What is in the Differential Diagnosis of Fatigue?

Patient Presentation
A 14-year-old male came to clinic for advice about seasonal allergic rhinitis. It usually was controlled with daily cetirizine but he was having more rhinorrhea, sneezing and some coughing and his mother complained that he always seemed very tired. He had some itchy eyes but denied pain or fever. The cough was non-productive but he said he would cough up clear mucous that was just like his rhinorrhea. He had just started high school where he was taking advanced courses and was in several extracurricular activities. Over the summer he had been active but had not been training before also starting running with the cross-country running team. He said that he tried to go to bed at a consistent time, but that he was only getting around 7 hours of sleep a night. He was eating a fairly good diet. He denied feeling overwhelmed and loved his classes and activities. The past medical history showed mild intermittent asthma and seasonal allergic rhinitis.

The pertinent physical exam showed a generally well-appearing male with normal vital signs. He had a 1-pound weight gain since his well adolescent visit a month previously. He had mild tearing and allergic shiners by his eyes. His nose had boggy membranes with copious clear/white rhinorrhea that was also seen in the posterior pharynx. His lungs were clear. His skin was not dry nor had any rashes. The diagnosis of seasonal allergic rhinitis and fatigue due to multiple reasons was made. The physician recommended to increase the amount of cetirizine and also beginning a nasal steroid. “You should also keep your albuterol inhaler with you and if you have more coughing, you should try it. The cough may be because of your asthma, especially if it gets worse when you are exercising. I also want you to call me, if these medicines aren’t helping in 5-7 days. I have some other medicines which may help,” she offered. The physician also discussed with the adolescent ways he could prioritize consistent sleep in his schedule. “Taking your medicine, good sleep, good eating and drinking lots of fluids, and some healthy exercise usually improves your energy,” she said.

Discussion
Fatigue is a subjective feeling of decreased energy, tiredness or feeling of exhaustion. Lethargy is often used synonymously, but lethargy is a state of being drowsiness or sleepy, and implies mental status changes. Both can cause the person to be apathetic or less active.

Fatigue is a common state that almost everyone experiences multiple times in his or her lifetime. For most people it is a relatively acute or short-term chronic problem, often with a relatively easily identifiable problem cause, such as inadequate sleep, acute illness, or overexertion. For some, it can be less readily identifiable such as depression, anemia, or hypothyroidism or because of a chronic illness with its waxing and waning natural history or being under- or over-treated. Chronic fatigue and cause decreased quality of life, school or work problems, and depression.

It seems to many health care providers that adolescents and their parents complain about fatigue. This is not surprising as adolescents often do not get enough sleep, may be either overexerting themselves with activities or conversely be deconditioned because of little activity, be worried about school and other life issues, or not eat or drink consistently or are dieting. They may also be taking medications or drugs, have a chronic disease or are pregnant.

The keys to the evaluation of fatigue often lie in a detailed history and review of systems that can then guide laboratory evaluation and treatment. Laboratory testing can include a complete blood count, complete metabolic panel, thyroid function testing, erythrocyte sedimentation rate, and urinalysis. Other simple tests to consider include pregnancy test, Epstein Barr titers or monospot, rheumatoid factor, tuberculosis testing, and chest radiograph. Many other tests can also be ordered based on history and previous testing.

Other PediatricEducation.org cases of interest:

  • Health problems caused by inadequate sleep, found here.
  • Obesity, activity, and weight loss, found here and here.
  • Growth and pubertal development, found here.

Learning Point
The differential diagnosis of fatigue is enormous. Below are only some of the potential causes given as a framework when considering the individual patient’s story.

