Immunological variants in children

INTRODUCTION:

             Throughout an individual’s lifespan, childhood is a time of great infectious susceptibility due to many factors.  Pound for pound, children inhale more air and consume more food and water than adults, exposing them to more environmental pathogens.  Daycare and school combined with the unhygienic habits of children also expose them to many new pathogens everyday.  According to Texas’ Children Hospital the most common infectious diseases in children are cytomegalovirus, influenza, group B Streptococcus pneumoniae, and Staphylococcus aureus.  Children have a functionally immature immune system when compared to adults for reasons discussed below.

The immune system is constantly changing and creating ways to protect host cells from potential foreign threats. This is particularly true for neonates. They have to quickly adapt to their new environment after leaving the sterile environment of their mother’s womb. To help them with this radical change newborns have the support of maternal IgG antibodies that provide not only passive protection, but also offer maternal immunologic memory and experience.  Another way to support the development of a healthy immune system is breast milk. A clear example is a study that showed that fatty acids are correlated with the potential immunomodulators sCD14 and PGE2 and that their composition in breast milk is related to the atopic eczema infant. This external source of sCD14 provided via breast milk may be of particular importance providing stimulus for the gut immune system. The development of a healthy intestinal flora is of key importance for the maintenance of a balanced immune system in all individuals. Another key feature that protects neonates and children is the fact that NK cell blood counts are higher in newborns than in adults. However, the higher number does not mean higher efficacy. Neonatal NK cells display lower cyto-lytic capacity that may contribute to the immaturity of the neonatal immune system.  Circulating levels of NK cells increase in children during pediatric infections and the ability of NK cells of newborns and children to produce interferon-γ upon encounter with pathogens indicate that NK cells participate in the immune response to infectious diseases in early life.  NK cells are not the only difference within a complete blood count (CBC) when comparing normal profiles at different ages.

            Notable white blood cell (WBC) count changes occur within the first few weeks of life.  An individual’s WBC count is highest during infancy with a normal range of 7.2 – 18 x 10^-9 cells/L.  WBC count values decline throughout childhood to an average value of 7.1 x 10^-9 cells/L between ages 2 and 6 while still declining during adolescence to a mean of 6 x 10^-9 cells/L. The decreased values seen in adolescence are more similar to those of an adult and highlight a key difference between a child and adult immune system. Early in life the thymus creates new T-lymphocyte lineages but undergoes involution around adolescence causing the cessation of new lymphocyte lineages. This leads to an expected decrease in the number of lymphocytes in an adult WBC profile. 

References: 

http://www.texaschildrens.org/carecenters/InfectiousDiseases/Default.aspx

Kaplan JL, Ning Shi H, Walker WA. The Role of Microbes in Developmental Immunologic Programming. Pediatric Research. 2011 Feb 28[Epub ahead of print] 

LAITINEN, KIRSI; HOPPU, ULLA; HÄMÄLÄINEN, MARI; LINDERBORG, KAISA; MOILANEN, EEVA; ISOLAURI, ERIKA. Breast Milk Fatty Acids May Link Innate and Adaptive Immune Regulation: Analysis of Soluble CD14, Prostaglandin E2, and Fatty Acids. Pediatric Research. Issue: Volume 59(5), May 2006, pp 723-727

Guilmot A, Hermann E, Braud VM, Carlier Y, Truyens C. Natural Killer Cell Responses to Infections in Early Life. Journal of innate immunity. 2011 Mar 12.

Thompson, Initials, & Thompson, Initials. (2007). Genetics in medicine.

Philadelphia: Saunders Elsevier.

Wayne, A, Capitini, C, & Mackall, C. (2010). Immunotherapy of childhoood cancer: from biological understanding to clinical application. Current Opinion in

Pediatrics, 22(1), 2-11.

Lichtman, M, & Kipps, T. (2010). Willams hematology. China: McGraw Hill.

CLINICAL CORRELATION #1: ASTHMA

            One of the most common chronic conditions in children is asthma. Asthma is a multifactorial disease caused by a hypersensitivity type I immune reaction (acute asthma) in addition to type IV hypersensitivity in chronic forms leading to inflammation of the bronchi and obstruction of airflow. It accounts for 47.8% of the emergency department visits and 34.6% of hospitalizations of children younger than 18 years of age¹. Inconsistency in the response to treatment between individuals is a factor that is recently being researched. According to recent studies, a link has been made between genetic variations and an improved response to different asthma treatments². In one of these studies variants of the DENND1B gene, which is expressed in natural killer and dendritic cells, were found to be associated with asthma in children. In this study an association of variants of DENND1B were made between children of Northern European ancestry and children of African ancestry³.  New research aims to find other methods to improve the response to asthma treatments and a better prognosis for asthmatic children.

Resources/References

Sharma, Girish. "Asthma in children." eMedicineHealth 06 Jan 2010: 10. Web. 28 Mar    2011. <http://www.emedicinehealth.com/asthma_in_chi ldren/page10_em.htm>.

Turner, SW. "Genetic predictors of response to therapy in childhood asthma."   Molecular Diagnosis and Therapy 13.2 (2009): 127-35. Web. 29 Mar 2011. <http://www.ncbi.nlm.nih.gov/pubmed/19537847>.

Sleiman, Patrick, James Flory, Marcin Imielinski, Jonathan Bradfield, and Kiran Annaiah. "Variants of DENND1B Associated with Asthma in Children ." New England Journal of Medicine 326.1(2009): 36-44. Web. 29 Mar 2011. <http://www.nejm.org/doi/pdf/10.1056/nejmoa0901867>

CLINICAL CORRELATION #2: GLOMERULONEPHRITIS

There is increasing evidence that certain genetic variants result in decreased immunologic susceptibility to glomerulonephritis. This disease presents with inflammation of the glomeruli and small vessels in the kidney. Some symptoms include blood in urine (hematuria), increased protein in urine (proteinuria) and acute or chronic renal failure. The most common form is IgA glomerulonephritis. It is characterized by deposition of the IgA antibody in the glomerulus. There is no definite explanation for the accumulation of IgA but it’s associated with certain infections and/or abnormalities in the IgA molecule

There are studies that suggest that children with glomerulonephritis have specific HLA alleles.  It’s been known for a long time now that certain HLA variants are associated with glomerulonephritis.

It’s been demonstrated that there is an increased frequency of HLA-DRB1 allele in Egyptian children with post-streptococcal acute glomerulonephritis (PSAGN). Children with HLA-DRB1 alleles have increased susceptibility to PSAGN.  In another study, it was found a relationship between certain HLA typing and hepatitis B associated glomerulonephritis/membranous nephritis (HVBMN).  There was a high frequency of DQB1-0603 HLA in study subjects compared to controls, suggesting a possible genetic predisposition to development of HBVMN.

Tissue typing can detect children who are predisposed to develop acute or chronic glomerulonephritis. This is useful to provide early treatment and predict trends in the disease course. Angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor antagonist are effective treatments for glomerulonephritis. If proteinuria has not increased over 0.3g over 24hrs, then administration of glucocorticosteroids is recommended. Glucocorticosteroids decrease proteinuria and slow the decline of renal function.

Streptococcal infections especially the B type, usually affect the immuno-compromised or immunodeficient.  Since children compared to adults have a less developed (immature) immune system they are more susceptible to these infections.

            Bakr, A., Mahmoud, L., Al-Chenawi, F., & Salah, A. (2006). Hla-drb1* alleles in egyptian children with post-streptococcal acute glomerulonephritis. Pediatric Nephrology, 22(3), 376-379.

                Terasaki, P., Mickey, R., & Patel, R. (1969). Leucocyte antigens and disease: association of hl-a2 and chronic glomerulonephritis. British Medical Jornal, 2, 424-426.

Illek, L., Zaitseva, G., & Tarasova, E. (1995). The immunogenetic parameters in acute and chronic glomerulonephritis in children. Urol Nefrol (Mosk), 3, 9-11.

Mautosovic, K., Mestecky, J., Tomana, M., & Novak, J. (2008). Treatment of iga nephropathy. Vnitr Lek, 54(3), 239-244.

Ogle John W, Anderson Marsha S, "Chapter 40. Infections: Bacterial & Spirochetal" (Chapter). Hay WW, Levin MJ, Sondheimer JM, Deterding RR: CURRENT Diagnosis & Treatment: Pediatrics, 20e: http://www.accessmedicine.com/content.aspx?aID=6590638.

CLINICAL CORRELATION #3: WBC COMPARISON OF NEONATES AND CHILDREN

Lymphocyte Subsets	0–3 months	2–6 years
WBC x 109/L	10.60 (7.20–18.00)	7.10 (5.20–11.00)
Lymphocytes x 109/L	5.40 (3.40–7.60)	3.60 (2.30–5.40)
CD3+
% of lymphocytes	73% (53–84)	66% (56–75)
Count x 109/L	3.68 (2.50–5.50)	2.39 (1.40–3.70)
CD19+
% of lymphocytes	15% (06–32)	21% (14–33)
Count x 109/L	0.73 (0.30–2.00)	0.75 (0.39–1.40)
CD16+/CD56+
% of lymphocytes	8% (04–18)	9% (04–17)
Count x 109/L	0.42 (0.17–1.10)	0.30 (0.13–0.72)
CD4+
% of lymphocytes	52% (35–64)	38% (28–47)
Count x 109/L	2.61 (1.60–4.00)	1.38 (0.07–2.20)
CD8+
% of lymphocytes	18% (12–28)	23% (16–30)
Count x 109/L	0.98 (0.56–1.70)	0.84 (0.49–1.30)

  This table demonstrates the immunological variation in children. As children grow it is normal to see a decrease in quantity of white blood cells (WBC). During the first months of life, the normal value for WBC is 7.20–18.00 x 10⁹ /L.  Then from 2 to 6 years old, the normal range for WBC is 5.20–11.00 x 10⁹/L.  In terms of distribution of different lymphocytes subtypes, B cells (CD19+); T- cells (CD3+); T helper 1 (CD8+); T helper 2 (CD4+); and natural killer cells (CD 16+/CD56+), the percentages change, but in general aspects it is mainly diminished over time. The only exception is B cells. The reason for this is that the body needs to start producing its own immunoglobulins (Igs) and B cells are the precursor of these Igs.

References:

Lichtman, M, & Kipps, T. (2010). Willams hematology. China: McGraw Hill.

MCQs and Short Answer Questions:

An 8-year-old boy is brought to the ER with a chronic cough. According to his mother: “he coughs frequently and this problem has been going on and off for about a year and seems to be worse in the spring and fall.” He coughs more when playing sports. Also, he was treated recently for “bronchitis” with antibiotics and cough suppressants but never seem to clear up completely. His physical exam is normal except for his lungs, which show expiratory wheezing.

1.) According to the signs and symptoms what could be a possible diagnosis?

1. H1N1 viral infection
2. seasonal allergies
3. chronic bronchitis
4. asthma

2.) What other tests can be done to confirm this diagnosis?

3.) Given all the information above what would you recommend for this patient?

Answers:

1.) (A) wheezing, coughing, chest tightness, exacerbation of symptoms during exercise and past medical history of bronchitis are all indicative symptoms for asthma

2.) Pulmonary function tests (PFTs) can be used in children 5 years old or   older or a Plethysmography; both of these test for lung capacity

3.) inhaled corticosteroid or bronchodilators

I. A 6 year old female is brought to the ER complaining of flank pain.  Mother complains that her child has been having difficulty breathing for the past 2 days and her urine is very dark. She had been treated for an upper respiratory infection caused about a month ago. Clinical findings show periorbital edema, pale conjunctiva and pallor lips. Laboratory results show: minimal hematuria, protenuria and leukocytosis.

1. What could be a possible diagnosis?

1. Severe Combined Immunodeficiency
2. Glomerulonephritis
3. Hemolytic uremic syndrome
4. Goodpasture syndrome.

2. What bacteria are associated with this condition disease?

Answers:

1. (A) Glomerulonephritis
2. Streptococcal pharyngitis or streptococcal tonsillitis

II.   A 4month old is brought to the ER. He appears to be lethargic. His mom complains he has a weak cry, poor feeding and has not evacuated throughout the whole day.  She said she ran out of formula and fed him canned milk mixed with water earlier that morning. Clinical findings show: ptosis, flaccid paralysis of the limbs and possible respiratory failure.

1. According to these findings what could be the possible diagnosis?

1. Meningitis
2. Tay Sachs Disease
3. Botulism
4. Malnutrition

Answer is C