IMMUNODEFICIENCIES

2020
CAMELIA BERGHEA
 INTRODUCTION
• Immune deficiency occurs and installs when one or more components of the
immune system exhibit dysfunctions either morphological or functional

• Good functioning of the immune system depends both on:

• → the degree of development, cooperation and harmonization that exists

between the hematogenic marrow, thymus and lymphoid tissue, on the one
hand, and the ...

• → functional capacity of monocyte / macrophage system, complement system

and molecular mediators, such as interleukins, adhesion molecules, growth
factors, prostaglandins
CLASSIFICATION OF ID

• IDP – primary ID-consequence of a genetic mutation

• Humoral specific system damage - LfB, Ig
• Affects cell specific systems - LfT
• Affect phagocytosis
• Affecting complement system
• IDS – secondary ID
• Viral infections - HIV, measles, varicella, flu
• Quantitative nutritional deficiencies: protein malnutrition = caloric or
qualitative - zinc, vitamin A, D, B12
• Malignant hemopathies
 Suggestive elements for IDP
anamnesis
• Repeated, severe, prolonged
infections with unusual germs
• Growth failure
• The need for antibiotic treatment
to eliminate infections
• Sepsis + hepatitis + coagulopathies
associated with infectious
mononucleosis (NK defects)
• Neonatal (hypocalcemic)
convulsions + congenital heart
defects
• Family history of IDP or possibly
IDP
Clinical
Growth failure
Hypo / atrophic tonsils in a child with
frequent infections
Lymph nodes not palpable
Clinical signs of otitis / sinusitis /
pneumonia especially for LB defects
Stomach, gingivitis, dental erosions,
neutrophil defects
Molluscum, warts, persistent oral
candidiasis for LT defects
Syndromatic associations
cutaneous-mucous-albinism, petechiae,
dermatitis, teleangiectasia
Neurological - ataxia, other progressive
deficiencies
Blowers, cyanosis
BIOLOGIC data
• ! Advanced immunological evaluation of all children with recurrent
infections is not appropriate
• Anamnesis + clinical examination = starting point
• Screening evaluation:
• CBC - lymphopenia <3000 / mcl, <1500 in the child over 1 year;
neutropenia <1500 / mcl; neutrophilia is constant in the leukocyte
adhesion defect (LAD)
• Immunogram (IgA, IgM, IgG, IgE):
• IgG decreased
• IgA, IgM, IgE may be low, normal or elevated

IMAGING
• Lack of thymus
• Heart malformations
IMPROVED ATTITUDE AS A CHILD WITH SUSPICIOUS IDP
• Isolation for protection
• Prompt recognition and aggressive treatment of crop infections and
empirical treatment
• Prohibition of live vaccines (BCG, ROR, VZV)
• Use (if needed) only irradiated blood products (to prevent graft versus
host) and blood donors without CMV (to prevent CMV sepsis, possibly
fatal)
• Performing HLG and immunogram
• Blood sampling, centrifugation and freezer storage for further analyzes
prior to Ig
• Blood collection on EDTA or fibroblast cultures for DNA extraction
• IV iv administration 0.4-0.5 g / kg in severe cases
• Contact regional center
 Antibodies deficyency IDP
• It represents over 50% of IDPs
• Affects the number or function of Lf B and antibody production
• Associates increased risk of infections involving specific humoral response -
capsulated bacteria, enteroviruses, giardia, H pylori, and the risk of
autoimmune diseases
• The most common are IgA deficiency, first-generation transient
hypogammaglobulinaemia, variable joint immunodeficiency and X-linked
Agammaglobulinaemia (Bruton disease)
• Without treatment, irreversible lesions, especially pulmonary, are present:
bronchiectasis with evolution to chronic respiratory failure, chronic
pulmonary cord and death in 2-4 decades, depending on severity
• With treatment - favorable prognosis
Selective deficit of IgA

• Prevalence: 1 / 800-1 / 400

• Gastrointestinal, respiratory, genitourinary infections
• Most asymptomatic
• IgG and normal IgM, including vaccine antibodies
• Frequent association with celiac disease
• It does not require IgG substitution treatment, may be associated with
anaphylaxis risk if adm products containing IgA
• It may evolve into variable immunodeficiency
TRANSIENT HYPOGAMMAGAGLOBULINEMIA OF THE FIRST CHILDHOOD

• Symptomatic variant of normal with delayed maturation of the immune

system
• IgG persistent decreased after the age of 6 months
• Normal IgA, variable IgM
• Isohemagglutinins and normal vaccine antibodies
• Increased risk of otitis and sinusitis
• If infections are significant, Ig replacement may be required until
resolution, usually up to 4 years of age
COMMON VARIABLE IMMUNODEFICIENCY
• Sinopulmonary infections
• Onset 15-35 years. M: F = 1
• Low IgG, decreased vaccine antibodies
• Variable level of IgA and IgM
• Increased risk of autoimmune and malignant diseases
• Phenotypic normal LB - in most cases
• Treatment:
• Substitution with Ig
• Immunosuppressants for the association of autoimmune diseases
• Chemotherapy for forms of lymphoproliferation
• Hematogenic bone marrow transplantation or haematopoietic stem cells
BRUTON DISEASE – X-LINKED AGAMMAGLOBULINEMIA

