What Are Common Drug Eruptions in Children?

Patient Presentation
A 4-year-old female came to clinic because of a rash for 24 hours. The pruritic rash began the evening before with a few red spots on her trunk. She had slept well, but this morning they were spreading and enlarging in size on her trunk, neck and extremities and did not seem to come and go. She also had a fever and her mother thought that she wasn’t moving as well and seemed to be sore. The patient had been started on cefaclor 9 days earlier for an ear infection and upper respiratory tract infection symptoms. She had previously taken penicillins and cephalosporin antibiotics without any problems. Her mother denied any new soaps/lotions/detergents, exposure to streptococcus, lice, scabies, pets or any travel. Her mother denied any difficulties breathing or eating, abnormal movements or mentation and she was urinating and stooling normally. The past medical history showed a relatively well child who had minor infections.

The pertinent physical exam showed a mildly ill child who was itching the rash. Her vital signs were normal except for a temperature of 100.9°F. Her growth parameters were 10-25%. HEENT showed no conjunctivitis, mild rhinorrhea, and right serous otitis media. Oral mucosa was normal. Her lungs were clear and she had a normal heart and abdomen examination. Her extremities showed swelling and mild warmth without erythema of both elbows and knees. She had decreased range of motion in those joints because of pain and also of her right ankle but there was no obvious swelling of the ankle. Her skin examination showed mainly macules that were 0.5-2 cm in size that were distributed mainly on her trunk and the proximal parts of her upper and lower extremities. It also extended up to her hairline on the back of her neck. Her palms and soles were spared. The many lesions were coalesced and they had a dusky/purplish color but blanched. None were pustular or vesicular. There were no petechiae and she had some regular bruising on her shins that was distinctly different than the rash.

The pediatrician considered the diagnoses of a general viral exantham, streptococcal skin rash and/or rheumatic fever, Henoch-Schonlein purpura, and a drug reaction such as urticaria multiforme, and serum sickness like reaction (SSLR). The first 3 seemed unlikely given the history and the patient also did not meet criteria for Kawasaki Disease and did not appear to have a sepsis-like presentation of meningococcemia. It was felt that this was most likely a drug reaction with SSLR being the most likely cause especially as the patient was taking cefaclor. The pediatrician discussed the patient by telephone with an infectious disease expert who agreed that it sounded most like SSLR. The laboratory evaluation showed a normal complete blood count, rapid strep testing was negative, and compliments and anti-streptolysin O titres were negative. Her erythrocyte sedimentation rate was 21 mm/hr (normal < 20) and C-reactive protein was 5.5 (upper limit of normal). The patient’s clinical course had her stopping the medication, using antihistamines for pruritis, acetaminophen for fever and starting her on prednisone for the SSLR to be tapered over the next 10 days. At 2 day follow up her arthritis and fever had resolved as had some of the rash. At phone followup 1 week later the patient had complete resolution of her symptoms.

Discussion
Drug reactions unfortunately are common in children and adults. These reactions have different but often overlapping appearances. Viral exanthams also often cloud the picture as these rashes can be because of the drug, the virus or both.

Patients with urticaria multiforme present with an acute rash that appears as urticaria plaques that have a hemorrhagic or dusky discoloration. It occurs 1-3 days after viral symptoms (including cough, rhinorrhea, diarrhea) and may also present with fever.

Morbilliform drug eruptions one of the most common drug reactions in children and usually occur 7-14 days after the onset of the medication, often amoxicillin. The rash is small, pink or red macules and papules that are diffuse and may coalesce. The rash can get worse with viral syndrome and can be mistaken for a viral exanthams, allergic exanthams or contact dermatitis. The rash usually improves in a few days.

Fixed drug eruptions occur 7-14 days after exposure to a drug including sulfa, acetaminophen, and common antihistamines. The rash may come and go but is in the same “fixed” spot usually as opposed to true urticaria which comes and go. The rash is erythematous patches or plaques that are round or oval with a central purple or dusky discoloration. They can last for weeks and may leave temporary hypo- or hyperpigmentation.