  • Overexertion
  • Deconditioning
  • Puberty
  • Sleep
    • Insufficient/deficit
    • Sleep disorders
      • Insomnia
      • Narcolepsy
      • Obstructive sleep apnea
  • Psychological/psychiatric
    • Boredom
    • Depression
    • Anxiety/stress/insecurity – worrier, bullying, self-esteem issues
    • School phobia
    • Normal quiet personality
  • Infections
    • Obvious – upper respiratory infection, streptococcal pharyngitis, pneumonia, gastroenteritis, etc..
    • Surreptitious – urinary tract infection, abscess, osteomyelitis, HIV, tuberculosis, parasites
    • Acute viral illnesses
      • Adenovirus
      • Epstein-Barr virus
      • Influenza
      • Lyme disease
      • Parvovirus
  • Medications and illicit drugs
    • Alcohol
    • Antidepressants
    • Antihistamines
  • Metabolic
    • Anemia
    • Abnormal diet or malnutrition
    • Hypoglycemia
    • Hyperammonemia
  • Obesity
  • Pregnancy
  • Chronic illnesses
    • Cardiovascular
      • Congenital heart disease
      • Acquired heart disease, e.g. endocarditis
    • Endocrine
      • Diabetes
      • Hypothyroidism
      • Hyperthyroidism
      • Addison disease
      • Cushing’s syndrome
    • Gastrointestinal
      • Crohn’s disease
      • Ulcerative colitis
      • Hepatitis or liver failure
    • Renal – renal insult or failure
    • Neurological/Genetic
      • Myasthenia gravis
      • Muscle weakness
      • Many other neurological or genetic problems
    • Miscellaneous
      • Chronic fatigue syndrome
      • Heavy metal intoxication
      • Pain, e.g. Fibromyalgia
    • Oncologic – malignancy
    • Respiratory
      • Allergies
      • Asthma – unrecognized or uncontrolled
      • Cystic fibrosis
    • Rheumatologic
      • Juvenile idiopathic arthritis
      • Dermatomyositis
      • Systemic lupus erythematosus

Questions for Further Discussion
1. How much cetirizine can be used for seasonal allergic rhinitis? To learn more click, here.
2. What is the definition of chronic fatigue syndrome?
3. What are indications for referral for a sleep study or sleep medicine specialist?

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: Fatigue.

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.

Illingworth RS. Common Symptoms of Disease in Children. Blackwell Scientific Publications: Oxford. 1988:42-45.

Fisher M. Fatigue in adolescents. J Pediatr Adolesc Gynecol. 2013 Oct;26(5):252-6.

Crichton A, Knight S, Oakley E, Babl FE, Anderson V. Fatigue in child chronic health conditions: a systematic review of assessment instruments. Pediatrics. 2015 Apr;135(4):e1015-31.

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

What Are Options for Acne Treatment?

Patient Presentation
A 14-year-old male came to clinic for his health maintenance evaluation. He was an avid athlete who had noticed an increasing amount of acne on his face. He was sporadically using an acne product but did not know what it was. He wasn’t being teased but did want some help to improve it. The past medical history was negative. The family history showed no dermatological problems. Both parents reported easily controlled acne as adolescents.

The pertinent physical exam showed a healthy male with normal vital signs. His height was 75% and his weight was 50%. He had an extensive amount of closed and open comedomes on his face along with moderate amounts of papules and pustules. He also had some closed and open comedomes on his upper back and chest. He did not have any scarring.

The diagnosis of a healthy male with moderate acne that was widespread on his face with affected areas on his trunk was made.
The pediatrician recommended he start a regimen of tretinoin and benzoyl peroxide. She said, “I want you to use tretinoin in the morning and the benzoyl peroxide at night. Each once a day but you can’t use them together because they interact. They can cause some dryness, so you can use a light moisturizer to help with that. They also can cause you to get sunburn so you should use a non-comedogenic sunscreen too everyday to help with this. Sometimes it says non-acne or something like that. Since you are an athlete and outside a lot, it is really, really important that you use the sunscreen. There are some other problems like bleaching of clothing and other fabrics with the benzoyl peroxide so I’ll go over that with you too and write everything down for you.” The pediatrician also said, “It’s going to take 2-3 months before you really see the results so don’t expect the acne to improve a lot overnight.”

Discussion
Acne vulgaris or acne is a problem of the pilosebaceous follicle. It occurs most prominently where sebaceous glands are abundant especially the face, neck, and upper back. Sebum production increases because of androgens. Keratin and sebum clog the pores of the pilosebaceous unit causing hyperkeratosis (clogged pilosebaceous unit = clogged pores = comedomes). Propionibacterium acnes, a gram-negative anaerobe, multiplies in the sebaceous unit causing an inflammatory reaction resulting in moderate or severe acne.

Skin lesions include:

  • Comedomal acne has comedomes
    • White heads = closed comedomes
    • Black heads = open comedomes
  • Inflammatory acne has papules and pustules
  • Nodulocystic acne has nodules and cysts

For each type, the density and extent of the lesions should be noted. Scarring presence or absence should be noted. Any scarring should be treated aggressively. Patients with cystic or scarring acne or who are difficult to treat should be referred to a dermatologist.

