sábado, 14 de mayo de 2011

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

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

22 comentarios:

  1. Bueno yo soy de las q creo y me reafirmo q a los niños hay q dejarlos q jueguen en la tierra, q pongan cosas en su boca, en fin q exploren el mundo para q construyan un sistema inmune fuerte. No hay manera q creen anticuerpos hacia ciertos patógenos si nunca se exponen a ellos. Yo considero q un niño se enferma más fácilmente cuando se tiene en una "burbuja" q cuando se deja q se ensucie

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  2. En el caso de los neonatos yo creo que nunca esta de más recalcar la importancia de la leche materna es realmente lo mejor para el bebé y el desarrollo de su sistema inmunológico.

    Excelente artículo, muy educativo. En Puerto Rico el asma es una epidemia he visto documentales de ello especialmente en comunidades cerca de plantas de cemento y es una pena que no hayan programas de salud pública para impactar estas areas.

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  3. En el programa de salud publica que participe estan corriendo una investigacion sobre asma precisamente por la falta de conocimiento que existe y porque Puerto Rico tiene una de las tasas mas altas de asma.

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  4. Secundo a Debora, yo pienso que el mejor sistema auto imune que uno puede obtener cuando pequeno, es corriendo descalso en el patio y dejando que el ni~o experiminete por su cuenta el mundo exterior. Para asi poder obtener un sistema imune a todo lo que podamos encontrar en el medio ambiente. Yo soy uno que cuando chiquito me crei en el patio y rara vez q me enfermo.

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  5. Estoy totalmente de acuerdo con Débora y LuisMa. Pienso que aunque los niños tienen un sistema inmune mucho mas comprometedor que los adultos, estando mucho más susceptibles a infecciones, hay que dejarlos fortalecer ese sistema inmune. Nunca se han puesto a pensar que muchas veces las personas que se enferman mucho son esos que de niños se quedaban más bien en sus casas, y no exploraban el mundo afuera?

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  6. It is completely true what you guys are saying. It is very important for the human body to get exposed to different immunogenics at an early age, in order to develop a strong immune system. But of course, this should be with care, or you will get a case such as that one in question 2, you do not want to expose your children to clostridium botulinum. Which represents an impossible challenge to the immune system.

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  7. Sobre lo que mencionó Yarelis sobre la leche materna, tiene mucha razón, hay que recalcar la importancia que tiene. Estuve escuchando una conferencia sobre la leche de fórmula para los ni`nos, son muchas las cosas que tienen que añadirle para que sea efectiva para ellos. La leche materna ya incluye mcuho de esos ingredientes escenciales que le añaden a las fórmulas.

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  8. I hope that in the near future we'll be able to identify HLA types for the most prominent conditions and treat our patients in a more specific manner. Specially children as adverse reactions to drugs is one of the leading reasons for longer hospital stays.

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  9. Los ninos tienen que ser expuestos a patogenos del ambiente para que poco a poco vayan desarrollando sus defensas y no esten desprotegidos al momento de llegar a la adultez.

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  10. Sobre la leche materna, además de sus beneficios inmunológicos preovee mayor seguridad en cuanto lo que está consumiendo su bebé. Hace unos días vi un artículo sobre la leche de formula en donde encontraron metales pesados y químicos que se encuentran en los pesticidas. Eso es muy preocupante.

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  11. Padezco de asma desde que tengo memoria, y en verdad que seria una gran ventaja que estas investigaciones puedan encontrar mas variaciones geneticas, y que a traves de ellas puedan llegar a la medicina personalizada.

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  12. Yo estoy de acuerdo con mis compañeros a lo ninos hay que dejarlos ser!! hay que dejar que disfruten y experimenten para que puedan crear buenas defensas (hay que dejar que aprovechen el timo al máximo).

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  13. Con respecto a lo de la leche materna!! no hay mejor suplemento nutricional en los primeros meces que la leche materna!!! la leche materna tiene todo lo necesario para que los bebes se desarrollen adecuadamente y ademas también le brinda defensas!! ademas en Colombia hay un mito de que las madres que amamantan a su hijo rebajan mas rápido!! pensando bien puede que los viejos de Colombia no esten tan mal debido a que la leche es alta en grasa y la grasa de obtiene de la madre!! A si que sino convencemos a las madres jóvenes de que amamanten a sus hijos por los beneficios nutricionales e imunologicos podemos intentar de convencerlas por lo estetico!!!

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  14. Tuve la oportunidad de hacer la preceptoria con una Alergista/Immunologa, y la cantidad de niños que se presentaban con asthma era increíble. Inhalar corticosteroides es muy efectivo en estos niños, ya que con lo que pude observar y lo que me comentaba la Dra, estos mostraban una mejoría. Esto es muy delicado, ya que como dice en este blog, aproximadamente un 34.6% de las hospitalizaciones de menores de 18 años son por asthma. Pienso una de las formas de reducir estos números seria con orientación. Orientando a los padres sobre la higiene y la interacción entre sus hijos con otros, reduciendo así el "shift" de Th-1 a Th-2 que se puede ver en pacientes con asthma.

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  15. Tuve asthma cuando era nino especialmente cuando estaba expuesto a temperaturas bajas, hace anos que no tengo problemas respiratorios quizas fue una adaptacion en el sistema ya que estuve viviendo seis meses en Minnesota y nunca tuve ningun problema respiratorio. Mucha gente se beneficiaria con medicamentos mas especificos.

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  16. I also suffered from asthma as a child and developed a tolerance to whatever was causing it. I also got over my anemia, low white blood cell count and being very, very short. Time has a funny way of changing everything.

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  17. El sistema inmune de los bebes es inocente y va madurando y estabelciendo respuestas inmunes al medida que se estimula . Un buen estimulo es la leche materna en loas primeras semanas de vida. Cuando entran a centros d cuido se contaminan con infecciones mayormente virales que van provocando una memoria que le servira el el futuro para defenderse. En este trayecto cierto virus puede provocar asma y el manejo es individualizado ya que varia la respuesta por rasgos geneticos y la interaccion con el ambiente,Puerto Rico tiene una alta prevalencia de asma

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  18. I am a firm believer that exposing our bodies to as many different allergens as possible at young age is extremely beneficial for our body's ability to naturally fight and resist getting sick. I have many friends that migrated to the states from Vietnam around the age of 10-15. Growing up with them over the years, I have witnessed many of them develop allergic reactions to previous harmless allergens and become increasingly susceptible to common colds and flu's. They would all tell me how back in Vietnam, you would rarely ever see anyone with allergies.

    Growing up in the States, I see how we live in a sort of sterile bubble. We don't expose ourselves enough to opportunistic pathogens at a young age when our immune system is working in overdrive to generate a varied set of antibodies that will hopefully suffice our lifetime. If I remember correctly, our body drastically reduces the ability in producing long term memory antibodies at about the age of 18. It has to do with the function of our thyroids, I believe.

    Anyways like Darwin stated, "Only the strong survive".

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  19. El Asma es definitivamente una enfermedad bien interesante para estudiar, especificamente en Puerto Rico donde la taza es tan alta. En mi familia yo creo que un 90% a padecido de Asma y yo no fui la excepción. Entiendo que nuestro ambiente tiene mucho que aporta a dicha enfermedad, ya que como podemos ver es un tipo de hipersensibilidad (I o IV) pero ahora me pregunto pq no fue hasta la adolescencia que gracias a las recomendaciones del doctor de participar mas activo en deportes, fue que mi asma desaprecio? Yo endiento que el atletismo me ayudaría a desarrollar mas mis pulmones pero yo creo que ya a los 12 o 13 años los pulmones están bastante desarrollados adicional a que siendo una hipersensibilidad no se supone que cambiara mucho mi estatus pq seguía expuesto al mismo ambiente pero sin embargo no fue así y desde la adolescencia no padezco mas de asma.

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  20. The role of NK cells in early development is curious in relationship to its higher quantity and lower efficacy in children. It would be interesting to learn more of its role in early immunological development. Great article, It makes me think that certain baby to adolescent milk might possibly need immunosuppliments.

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  21. Nice to have a topic in children immunology to compare with aging immunology. Seems curious to me that children are provided with all the tools necessary to grow into healthy adults that will in time also have children to continue with the chain of life. But as we age our immune system shuts down and I think it mother nature's way of telling us that our job has been done and we need to go.

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  22. Este artículo, es primeramente bonísimo; segundo, estoy totalmente en acuerdo con mis compañeros, los niños deben ser niños y punto. La importancia de la leche materna denota la trascendencia que tiene a la hora del desarrollo y el futuro de los infantes. La ciencia siempre comprueba que los mecanismos y eventos de la naturaleza están perfectamente sincronizados y contienen un propósito como lo recalca este artículo.

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