Acute generalized exanthematous pustulosis occurs 1-14 days after drug exposure with pruritis and tiny sterile non-follicular pustules. Fever may also occur. The pustules are sterile and not follicular. It occurs more often in adults but can occur with children. It usually resolves in 1-2 weeks after stopping the medication, often antibiotics, or resolution of a viral illness.

True serum sickness is a type III hypersensitivity reaction to medications that results in circulating immune complexes that cause complement activation, which then leads to systemic inflammation and immune complex deposition within tissues particularly in the kidneys. Historically the reaction was caused by horse or rabbit antiserum.

Learning Point
Serum-sickness like reaction (SSLR) is similar to true serum sickness but is clinically distinct. The cause is unknown but it is hypothesized that medication metabolites may have a direct effect on tissues. SSLR does not cause circulating or deposition of immune complexes. SSLR is known to be caused by many medications particularly cefaclor but also cefuroxime, bupropion, griseofulvin and minocycline. It typically occurs 7-21 days after exposure.

SSLR has a rash, fever and at least arthritis without evidence of systemic or cutaneous vasculitis. The rash of SSLR is urticarial or morbilliform with annular plaques or patches with a central dusky or purple discoloration. Arthralgia can occur alone or arthritis with mild or significant edema of the joints can be seen. Lymphadenopathy can also be a component of SSLR.

SSLR treatment is stopping the medication and oral antihistamines for pruritis and antipyretics for fever. Oral corticosteroids are used for severe cases particularly those with arthralgias and/or edema. Improvement after stopping the medication is usually seen within a few days to week but may take longer.

Questions for Further Discussion
1. What is the difference between the drug reactions above and drug hypersensitivity reactions?
2. What are criteria for labeling a patient as drug sensitive or drug allergic?

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: Drug Reactions

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.

Newell BD, Horii KA. Cutaneous drug reactions in children. Pediatr Ann. 2010 Oct;39(10):618-25.

Tolpinrud WL, Bunick CG, King BA. Serum sickness-like reaction: histopathology and case report. J Am Acad Dermatol. 2011 Sep;65(3):e83-5.

Mathur AN, Mathes EF. Urticaria mimickers in children. Dermatol Ther. 2013 Nov-Dec;26(6):467-75.

Author

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

What Health Problems are Caused by Inadequate Sleep?

Patient Presentation
A 16-year-old male came to clinic for his health supervision visit. He said he was a good student receiving A’s and B’s in accelerated classes. He also played basketball and baseball and participated in other outside activities. He reported no health problems but said that he often went to sleep between midnight and 1 AM because of needing to finish his homework. He got up at 6:30 AM to be able to start school at 8 AM. He said on the weekends he would try to sleep later but even then it was difficult because of weekend activities. The past medical history showed a sprained ankle and overuse shoulder injury in the past two years. The family history was negative for any sleep disorders including obstructive sleep apnea.

The pertinent physical exam showed a healthy male with growth parameters in the 50 to 75th percentile. The rest of his physical examination was normal. The diagnosis of a healthy male with sleep deprivation was made. The pediatrician discussed with the patient and his father some of the difficulties of not having enough sleep and provided more information about sleep hygiene. The pediatrician emphasized that inadequate sleep had negative effects on academic achievement and had increased accident risks especially when operating an automobile.

Discussion
In humans, sleep is regulated by two systems. The first is the homeostatic sleep drive which assumes that the longer the person is awake the more pressure there is to fall asleep. The second process is the circadian system which controls periods of activity and inactivity throughout the day. The circadian rhythm is slightly longer than 24 hours in humans and is controlled by the hypothalmic suprachiasmatic nucleus. When the circadian system and the external environment are misaligned, such that sleep occurs outside of normal times, a circadian rhythm sleep disorder can occur.

During adolescence, there is a normal physiologic change of the homeostatic and circadian systems such that there is a shift to a later sleep phase for adolescents. Adolescents also commonly have inadequate sleep that occurs on an ongoing basis because of societal norms. These adolescents normally have sleep onset later but need to get up in the morning for school and other activities resulting in inadequate sleep amount. Adolescents, if left alone without external influences, will sleep slightly more than 9 hours. However, 45% of adolescents sleep < 8 hours and 31% sleep between 8-9 hours on school nights. Adolescents may "catch-up" their sleep on the weekends, but the problems of inadequate sleep during the school week may not be mitigated with the additional weekend sleep.

Adolescents in addition to the normal physiologic change can have circadian rhythm sleep disorders. Delayed sleep phase disorder (DSPD) is the most common in this group a the prevalence of 7-16%. DSPD delays sleep onset by 3 to 4 hours compared to usual normative evening time (i.e. 10-11 PM). If left alone, the sleep is normal in quality and duration. Sleep wakening is then necessarily delayed causing problems with social needs (e.g. not getting up in time to go to school). The adolescent then has inadequate sleep which then leads to poor sleep hygiene which helps to change the intrinsic circadian rhythm which continues to cause the delayed sleep onset. Overtime, DSPD develops. DSPD is treated using good sleep hygiene but other interventions may be necessary.

  • Chronotherapy delays sleep onset progressively over several days until the normal sleep onset time is achieved and then anchors that new time with post-sleep morning light.
    Light therapy especially in the morning can be helpful.

  • Light in the evening delays sleep onset and light in the morning advances it (i.e. makes it earlier in the evening the next night). Light intensity between 2500-10000 lux will advance circadian rhythms.
  • Melatonin is a chronobiotic that can be used to help sleep onset. Melatonin is given ~5 hours before desired sleep onset. Once consistent sleep onset is achieved, a smaller dose given 2 hours before desired sleep onset helps to establish the circadian pattern.

The opposite of DSPD can occur called advanced sleep phase disorder. It is not common in adolescence. The sleep onset occurs early in the evening despite trying to stay awake until normal times with typical wakening in the early AM (e.g. between 2 and 5 AM).

Good sleep hygiene includes:

  • Consistent sleep onset and waking times
  • Limited caffeine and food in the evenings before bedtime
  • Limited exercise before bedtime
  • Limited computer, television and other screen time to limit evening light exposure
  • Bed and bedroom with comfortable temperature, no or low level lighting. Bed not used for activities associated with mental alertness such as homework, electronic screens, etc.

Psychophysiologic insomnia is a sleep-onset disorder and is not a circadian rhythm sleep disorder.

Learning Point
Overall, good sleep amounts and patterns have positive health benefits while poor sleep amounts and patterns have negative health benefits. Many of these problems are dose response related and can be reciprocal. For example inadequate sleep can lead to depressive symptoms and depressive symptoms can lead to poor sleep.
Problems associated with inadequate sleep include:

  • Mental health
    • Anxiety
    • Attention problems
    • Depression (strongly associated with poor sleep)
    • Suicidal ideation
    • Poor perceived mental health
    • Poor perceived physical health
    • Low self esteem
    • Poor psychosocial functioning
    • Fatigue and tiredness
  • Physical health
    • Pain (in females only)
    • Cardiovascular problems
    • Cardiometabolic problems
    • Overweight and obesity
  • Health risks
    • Accidents and injuries particularly automobile accidents
    • Aggression (being in fights, weapons carrying, etc.)
    • Use of cigarettes, alcohol and drugs
    • Unprotected sexual activity
  • Occupational
    • Poor academic achievement (especially in older adolescents)

Questions for Further Discussion
1. How is psychophysiological insomnia diagnosed and treated?
2. What are indications for referral to a sleep medicine specialist?
3. What are other sleep disorders and how are they defined?

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: Sleep 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.

Bartlett DJ, Biggs SN, Armstrong SM. Circadian rhythm disorders among adolescents: assessment and treatment options. Med J Aust. 2013 Oct 21;199(8):S16-20.

Reiter J, Rosen D. The diagnosis and management of common sleep disorders in adolescents. Curr Opin Pediatr. 2014 Aug;26(4):407-12.

Shochat T, Cohen-Zion M, Tzischinsky O. Functional consequences of inadequate sleep in adolescents: a systematic review. Sleep Med Rev. 2014 Feb;18(1):75-87.

Author

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

Are These Abscesses?

Patient Presentation
A 35-day-old female came to clinic with a one-day history of two new lesions in her diaper area. The first lesion located near her right labia began 4 days ago and had not changed according to the mother. Last night a second lesion appeared in her left inguinal crease. Initially it was red and swollen but became bluish overtime. The lesions did not appear to cause pain, nor had spreading redness or warmth in this area. Her mother stated that she was otherwise well with no fever orrash and she was feeding, urinating, and stooling well. The mother denied her being around other people that were sick including herself. Her mother denied any open skin lesions nor herpetic ulcers. The past medical history showed a full term infant born by NSVD who went home from the hospital on time. She had been gaining weight well and had been examined for her 1 month check 1 week earlier. The family history was not contributory. The review of systems was negative.

The pertinent physical exam showed of a smiling infant in no distress. Her vital signs were normal including being afebrile. Her growth parameters were 75th to 90th percentile for age. HEENT examination was normal including a flat fontanelle. Her heart, lungs, abdomen, and musculoskeletal examinations were normal. Her genitourinary examination revealed two masses. The first was in the left inguinal crease that was 13 x 7 mm in size. It was purple red in color with no surrounding erythema or edema of the surrounding skin or structures. It was firm but mobile. The second lesion was at the confluence of the right external labia, perineum and leg crease. It was 10 mm x 5 mm with the longitudinal axis oriented parallel with the spine. An area of approximately 5 mm was able to be seen on the perineum that was also purple red in color and there was no surrounding erythema or edema or warmth. From the caudal end, a thread-like structure was possibly palpated. Because of the location and the unusual coloring, the pediatrician considered that these could be abscesses with or without a fistula in the perineal mass or lymph node abscesses. Much less likely was aberrant testes in a phenotypic female or an unusual presentation of a metastatic cancer.

The radiologic evaluation of an ultrasound was performed and confirmed that these masseswere abscesses. The patient was referred to surgery who drained the abscesses of a small amount of purulent material. The patient was placed on amoxicillin-clavulanic acid oral antibiotic. The patient’s clinical course over the next two days showed that the patient remained afebrile and had no obvious discomfort. The abscesses were markedly decreased in size. Laboratory testing at that time showed methicillin-resistant Staphylococcus aureus (MRSA). She was to follow up again in one more week.

Discussion
Staphylococcus aureus is a gram-positive, catalase-positive coccal bacterium that is found on the skin and respiratory tract. It is the most common cause of skin and soft tissue abscesses. Staphylococcus can also cause enteritis, pneumonia, and toxic shock syndrome. In addition to abscesses, Staphylococcus can cause pustulosis, cellulitis, necrotizing fascitis and other exfoliative skin disease such as bullous impetigo.

Staphylococcus is well-known to colonize the human skin, nail and nares. It is spread by physical contact and aerosolization. Skin breaches allow Staphylococcus to enter the body and to disseminate by hematogenous spread in as little as 1-3 hours. The host immune defenses may clear the bacteremia or Staphylococcus may provoke disseminated disease including sepsis, multiorgan system failure or distant abscesses. Local skin disruption may also cause localized skin disease without bacteremia or dissemination.

To review stages of Staphylococcus abscess formation see To Learn More below.

Learning Point
In the study of afebrile neonates presenting to two emergency rooms with skin and soft tissue infections, 104 infants were evaluated out of > 120,000 emergency department visits. Pustulosis was most common in the genitourinary areas and abscesses were commonly found on the buttocks. All of these patients did not have bacteremia or other serious bacterial infection. When looking at the types of evaluations and treatments the patients received, neonates with abscesses were treated with antibiotics 59% of the time and were admitted to the hospital 55% of the time. Compared to pustulosis and cellulitis, neonates with abscesses had the most variation in evaluation and treatment, as patients with pustolosis generally were less aggressively evaluated and treated and patients with cellulitis were more aggressively evaluated and treated. All patients did well upon discharge.

In another study evaluating methicillin-resistant Staphylococcus in children with superficial genitourinary abscesses, found that MRSA was more common in the groin and external genitalia similar to the patient presented. Their patients ranged in age from 29 days to 17 years with the median age of three years. Young infants were not characterized more specifically. All patients were treated with routine incision and drainage of the abscesses and did well.

There are case reports of neonatal cold abscesses of the large folds of the body caused by Staphylococcus. In 2006, three patients were described that had multiple cold abscesses due to Staphylococcus. The locations were the axillary folds, inguinal folds, supraclavicular fossa, submandibular area, and umbilicus. All of these patients were well, without fever, and had none or very slight surrounding inflammation. All grew MSSA (methicillin sensitive Staphylococcus aureus). All were treated with incision and drainage and antibiotics and did well. The mode of dissemination was unclear but could have been direct invasion of the skin in that location or transitory bacteremia that was controlled by the neonate’s immune system. The patient presented above is similar in that she was a full term infant without any systemic findings and without a specific source of infection. She however had MRSA instead of MSSA.

Questions for Further Discussion
1. What organisms commonly cause cold abscesses?
2. What are indications for an immune evaluation? Click here for more information.
3. What are risk factors for methicillin-resistent Staphylococcal aureus (MRSA)?

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: Staphylococcal Infections and Abscess.

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.

Huber F, Leaute-Labreze C, Lina G, Sarlangue J, Taieb A, Boralevi F. Multiple neonatal staphylococcal cold abscesses of the large folds. J Eur Acad Dermatol Venereol. 2006 Nov;20(10):1197-200.

Alt AL, Routh JC, Ashley RA, Boyce TG, Kramer SA. Superficial genitourinary abscesses in children: emergence of methicillin resistant Staphylococcus aureus. J Urol. 2008 Oct;180(4):1472-5.

Cheng AG, DeDent AC, Schneewind O, Missiakas D. A play in four acts: Staphylococcus aureus abscess formation. Trends Microbiol. 2011 May;19(5):225-32.

Kharazmi SA, Hirsh DA, Simon HK, Jain S. Management of afebrile neonates with skin and soft tissue infections in the pediatric emergency department. Pediatr Emerg Care. 2012 Oct;28(10):1013-6.

Author

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

How Effective is Inactivated Hepatitis A Vaccine?

Patient Presentation
A mother of two school aged children called because she was worried that they had consumed contaminated strawberries at their elementary school in their school lunch. There had been a recent outbreak in another state of Hepatitis A contaminated strawberries. The strawberries had been mislabeled as being manufactured in the US when they had been produced in Mexico. The outbreak in the other state had caused 150 cases of Hepatitis A disease. In the mother’s state, the strawberries had been distributed to various schools but it was unclear if any had actually been served to students and there had been no reported disease cases. It was unclear if the patients had even eaten any strawberries of any type at their own school. The patients were asymptomatic, healthy and fully immunized.

The diagnosis of an unlikely exposure to Hepatitis A was made. The state Department of Health was recommending immunoglobulin only for specific high-risk populations at that time and these children were not high risk. Therefore there was nothing specific to do but to monitor the children. Since this time period, recommendations for post-exposure prophylaxis to Hepatitis A have changed to include active vaccination.

Discussion
In 1997, 150 cases of Hepatitis A (HAV) were reported in Michigan from contaminated strawberries. The strawberries were produced in Mexico and distributed to the US Department of Agriculture sponsored school lunch programs in six states. Most of the containers were not served to students and the majority of cases occurred in Michigan only.

HAV is an RNA virus of the picornavirus family. The virus is spread mainly by fecal-oral contamination and contaminated food and water supplies. The incubation period is 15 to 50 days. The average is 28 days. Patients are most infectious during the one to two weeks before onset of jaundice or elevation of liver enzymes and risk of spread to others is minimal by one week after the onset of jaundice.

HAV is a self-limited illness whose symptoms usually include fever, jaundice, anorexia, nausea, and malaise. Risk factors include close personal contact or exposure to persons with HAV, child in a day care center where a case has been report, international adoptee, men who have sex with men, and use of illegal drugs and of course, food borne exposure. In approximately 2/3 of cases, the source cannot be determined.

In areas of the world where HAV is endemic, young children who acquire the disease early in life are usually asymptomatic. In areas of the world where the virus is not endemic, disease is acquired much later in life and is symptomatic. Endemicity rates are highly correlated to socioeconomic status and clean water supplies.

Because it can be difficult to distinguish HAV from other hepatitides, testing for anti-HAV is recommended. Anti-HAV IgM occurs without 2 weeks of infection and IgG occurs generally after that time.

Treatment is symptomatic with rest and good nutritional support. Fulminant hepatitis is rare but can require emergency liver transplantation. Post-exposure prophylaxis at the time of this case was to treat specific high-risk patients with immunoglobulin. Since that time the recommendations have changed and HAV vaccine is given to patients within one to two weeks of exposure. Benefit of HAV vaccine after this time has not been clearly determined. Since 2006, the United States universal HAV vaccination of the pediatric population has been recommended at after 12 months of age with 2 doses of inactivated vaccine.

Prior to licensing of the inactivated vaccine in 1995, approximately 100 deaths in the United States occurred per year because of Hepatitis A, but has markedly decreased since.

In areas of the world where HAV is endemic, HAV vaccination is usually not given because of the cost-benefit ratio. In areas where HAV is not endemic such as high socioeconomic countries, HAV vaccine is recommended. In mixed endemic areas, the vaccine is generally recommended, but cost may be a limiting factor in certain countries or circumstances globally.

Learning Point
HAV vaccine is highly immunogenic.
After the first vaccine, antibodies are detected by two weeks with 95% of healthy individuals having protective antibody concentrations at one month post-vaccination. After the second dose, 99-100% of patients have protective antibody concentrations. The protection duration is felt to be at least 15 years or more, and many scientists feel that the vaccination may offer lifetime community. The adverse effects are usually mild local pain or even less commonly, induration of the injection site.

Questions for Further Discussion
1. Is Hepatitis A vaccine given locally and why?
2. In an unimmunized individual who is traveling to an endemic area, when should Hepatitis A vaccine be given?
3. How are exposures of food handlers treated?

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 A

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.

Hepatitis A Associated with Consumption of Frozen Strawberries — Michigan, March 1997. MMWR. April 4, 1997. 46 (13);288, 295.

Jacobsen KH, Wiersma ST. Hepatitis A virus seroprevalence by age and world region, 1990 and 2005. Vaccine. 2010 Sep 24;28(41):6653-7.

Ott JJ, Irving G, Wiersma ST. Long-term protective effects of hepatitis A vaccines. A systematic review. Vaccine. 2012 Dec 17;31(1):3-11.

Matheny SC, Kingery JE. Hepatitis A. Am Fam Physician. 2012 Dec 1;86(11):1027-34; quiz 1010-2.

American Academy of Pediatrics. Hepatitis A, In Pickering LD, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th edit. Elk Grove Village, IL: American Academy of Pediatrics; 2012;361-369.

Author

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