• History of similar problems to uncles, grandchildren and maternal cousins

• Debut after 6-9 months

• Recurrent infections with pneumococcus, H influenzae, Giardia

• Hypo / atrophic tonsils, gg lymph impalpable

• IgA, IgG, IgM, IgE levels with> 2SD below normal

• Low number of LB (CD19)

• Btk (Bruton tyrosine kinase) gene defect

• Treatment:
Substitution of Ig
Immunosuppressants for associated autoimmune diseases - arthritis,
cytopenias
Hyper IgM syndrome

• the immune system produce IgM with lower affinity and pro-
inflammatory effects higher than IgG and no LB with memory
• Most cases are X-linked and is a combined IDP because the affected
protein is CD40L that is LT-co-receptor
• There are also autosomal recessive forms that almost exclusively affect
the LB function
• IgG and IgA decreased
• Normal or increased IgM
• Clinical manifestations characteristic of antibody defects
• Treatment:
• Substitution of Ig
• Marrow transplantation or stem cells in severe X-linked forms
CELLS PID

• 20-30% of PIDs
• Predominantly affects LT
• vulnerability to all infectious agents - bacteria, viruses, parasites, fungi
• Autoimmune diseases - vitiligo, cytopenias, thyroiditis, diabetes type I, arthritis
• Malignancies - leukemias, lymphomas, and rarely solid tumors

• COMBINED SEVERE IMMUNODEFICIENCY

• Life expectancy does not exceed 1-2 years
• In recent years - racial cases of partial forms with survival 1-2 3 decades but
with severe impairment of quality of life - hospitalizations, aggressive
treatments
• For this reason, genetic dg is important
• Sampling for DNA, urgent – for correct molecular diagnosis
Defect:

• About one half of cases represented by severe common

immunodeficiency X-linked – generated by mutations of common chain
gamma of receptor for IL-2, IL-4, IL-7, IL-9, il-15, IL-21
• Rare forms of disease are the result of damage of:
• Jak3 - tyrosin-kinase involved as a second messenger on the
pathways for the above mentioned interleukins
• CD3/TCR complex
• Enzymes system involved in generation of TCR diversity (RAG1/2)
• Enzymes system involved in repairing DNA breaks (Artemis,
Cernunnos, Ataxia-teleangiectasia) – diseases that associate
vulnerability to ionizing radiation, or metabolic pathways for
nucleotide recovery
• immunophenotypically they are divided into>
• T-B+ - X-SCID, Jak3, CD3?TCR
• T-B- - RAG1/2, Artemis, ADA, PNP
Treatment

• Bone Marrow transplant or stem cells - the only current curative

treatment
• Mortality risk 10-15%
• Survivors - 80-90% are * immunologically cured
• Up to transplant:
• Isolation for strict protection - hospitalization in reserves or home
isolation, washing hands with water and soap, mask, gloves, disposable
gown, strict hygiene \
• Prompt recognition and aggressive treatment of infections
• Prohibition of live vaccines
• Administration of irradiated blood products without CMV
• Substitution of Ig
• Prophylaxis of infections (amoxicillin, azithromycin, cotrimoxazole),
viruses (acyclovir), fungi (azoles), Pneumoniae, mycobacteria (HIN)
neutrophil PID
Congenital / cyclic neutropenia
Leukocyte adhesion defect - LAD
Bactericidal Defect - Chronic Granulomatous Disease - CGD
•severe infections from the first year of life, with bacteria in the first two
forms and with bacteria (staphylococcus, Burkholderia cepacia, Serratia
marcescens, Nocardia, mycobacteria) and fungus (aspergillus) in CGD -
stomatitis, gingivitis, , ulcerations, abscesses, omphalitis and delayed
umbilical detachment in LAD, osteomyelitis, pneumonia, otitis.
•Granulomas with mechanical problems of the obstructive type -
respiratory, digestive, urinary, or restrictive tract - respiratory tract,
sometimes autoimmune diseases
•Neutrophils - severe low number (below 500) in neutropenia, increased
in LAD, normal in CGD
•Ig - they may be raised
• The mode of transmission can be dominated, recessive, X-linked
• analysis:
• HLG 2 times per week for 6 weeks
• Oxidative neutrophil function
• The nitrobluetetrazolium test (NBT)
• Phagoburst

• Treatment:
• Congenital Neutropenia: curative or prophylactic antibiotics, G-CSF,
marrow transplant or stem cells
• LAD - curative or prophylactic antibiotics, marrow transplant, stem cells
• BGC: curative and prophylactic antibiotics and antifungals, curative
antituberculosis, IFN gamma, marrow transplant, stem cells
Complement deficiencies
• Less than 1% of IDP
• Mannose binding lectin (MBL) deficiency occurs in homozygous form
(below 100 ng / ml) in 3-5% of the population and heterozygous (100-
400 ng / ml) in up to 30% of the population
• The heterozygous form appears to protect against autoimmune diseases
by some authors
• The homozygous form is asymptomatic unless it is associated with other
primary or secondary deficits
• Other defects in the complement system:
• C5-C9 membrane attack complex - risk of Neisseria infection
• C1, C2, C4 - associated with autoimmune diseases
• C3 - severe sepsis risk, especially Gram negative
• Deficiency of C1-inhibitor - associated with hereditary angioedema
Immunoglobulins treatment
• Provides protection in humoral and cellular PIDs in the first months post-
transplant or post-stem cell, also in secondary ID

