
2. What are indications for brain imaging using computed tomography vs magnetic resonance imaging or positron emission tomography?
3. What are indications for consultation with a neurologist?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Multiple Sclerosis and Neuromuscular Disorders.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Alper G, Heyman R, Wang L. Multiple sclerosis and acute disseminated encephalomyelitis diagnosed in children after long-term follow-up: comparison of presenting features. Developmental medicine and child neurology. 2009;51(6):480-486. doi:10.1111/j.1469-8749.2008.03136.x.


Kornek B. Treatment of pediatric multiple sclerosis. Neuropediatrics. 2013 Dec;44(6):309-13.

Razaz N, Nourian R, Marrie RA, Boyce WT, Tremlett H. Children and adolescents adjustment to parental multiple sclerosis: a systematic review. BMC Neurol. 2014 May 19;14:107.

Waldman A, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M, Banwell B. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research. Lancet Neurol. 2014 Sep;13(9):936-48.

Online Mendelian Inheritance in Man. #142860 Major Histocompatibility Complex Class II, DR Alpha; HLA-DRA. Available from the Internet at http://omim.org/entry/142860 (rev. 12/11/14, cited 1/12/16).

Online Mendelian Inheritance in Man. #126200 Multiple Sclerosis, Susceptibility to; MS. Available from the Internet at http://omim.org/entry/126200 (rev. 11/18/14, cited 1/12/16).
Narula S, Banwell B. Treatment of multiple sclerosis in children and its challenges. Presse Med. 2015 Apr;44(4 Pt 2):e153-8.

Dictionary.com.
Available from the Internet at http://dictionary.reference.com/browse/multiple-sclerosis?s=t (cited 1/12/16).

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

What is the Recurrence Risk for Clostridium difficile Infection?

Patient Presentation
A 13-year-old male came to clinic with 1 week of non-bloody water diarrhea without mucous. The stools occurred 5-6 times per day and were of large amounts. The patient did not have bowel incontinence but noted that he was always knew where the bathroom was. He had mild abdominal pain that was associated with stooling. He did not have problems during sleep and was afebrile. He denied any recent travel, being around animals, ingesting unpasteurized foods, but did have a buffet style meal with his family. They did not have any problems. There were no specific ill contacts. He had taken antibiotics about 3 weeks prior to onset of diarrhea for a strep throat. The past medical history was non-contributory. The review of systems was negative for fever, chills, nausea, emesis, rash or cough. He denied any joint or muscle pain or eye changes. His mother thought that he had lost a little bit of weight but was eating, drinking and urinating well.

The pertinent physical exam showed normal vital signs but a 2 kilogram weight loss since his ill visit about 1 month ago.
His abdominal examination was negative including no hepatosplenomegaly. He had mild erythema of the perianal skin but no skin tags or fistula. There was no jaundice. The diagnosis of probable viral diarrhea was made but because of the prolonged course stool studies were done. The laboratory evaluation was positive for Clostridium difficile toxin. He was started on metronidazole and when the pediatrician contacted the family the mother asked how often this could recur. The pediatrician said he didn’t know exactly but it was unfortunately fairly common. He gave instructions about how to keep the patient hydrated and to call if the stooling did not stop or if the diarrhea recurred in the future.

Discussion
Clostridium difficile infection (CDI) is a common cause of nosocomial diarrhea.
Clostridium difficile is an obligate, anaerobic, gram-positive bacillus that is spore-forming and toxin producing. It is resistant to acid, heat, antibiotics and many antiseptic agents. Spores are acquired from the environment or by oral-fecal route. Once in the colon, the bacteria attach and proliferate making vegetative forms. Two main toxins are produced which disrupt the colonic integrity. Toxin A (TcdA) is an endotoxin that disrupts the mucosal cells. Toxin B (TcdB) is a cytotoxin that is 1000x more potent than TcdA and causes apoptosis. An inflammatory reaction occurs along with cell death.

There has been a significant increase in childhood CDI over the past 20 years. While this is mainly in the inpatient setting, community acquired CDI is also increasing, especially in patients without a history of antibiotic exposure who are young. The changing epidemiology is being attributed to the emergence of a more virulent strain called NAP1.

Risks for CDI include young age, antibiotic therapy (of all types), potentially proton-pump inhibitor therapy, instrumentation with feeding tubes, prolonged hospitalization, viral gastroenteritis and underlying medical problems such as an immunodeficiency state (e.g. neoplasia, transplant, HIV) and cystic fibrosis. Potentially other diseases have also been linked in small series.

Clinical manifestations include:

  • Asymptomatic colonization
    • Very common especially in infants < 12 months old and who may have up to 71% may be colonized
    • This decreases with age and in adults colonization is 5%
  • Mild-to-moderate diarrhea
    • Usually with 6 or less stools/day, without signs of systematic disease, usually afebrile
    • Uncomplicated course and recovery
  • Severe colitis
    • Usually > 6 stools/day, with signs of systematic disease such as fever, severe abdominal pain, azotemia, leukocytosis
    • Fulminant colitis
    • Multiorgan system dysfunction with shock, sepsis and potential death
    • Ileus or megacolon can occur and cause a paradoxical decrease in stool frequency
  • Other
    • Small bowel colitis
    • Arthritis
    • Potentially malabsorption or failure to thrive
    • Rectal prolapse
    • Hemolytic uremic syndrome

Because of the high rate of carriage, testing is not recommended in young children particularly those < 12 months. Cell-based cytotoxicity testing is the gold standard but is expensive. Testing can be done by enzyme immunoassay (EIA) and enzyme linked immunosorbent assay (ELISA) but there are problems with these tests in the pediatric population. Many hospitals are using polymerase chain reactions for diagnostic testing. Testing is not recommended for test of cure as toxin levels can remain for several weeks. Antibiotics are not used for asymptomatic patients. Metronidazole and vancomycin are commonly used antibiotics for mild to severe symptoms. Surgical interventions such as colectomy are sometime needed.

Prevention is through proper hand hygiene. Environmental surfaces must be cleaned with chlorine-containing or other sporicidal products.

Learning Point
First recurrence risk for CDI is 20-30% and second recurrence increases to 45%.

Questions for Further Discussion
1. What are the most common causes of acute diarrhea in your location?
2. What are the most common causes of bloody diarrhea?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Clostridium difficile Infections

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Pant C, Deshpande A, Altaf MA, Minocha A, Sferra TJ. Clostridium difficile infection in children: a comprehensive review. Curr Med Res Opin. 2013 Aug;29(8):967-84.

Sammons JS, Toltzis P, Zaoutis TE. Clostridium difficile Infection in children. JAMA Pediatr. 2013 Jun;167(6):567-73.

Schutze GE, Willoughby RE; Committee on Infectious Diseases; American Academy of Pediatrics. Clostridium difficile infection in infants and children. Pediatrics. 2013 Jan;131(1):196-200.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital