How Effective is Oseltamivir?

Patient Presentation
A 2-year-old male came to clinic with a 24 hour history of fever to 102-103°, rhinorrhea, cough and what his parents believe were muscle aches. There was no nausea, emesis or rash. He was drinking but not eating solid foods and was urinating well. He had received acetaminophen for his fever and discomfort with symptomatic relief. He had received a seasonal influenza vaccine 3 months prior to the visit. Influenza was circulating in the community and he had a known exposure to influenza at his daycare. Additionally there was a 2-month old sibling at home. The past medical history was positive for 3 otitis media episodes in the past.

The pertinent physical exam showed a tired, sick appearing male. His temperature was 38.5°C. His respiratory rate was 36 without increased work of breathing. His oxygen saturation was 95% on room air. The rest of his vital signs were normal with growth parameters in the 75-95%. He had copious clear rhinorrhea and tearing with some mild conjunctival injection. His mouth and ears were normal. His lungs were clear. There were no rashes. He complained of muscle aches with palpation of his arms and legs but did not appear to have any joint involvement. The rest of his examination was normal. The diagnosis of presumed influenza was made. He was started on oseltamivir for treatment. His parents had also received a seasonal influenza vaccine and they contacted their own physicians and received prophylactic oseltamivir. At followup for a health maintenance visit for the sibling the following week, the mother said that the infant did not develop influenza.

Discussion
Oseltamivir (Tamiflu®) is an oral neuraminidase inhibitor of influenza viruses types A and B. It first came on the market in Switzerland in 1999 and currently is used around the world along with other neuraminidase inhibitors to treat seasonal and pandemic influenza.

Oseltamivir is easily absorbed from the gastrointestinal tract, and circulates to the liver where it is converted to its active metabolite oseltamivir carboxylate (OC). In adults approximately 75% of the oral medication is converted and it then travels to the upper and lower respiratory tracts. Unchanged oseltamivir is eliminated in the urine. OC “inhibits the conserved active site of the neuraminidase enzymes that are present as major surface antigens on all types of influenza viruses. As neuraminidase is essential for the release of progency virions from infected cells, inhibiting this enzyme limits the duration and severity of the infection.” OC half-life is about 1-2 hours and the maximal concentrations occur ~ 3-4 hours after administration. Children < 12 years of age clear OC faster than teenagers and adults resulting in a lower drug exposure.

Oseltamivir is approved for use for treatment of uncomplicated influenza especially for those at increased risk such as infants, pregnant women and those with chronic cardiac, respiratory or metabolic problems, for severe or progressive influenza, and for those that are immunosuppressed. It can also be used for post-exposure prophylaxis. Oseltamivir can be used more than once during the season and has been used for seasonal prophylaxis particularly in institutional settings such as nursing homes. If resistance to oseltamivir is known (such as the H275Y mutation in season H1N1 viral strains) then other neuraminidase inhibitors such as zanamivir are recommended.

The most common side effects in children are nausea and vomiting. Neuropsychiatric symptoms that have been reported with use of oseltamivir include mental status changes, agitation, anxiety, confusion, delusions, hallucinations and nightmares. It is not clear why these symptoms may occur as oseltamivir does not cross the blood-brain barrier to any appreciable extent.

One study estimated the cost-effectiveness of different treatment strategies using oseltamivir for uncomplicated seasonal influenza in unimmunized patients 1-17 years. Empirically treatment was more cost effective than testing and then treating. Both empiric treatment or testing and then treating were more cost effective than no treatment. However, the cost effectiveness was very sensitive to the prevalence of oseltamivir-resistant strains that are circulating.

Of course, oseltamivir is not a substitution for receiving the seasonal influenza vaccine. Treatment recommendations or prophylaxis are always changing because of the changes in the influenza virus and its epidemiology. Health professionals should follow current recommendations from public health authorities.

Learning Point
The burden of influenza is often not apparent to many individuals. In the United States, up to 20% of the population develop influenza each year, deaths occur in 36,000-49,000 people, and ~250,000 require hospitalizations for complications such as pneumonia. Some strains have higher morbidity and mortality. For example, children and young adults had higher morbidity and mortality during the 2009-2010 H1N1 pandemic. The Avian H5N1 strain are more virulent than seasonal strains and have mortality rates >50%.

A 2014 Cochrane Review of the effectiveness of oseltamivir treatment included 107 clinical studies and 73 trials and found:

For treatment of symptomatic patients, time to first symptom alleviation was reduced by 16.8 hours or from 7 to 6.3 days. In children the reduction was 29 hours. There was no change for asthmatic children. In children there was no significant effect on hospitalizations. There also were no significant reduction in serious complications or in hospitalizations, but there are problems with the data because of lack of diagnostic definitions. Oseltamivir did reduce the risk of symptomatic influenza for individuals or households for those who used it for prophylaxis.

Questions for Further Discussion
1. What is the cost of oseltamivir in your local area?
2. What other neuraminidase inhibitors do you have available in your local area?
3. What is the rate of season influenza vaccination in your own practice?

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: Flu and Flu Shot.

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.

Smith JR, Rayner CR, Donner B, et. al. Oseltamivir in seasonal, pandemic, and avian influenza: a comprehensive review of 10-years clinical experience. Adv Ther. 2011 Nov;28(11):927-59.

Lavelle TA, Uyeki TM, Prosser LA. Cost-effectiveness of oseltamivir treatment for children with uncomplicated seasonal influenza. J Pediatr. 2012 Jan;160(1):67-73.e6.

Jefferson T, Jones MA, Doshi P, et. al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2014 Apr 10;4:CD008965.

Centers for Disease Control. Estimating Seasonal Influenza-Associated Deaths in the United States: CDC Study Confirms Variability of Flu.
Available from the Internet at http://www.cdc.gov/flu/about/disease/us_flu-related_deaths.htm (rev. 3/18/16, cited 5/24/16).

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

In Klinefelter Syndrome Patients, What are the Common Behavioral Problems?

Patient Presentation
A 17-year-old male with known Klinefelter syndrome (KS) came to clinic for his health supervision visit. He had his attention deficit disordertreated with a stable amount of long-acting methylphenidate with good response and few side effects. He was entering his high school senior year and was doing fairly well in school with some extra time and help with reading skills. He had some friends who liked to play pickup basketball. The past medical history revealed he had been diagnosed 15 months before because of tall stature, small testes and lack of androgen pubertal changes. He was being followed by endocrinology for testosterone treatment. He had received speech therapy when he was younger and always had struggled with reading skills. The family history was positive for diabetes mellitus. The review of systems was negative.

The pertinent physical exam showed a tall male who spoke softly. His height was 185 cm (90%), weight was 90 kg (~95%) and BMI of 26.3 (85-95%) for age. He was Tanner 3 for pubic hair and had a small phallus and small testes. The rest of his examination was negative. The diagnosis of a healthy male with Klinefelter syndrome was made. As the resident and his attending physician had discussed some of the potential needs of the patient before his visit, the resident re-ordered his medications and emphasized that he should continue exercising and eating right to help with his weight. The patient had earlier noted that he wanted to go to college after high school and the resident said that it was very common for people with Klinefelter syndrome to have some academic problems and maybe the patient would benefit from formal testing so that he could get the appropriate help for school and college. The patient and resident discussed this with his mother who also thought this was a good suggestion and a referral for neuropsychiatric/educational testing was made.

Discussion
Klinefelter syndrome (KS) is a common genetic abnormaly with a prevalence of 1 in ~650 male births. It was first described in 1942 by Dr. Harry Klinefelter. It is associated with at least one extra X chromosome with the most common karyotype (~80% of patients) being 47 XXY. Other karyotypes are seen along with mosaicism. It is believed that although it is very prevalent, only about 25-33% of people with KS are identified. About 10% are identified before puberty with the rest usually identified because of hypogonadism and tall stature especially in teenage years or due to infertility in adulthood. KS is diagnosed by karyotype.

The phenotype varies but most commonly is associated with hypogonadotropic hypogonadism, infertility, gynecomastia and tall stature. The tall stature is remarkable for a lower segment > upper segment body habitus which can be noted after age 5 years. It is felt that the SHOX gene located on the X chromosome may play a part in this growth pattern.

KS patients have underdeveloped genitalia with small phallus and small testes (or cryptochidism). The testes have changes from fetal life but the testes start to enlarge at the time of puberty and then rapidly undergo fibrosis particularly of the Sertoli cells. Patients have elevated follicle-stimulating hormone and luteinizing hormone, but decreased testosterone. Decreased androgen can lead to decreased body hair or muscle strength and treatment with testosterone is usually given in adolescence if the patient is identified. Semen analysis usually reveals azospermia (>90%) but testicular sperm extraction and some other techniques can harvest active sperm. The rates of successful pregnancy still are low.

KS patients have a higher rate of gynecomastia and breast cancer than other males.
They also have higher rates of diabetes mellitus, obesity, metabolic syndrome, osteopenia/osteoporosis and autoimmune disorders especially systemic lupus erythematosus. Other features seen in KS include varicose veins and mitral valve prolapse. They also have a lower median life expectancy by 2.1 years.

Patients need comprehensive management from a variety of specialists to address their medical and psychosocial needs throughout their lifetime.

Learning Point
As noted before, the phenotype for people with KS is quite variable. KS patients overall have normal to lower intelligence with the overall IQ distribution being lowered by about 10 points relative to the general population. KS patients also overlap areas of psychological and social functioning but do have higher numbers of people with the problems listed below. Academic problems are found in 60-85% of patients.

Behavioral and educational problems found more commonly in KS include:

  • *Attention problems – including attention deficit/hyperactivity disorder
  • Learning disabilities – reading disabilities, spelling disabilities. Visual, spatial and math skills are usually normal.
  • Psychological problems – *anxiety, *depression, somatic complaints, *social problems, autism spectrum disorder, schizophrenia
  • *Speech impairment – delayed expressive speech

* some of the more common problems

Questions for Further Discussion
1. How is Klinefelter syndrome similar to Turner Syndrome?
2. What are indications for neuropsychiatric and/or educational testing?

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: Klinefelter’s Syndrome

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.

Tartaglia N, Cordeiro L, Howell S, Wilson R, Janusz J. The spectrum of the behavioral phenotype in boys and adolescents 47,XXY (Klinefelter syndrome). Pediatr Endocrinol Rev. 2010 Dec;8 Suppl 1:151-9.

Wikstrom AM, Dunkel L. Klinefelter syndrome.
Best Pract Res Clin Endocrinol Metab. 2011 Apr;25(2):239-50.

Kingery SE, Wintergerst KA. Turner Syndrome and Klinefelter Syndrome. Adolesc Med State Art Rev. 2015 Aug;26(2):411-27.

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

What is a Hydrocoele of the Spermatic Cord?

Patient Presentation
A 54-day-old male came to clinic after his parents noticed a lump in his left groin the prior evening while giving him a bath. They said that it did not appear to bother the patient, had not changed in size nor had any color changes since they had noticed it. He had not been ill. They denied any fevers, rashes, scratches, nausea or emesis. The past medical history showed a term infant without complications. The family history was negative for anatomic genitourinary problems or cancer. The review of systems was negative.

The pertinent physical exam showed a smiling infant with weight in the 50% and normal vital signs. A 1×1.5 centimeter firm mass was noted in the left groin. It was located medially to the inguinal canal. It appeared be aligned with the spermatic cord and move with it. It could not be transilluminated and was not physically pulsatile. Both testes were palpable in the scrotum with normal alignment. Both testes were the same size bilaterally and hydrocoeles were noted in the scrotum bilaterally. There were no diaper rashes, other rashes or skin changes on the legs or groin. The examination was otherwise normal.

The diagnosis of an inguinal mass was made and the resident and attending pediatrician considered that this could be an inguinal hernia or lymph node but the location and mass characteristics didn’t appear to be as consistent. A hydrocoele was also considered but the mass was in the inguinal area and not in the scrotum. A soft tissue tumor was considered but seemed again unlikely because of age. Anatomic variations of the vasculature or vas deferens were considered and seemed more consistent because of the location. The radiologic evaluation of an ultrasound found the diagnosis of a hydrocoele of the spermatic cord. The attending pediatrician was surprised as she had not seen this variation of a hydrocoele in her clinical practice. The patient was referred to pediatric surgery and was being monitored for resolution.

Case Image

Figure 119 – Longitudinal ultrasound image thorough the inguinal canal (to the left of image) and the scrotum (to the right of image) shows a cystic structure within the inguinal canal consistent with a spermatic cord hydrocoele. Within the scrotum is the normal epididymis and testicle and a small hydrocoele.

Discussion
Hydrocoeles are common anatomic variations caused by the incomplete obliteration of the processus vaginalis. The processus vaginalis is a peritoneal remnant that follows the testis and spermatic cord into the scrotum as the testis descends into the scrotum during development. As the processus vaginalis traverses from the testis back to the peritoneum, a hydrocoele can occur at any point along its length. The obliteration of the processus vaginalis occurs with the closure at the internal inguinal ring, followed by closure just above the testes with atresia of the area in between. The closure of the area around the testes itself is often not complete by the time of birth and hydrocoeles are commonly seen in the scrotum; most resolve by 1 year of age. The hydrocoeles may be uni- or bilateral.

Learning Point
Hydrocoele of the spermatic cord (HSC) is a uncommon variation of hydrocoele. There can be a chronic or acute onset of swelling in the upper groin or inguinal area above the testis and epididymis. HSC is divided into 2 or 3 types depending on the author.

  • An encysted HSC occurs when there is obliteration of the processus vaginalis at both ends with solitary cyst formation. This does not change in size.
  • A funicular HSC occurs when there is obliteration of the processus vaginalis distally leaving open the proximal processus vaginalis to communicate with the peritoneum. This may change in size because of differing amounts of peritoneal fluid in the cyst.
  • A mixed HSC has a proximal opening of the processus vaginalis but has an integrated wall around the cyst that causes it to act like a encysted HSC. It does not change in size because the wall prevents fluid from entering the cyst. These types of cysts can be solitary or multiple.

HSC is usually treated by pediatric surgeons and treatment may be watchful waiting if there is a funicular HSC up to around 1 year of age after which it is repaired. If there is an encysted HSC or there appears to be a related inguinal hernia then surgery is usually recommended earlier. HSC torsion can occur but is very rare. In one study of HSC, 30% of patients had anatomic inguinal defects on the contralateral side.

Hydrocoeles have been known to the medical profession for hundreds of years. In an 1843 article, Dr. Robert Liston describes encysted hydrocoeles:

    “I. On the testicle, betwixt the albuginea and tunica vaginalis – at first as transparent cysts, but gradually increasing in size.

    II. As presenting by the side of the epididymis, betweixt that body and the reflection of the processus vaginalis from the testis.

    III. As appearing in the course of the spermatic chord above the testicle. In this latter situation, no doubt, collections of various kinds are to be met with in the loose filamentous tissue of the chord; in the unobliterated portions of the spermatic process covering that body; or possibly, in more immediate connexion with the vas deferens itself.”

Questions for Further Discussion
1. What is the differential diagnosis of testicular pain? For a review click here
2. What is the differential diagnosis of scrotal swelling? For a review click here
3. What is the differential diagnosis of vulvar masses? For a review click 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 this topic: Testicular 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.

Liston R. A few observations on encysted hydrocele. Med Chir Trans. 1843;26:216-22.

Chang YT, Lee JY, Wang JY, Chiou CS, Chang CC. Hydrocele of the spermatic cord in infants and children: its particular characteristics. Urology. 2010 Jul;76(1):82-6.

Senayli A, Senayli Y, Sezer E, Sezer T. Torsion of an encysted fluid collection. Scientific World Journal. 2007 Apr 9;7:822-4.

Rathaus V, Konen O, Shapiro M, Lazar L, Grunebaum M, Werner M. Ultrasound features of spermatic cord hydrocele in children. Br J Radiol. 2001 Sep;74(885):818-20.

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

What Medical Problems Can Patients with Turner Syndrome Have?

Patient Presentation
A 6-year-old female with known Turner Syndrome (TS) came to clinic for her health maintenance examination. She had just finished kindergarten which she enjoyed. Her parents’ main concern was about attentional issues as her teacher had noted that she seemed more distracted in the classroom. The teacher was able to help redirect her and at this time did not have any concerns about her learning. Her parents noted that she did need more redirection and they had to do more physical redirection or verbally pointing out social cues to her at home. Currently, these issues generally did not cause any problems in the family or for the child. She was well-liked by teachers, peers and her family. The past medical history revealed that she was diagnosed around birth because of growth retardation, lymphedema, webbed neck, shield chest, and shorted metacarpal bones. She had been comprehensively managed by specialists at the local children’s hospital. She had no cardiac defects, hearing loss or hypothyroidism. She had multiple episodes of otitis media which required 2 sets of pressure equalizing tubes. She also had 1 urinary tract infection and was known to have a duplicated renal collecting system. The review of systems was normal.

The pertinent physical exam showed a smiley school-age female with normal vital signs. Her weight was 10% (on a normal growth chart). Her height was 102 centimeters (5% on normal growth charts and 50% for height on TS growth chart) and was consistent with previous measurements. She had wide-spaced nipples, webbing of her neck, short 4th metacarpal bones bilaterally, and an increased carrying angle to her arms. She had otosclerosis bilaterally. Her thyroid was not enlarged and her cardiac examination had no murmurs. She was Tanner 1 for pubertal development. The rest of her examination was unremarkable.

The diagnosis of a healthy child with TS was made. In addition to reviewing that she was properly following up with her multiple specialists at the children’s hospital, the pediatrician made sure that she had a dental home and her immunizations were complete. “I know that people with Turner Syndrome can have more problems with learning and also with attention problems. At this time you and the teachers seem to be meeting her social and school needs and she isn’t have problems, but I can refer you to a psychologist who could do an initial evaluation for her attention plus give us more insights if she has other learning needs. We can also wait a few months and monitor her closely and then refer her. I don’t want to overlook the things her teacher and you are seeing,” he said. After some discussion, the parents decided to make the psychology appointment so they could continue to understand their daughter’s needs and try to meet them.

Discussion
Turner Syndrome (TS) is one of the most common genetic disorders in females. It was first described by Dr. Henry H. Turner in 1938. It affects 1 in 2000-2500 births and ~70,000 girls and women have TS in the United States. It is caused by the absence of all or part of the second X chromosome. The most common variation is 45X which affects about 50% of TS patients and usually has the most complications, but there are other variations. Phenotypes vary and therefore the age of diagnosis varies. Mean age of diagnosis unfortunately is 15 years. Diagnosis is made by chromosomal analysis. Haploinsufficiency of the SHOX gene is associated with short stature in Turner syndrome.

Patient presentations depend on age and phenotype. Most (almost all) TS patients have short stature and primary ovarian failure, but patients can have a variety of medical problems. Patients need comprehensive management from a variety of specialists to address their medical and psychosocial needs throughout their lifetime. Recommendations for comprehensive management can be found in the To Learn More section below.

Learning Point
Medical problems that patients with Turner Syndrome can have include:

  • *Short stature/growth retardation – almost 100% of patients
    • Short stature occurs in almost all patients with an average of 8 in (20 cm) shorter than predicted mid-parental height. Final adult height has been dramatically improved with growth hormone treatment. Short stature or growth failure are reasons to consider TS in females at any age as this can be the only sign of TS. Special growth charts are available for monitoring TS patients.
  • Endocrine – almost 100% of patients
    • *Primary ovarian failure
      • Patients have a hypoplastic sometimes “streaked” ovary with few or no follicles. Estrogen is inadequately produced and patients often have delayed puberty.
    • *Delayed puberty or pubertal arrest
    • *Infertility
      • Infertility is common. Having TS may be a relative contraindication to pregnancy because of higher risk of maternal complications.
    • Diabetes
    • *Thyroid disorders
  • Lymphatic
    • *Nuchal lucency on prenatal ultrasound
    • Cystic hygroma
    • *Lymphedema
    • Webbed neck with or without lower hairline
  • *Cardiac anomalies – 30-50% of patients
    • Mainly left sided anomalies and is the most common reason for premature mortality
    • Bicuspid aortic valve
    • Aortic coarctation
    • Aorta, dilated
  • Cognition/Educational/Psychological
    • Patients have normal intelligence but may have other problems
    • Attention deficit/hyperactivity disorder
    • Mathematics problems
    • Mental health issues – anxiety, decreased self-esteem, social isolation
    • Non verbal impairments – visual-spatial, problem-solving, social cognition and other executive function problems
  • Gastrointestinal
    • Celiac disease
    • Liver disease
    • Obesity
  • Renal
    • *Collecting duct anomalies
    • Horseshoe kidney
    • Hypertension
  • Skeletal
    • Shield chest with inverted/wide-spaced nipples
    • Nail hypoplasia
    • Short 4th metacarpal/metatarsal
    • Cubitus valgus (increased carrying angle)
    • Madelung deformity of the wrist
    • High arched palate
    • Micrognathia/retrognathia
    • Dental malocclusions
    • Hip dislocation
    • Scoliosis/kyphosis
    • Pes planus
    • Osteoporosis
  • Ophthalmology
    • Hyperopia
    • Strabismus
  • Otolaryngology
    • *Hearing loss – sensorineural and conductive
    • Abnormal ear position – low set or rotated
    • Otitis media

* some of the most common medical problems

Questions for Further Discussion
1. How are Turner Syndrome and Kleinfelter syndrome similar?
2. What is the role of the primary care provider in the care of patients with multiple medical problems?

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: Turner Syndrome

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.

Turner Syndrome Society of the United States. Available from the Internet at http://www.turnersyndrome.org.

Bondy CA, Turner Syndrome Study Group. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab. 2007 Jan;92(1):10-25.
http://media.wix.com/ugd/8fb9de_e000a4b246f44f2cbd4e5cd026576d74.pdf.

Milbrandt T, Thomas E. Turner syndrome. Pediatr Rev. 2013 Sep;34(9):420-1.

Lee MC, Conway GS. Turner’s syndrome: challenges of late diagnosis. Lancet Diabetes Endocrinol. 2014 Apr;2(4):333-8.

Kingery SE, Wintergerst KA. Turner Syndrome and Klinefelter Syndrome. Adolesc Med State Art Rev. 2015 Aug;26(2):411-27.

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