Some reasons for treatment failures include:

  • Lack of adherence is the most common reason for failure. Discussing with the patient what part(s) of the treatment regiment are not working and why can help adherence.
  • Unrealistic expectations – Need to follow the treatment for at least 2-3 months before effectiveness can be evaluated.
  • Irritation because of drying, itching, burning, etc. Check to make sure that patients are also not using other medications such as astringents, antibacterial soaps, scrubs etc. which can be drying or irritating.
    Options can include decreasing the frequency of the medications and/or adding a ceramide-containing moisturizer (such as CeraVe®) to help maintain the skin barrier.

Acne is the 8th most prevalent disease worldwide (9.4%). Peak incidence is late teens. Teen males are more likely to be affected than females and also to have more severe disease. Females are more common before and after adolescence. The mean duration is 2 years. Infantile acne, occurs in 1-12 month old infants and is usually inflammatory. Although there are no FDA approved medications for acne for children < 10 years, infants who need therapy are often treated with the same agents as moderate acne below. Mid-childhood acne occurs in 1-7 years old and is rare. A hyperandrogen state should be considered if acne is seen at this age. Preadolescent acne occurs in 7-11 year olds and is thought to be due to the onset of puberty. It is usually comedomal and is treated with the same medications as mild acne below.

Learning Point
Acne treatment for adolescent and adult patients is based on subtype, according to the American Academy of Dermatology. Check all dosing before prescribing. There are some other options that dermatologist also consider:

  • Mild acne, comedomal acne with few inflammatory lesions
    • Initial treatment:
      • Topical retinoid or benzoyl peroxide (BP)
        • Topical retinoid (also includes Adapalene, Tazarotene)
          • Tretinoin
            • Cream, gel, lotion, solution
            • Apply a thin film to affected area daily (at night) where lesions occur. Keep away from eyes, mouth, nasal creases and mucous membranes
            • Problems: dry skin, peeling, burning, erythema, pain, photosensitivity
            • Ultraviolet light and environmental exposure can increase irritation
            • Do not use at same time as BP as BP oxidizes tretinoin. Use one medication in am and one in pm.
            • Use sunscreen
        • Benzoyl peroxide
          • Dosing 2.5%, 5% or 10% gel, wash or cream
          • Applied 1-2x/day
          • Problems: hypersensitivity, erythema, peeling, bleaches clothing and fabric
    • Alternative:
      • Combination BP and topical retinoid
      • Combination BP and topical antibiotic
        • Erythromycin, topical
          • 2% solution, gel or ointment
          • Apply a thin film to affected area 1-2x/day
          • Problems: Do not use as monotherapy because of bacterial resistance, use with other agents, can cause irritation or drying
          • If using commercially precombined BP and Erythromycin, apply twice daily
        • Clindamycin, topical
          • 1% gel, lotion, solution, foam
          • Apply a thin film to area where acnes develops daily
          • If using commercially precombined BP and Clindamycin, apply daily at night
          • Problems: colitis, dermatitis, photosensitivity, redness, dry skin and peeling
      • Combination BP and topical retinoid and topical antibiotic

  • Moderate acne – comedomal acne with many inflammatory lesions
    • Initial treatment:
      • Combination BP and topical retinoid
      • Combination BP and topical antibiotic
      • Combination BP and topical retinoid and topical antibiotic
    • Inadequate response:
      • Consider dermatology referral
      • Combination BP and topical retinoid and topical antibiotic
      • Consider for females oral contraceptives
        • Oral contraceptive
          • Makes sure the patient also meets criteria for usage for contraception
          • Yaz®, Ortho Tri-Cyclen® and Estrostep® are FDA approved for acne
          • Problems include weight gain, nausea, emesis, headache, breast tenderness, increased risk of thromboembolic events
  • Severe acne – extensive inflammatory lesions with scarring
    • Initial treatment:
      • Consider dermatology referral
      • Combination with oral antibiotic and BP and topical retinoid
        • Oral antibiotics should not be used as monotherapy because of risk of resistance
        • Tetracycline, oral
          • > 8 year old: 25-50 mg/kg daily in 4 divided doses
          • Adults: 1 gram in divided doses until improvement 1-2 weeks later then decrease slowly to maintenance dosage of 125-500 mg daily
          • Problems: permanent discoloration of teeth in children < 8 years, gastrointestinal, renal, and hematological problems, rashes, photosensitivity
          • Sunscreen is recommended
        • Minocycline, oral
          • > 8 year old: 4 mg/kg initially followed by 2 mg/kg every 12 hours
          • Adults: 50 mg 1-3x/day
          • Problems: vertigo, dizziness and hyperpigmentation can occur along with other gastrointestinal, respiratory, renal, musculoskeletal, hematological, central nervous system problems, rashes, photosensitivity
        • Doxycycline, oral
          • > 8 years of age and < 100 pounds: 2 mg/pound of body weight divided into 2 doses on first day, followed by 1 mg/pound of body weight given as a single daily dose or divided into 2 doses on subsequent days
          • Adults and children > 100 pounds, 200 mg on first day (given as 100 mg every 12 hours x 2 doses), then 100 mg/day
          • Problems: gastrointestinal, renal and hematologic problems, rashes and photosensitivity
      • Combination with oral antibiotic and BP and topical retinoid and topical antibiotic
    • Inadequate response:
      • Consider dermatology referral
      • Consider isotretinoin
        • Isotretinoin
        • This is usually prescribed by a dermatologist
        • Is a known teratogen
      • Consider for females oral contraceptives

Questions for Further Discussion
1. What evaluation can be considered for a potential hyperandrogen state?
2. What are some of the mental health risks for a patient with scarring acne?
3. What else is in the differential diagnosis of acne?

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: Acne

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.

Admani S, Barrio VR. Evaluation and treatment of acne from infancy to preadolescence. Dermatol Ther. 2013 Nov-Dec;26(6):462-6.

Tan JK, Bhate K. A global perspective on the epidemiology of acne. Br J Dermatol. 2015 Jul;172 Suppl 1:3-12

Zaenglein AL, Pathy AL, Schlosser BJ, et. al.. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016 May;74(5):945-73.e33.

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

What Precautions Should A Childcare Center Take For A Child with Hepatitis C Infection?

Patient Presentation
A pediatrician got a phone call from a childcare center director regarding a preschool child with Hepatitis C infection. They had recently moved to the area and the child had not previously been in childcare. The parents had disclosed this information to the director and told her that they had been told that the child could safely attend childcare and only universal precautions needed to be followed for the child’s health and the health of the other children and childcare professionals. After receiving verbal permission from the parents, the director had placed a telephone call to the state childcare regulating agency to confirm any particular regulations the center needed to follow. While awaiting a response, she also contacted the pediatrician for guidance. The pediatrician reviewed the current American Academy of Pediatrics RedBook® recommendations which confirmed that the child could safely attend the childcare center, and that universal precautions should be used. Additionally the pediatrician noted, “That you already have policies and procedures in place for using gloves and other protective equipment for minor cuts or blood spills. You and the other people just need to follow them for this child just like you would for any other child.” Later, the pediatrician heard from the director that the state regulating agency also reiterated the same advice.

Discussion
It is estimated that 180 million people worldwide are infected with Hepatitis C (HCV) which includes ~11 million children. In the United States it is estimated that there were 30,500 acute HCV cases in 2014, and 2.7-3.9 million people with chronic HCV. Many infections are not identified. It is estimated that “…only 5-15% of HCV-infected children in the United States are identified.”

Problems associated with HCV include acute hepatitis (including fever, malaise, dark-urine, abdominal pain, jaundice, appetite loss, nausea, emesis, clay-colored stools), acute fulminant hepatitis (not common in children), hepatic fibrosis, hepatic cirrhosis, and hepatocellular carcinoma.
Vertical transmission (particularly with HIV-coinfected mothers), injection drug use and iatrogenic exposures (blood, blood product or solid organ recipients, blood exposures through needlesticks, tattooing, etc.) are the most common ways children and youth are infected. International adoptees, particularly from the high prevalence areas of Africa, China, Russia, Eastern Europe, and Southeast Asia, are also at risk. Sexual transmission between heterosexual partners has not been demonstrated in prospective studies. Transmission among family contacts is uncommon.

Acute symptoms can appear from 2-12 weeks (up to 24) weeks after infection. Clearing of the HCV infection does occur especially in infants and toddlers (clearing after age 3 with vertical transmission is uncommon), but 60-80% of pediatric infections persist. Being asymptomatic is the most common symptom with chronic HCV infection. Adult patients may only be recognized when they donate blood which is screened for HCV, or have elevated transaminases on routine testing. More serious problems with chronic HCV infection can occur decades after infection.

Liver disease and other problems progress more slowly in children than adults so only 1-2% of children will have cirrhosis. Factors for progression include being immunocompromised, obese, co-infected with HIV or Hepatitis B and probably other viral factors. For adults the numbers are not as good. According to the Centers for Disease Control in the United States:
“Of every 100 persons infected with HCV, approximately

  • 75-85 will go on to develop chronic infection
  • 60-70 will go on to develop chronic liver disease
  • 5-20 will go on to develop cirrhosis over a period of 20-30 years

    1-5 will die from the consequences of chronic infection (liver cancer or cirrhosis)”

    Diagnosis is made by being seropositive for anti-HCV IgG which is confirmed by polymerase chain reaction for HCV RNA. Genotyping is also helpful to guide treatment. Genotype 1 is most common. Other biomarkers are being evaluated to also help guide treatment such as possibly Vitamin D or single nucleotide polymorphisms. Treatment by an experienced team of specialists is recommended. Currently approved treatment includes interferon and ribaviran but these drugs have side effects. There are currently new treatment for adults (HCV protease, polymerase and NS5A inhibitors) that are more effective with fewer side effects and pediatric trials are ongoing in 2016 that researchers are hopeful will show that these drugs can be used in the pediatric population. Because of the slow progression in the pediatric age group, some patients are being carefully watched and not treated while awaiting the results of these new studies.

    Unfortunately good prevention techniques for vertical transmission are not available. There is no current vaccine or immunoglobulin such is used for Hepatitis B vertical transmission. Elective caesarean section does not appear to decrease the risk of transmission, but other interventions such as no scalp monitoring or amniocentesis may.

    Learning Point
    Health considerations for children with HCV include:

    • Post exposure prophylaxis with immunoglobulin is not recommended.
    • Exclusion from childcare attendance is not recommended.
    • General household contact is recommended as HCV is not transmitted by general contact such as sharing utensils, food/water, touching, etc. Infected children should not share nail clippers, razors, and toothbrushes. Transmission in saliva is low.
    • Universal precautions are recommended for minor cuts. Fresh or dried blood should be cleaned with 1 part bleach/10 parts water solution with protective gloves.
    • Breastfeeding by a HCV-positive mother is okay, but the mother should consider abstaining if nipples have sores or cracks.
    • Routine maternal testing while pregnant is not indicated.
    • Routine immunizations are indicated.
    • Sports and school participated are indicated.
    • Healthy behaviors should be encouraged including avoidance of alcohol, drugs, self-tattooing and piercing and multiple sexual partners.

    Questions for Further Discussion
    1. Why do health care providers not worry about Hepatitis D and E as much as A, B, and C?
    2. What precautions should be taken for people with active Hepatitis A or Hepatitis B?
    3. How is Hepatitis B prevented?

    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: Hepatitis C.

    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.

    Centers for Disease Control. Hepatitis C. Available from the Internet at: http://www.cdc.gov/hepatitis/HCV/index.htm (rev. May 31, 2015, cited 11/1/2016).

    Red Book® Online. Hepatitis C. American Academy of Pediatric Committee on Infectious Diseases. Kimberlin, DW, Brady MT, Jackson MA, Long SS. eds. 2015. Available from the Internet at http://redbook.solutions.aap.org/chapter.aspx?sectionid=88187160&bookid=1484 (cited 11/1/16).

    Pawlowska M, Domagalski K, Pniewska A, Smok B, Halota W, Tretyn A. What’s new in hepatitis C virus infections in children? World J Gastroenterol. 2015 Oct 14;21(38):10783-9.

    Lee CK, Jonas MM. Hepatitis C: Issues in Children. Gastroenterol Clin North Am. 2015 Dec;44(4):901-9.

    Ohmer S, Honegger J. New prospects for the treatment and prevention of hepatitis C in children. Curr Opin Pediatr. 2016 Feb;28(1):93-100.

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

  • Mid-Winter Break

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    We wish you a Happy New Year,
    Donna D’Alessandro and Michael D’Alessandro, curators.