• Immunoglobulins come from donor plasma and their effectiveness

depends on the donor's immunological experience and the similarity of
the microbial environment to which donors and patients are exposed

• The products available on the market contain almost exclusively IgG and
can be administered iv every 3 weeks or less 1-2 times per week
(adolescents, adults, to avoid hospitalization and absences from school,
work)

• Efficacy is measured by the absence of infections and by the minimal IgG

(immediate-dose concentration) that should be maintained at 600 mg /
dl, even 800-1000 in those with bronchiectasis
Immunoglobulins treatment
• administration is done at body temperature, do not shake the vial to
avoid foam formation, infusion rate as recommended by the
manufacturer
• no premedication is required
• Common advers reactions: fever, chills, headache, vomiting, arthralgia,
chest pain, hypotension,
• in most cases these are resolved by reducing the infusion rate or by
stopping the infusion
• rare but serious side effects requiring stopping the infusion and
contraindicating its resumption are: systemic hypersensitivity reactions,
acute tubular necrosis, non-cardiac pulmonary edema
CITOKYNE THERAPY
Gamma IFN in chronic granulomatous disease. Growth Factors - In
Congenital Neutropenia
Very expensive, variable availability in pharmacies
Associated pathology - lymphohistiocytosis to IFN, leukemia to growth
factors

ENZYMES THERAPY
Designed for IDPs with unique enzyme deficiencies - adenosine deaminase
ADA, purine nucleotide phosphorylase - PNP. Manifested as severe
combined illness, in patients with no compatible donor
Periodic administration of the enzyme, linked to a large GM molecule
Feasible for ADA

BONE MARROW TRANSPLANT OR STEM CELLS

BONE MARROW TRANSPLANTATION OR STEM CELLS TRANSPLANTATION

• the only curative treatment method

• Could be used in SCID, Wiskott-Aldrich syndrome, chronic granulomatous
disease, LAD, Job syndrome, etc.
• the presence of a functional thymus for the success of the treatment is
mandatory
• mortality over 10% even in centers with experience, so we have to weigh
this risk in relation to the risk of death by the disease itself
ACQUIRED IMMUNODEFICIENCY - HIV / AIDS INFECTION
•CD4 + Lt infection, macrophages, dendritic cells with HIV
•HIV infection in the pediatric population = particularities:
•Vertical transmission - prevention by antenatal, perinatal and postnatal
antiretroviral therapy, cesarean delivery and avoided nursing
•Horizontal pathway - blood products
•Clinical:
•Acute infection has a short period and little or no clinical signs
• gastrointestinal - chronic diarrhea, growth failure
•CNS - delayed psychomotor retardation, cerebral palsy
•Pulmonary involvement with cough, hypoxemia, variable nodular infiltrates
•Generalized lymphadenopathy and hepatosplenomegaly
•Recurrent viral infections, bacterial, fungal, with opportunistic agents
DIAGNOSIS
• Serological tests
• The baby's immune response can only develop after 4-6 months
• In the case of children exposed perinatally, circulating circulating blood from
the mother can be found up to 18-24 months - they test positive without the
infection being present
• Seroconversion occurs at 15 months but there are also slow serovers (18
months but under 24 months)
• For these reasons, PCR is recommended for any child under 18 months
exposed perinatally
• Children in HIV + mothers are tested at 14-21 days
• Then retest at 1-2 months, 4-6 months
DIAGNOSIS
• Serological tests
• Any virological test should be confirmed by retesting with the collection of a
new biological sample
• The definitive exclusion of HIV from the non-fed infant breast is based on at
least 2 negative virological tests from blood samples taken at the age of 6
months
• After the age of 24 months, dg is dosed with Ac anti HIV but here PCR tests
are also required if acute infection and possibly the serological window is
suspected
• Any serological test should be confirmed by Western Blot/IFA methode
• HIV infection exclusion for kids on cows formula is based on at least 2
negative blood tests, 1 test done after 1 month old age and the second
one after 4 months old age OR by 2 negative blood tests for HIV
infection, obtained after the age of 6 months
PROPHYLAXIS
•Prophylactic zidovudine from the first 6-12 hours of life for 4-6 weeks in
all perinatal exposed
•All receive prophylaxis for Pn carinii at the age of 4-6 weeks, until the
exclusion of dg
•Avoid attenuated virus vaccines
•Antiretroviral tract is initiated as soon as dg is confirmed
•Child included in the national multidisciplinary monitoring network

PROGNOSIS
•Much better, early dg, effective therapies
•I get in adulthood, the risk of vertical transmission with the emergence of
a new wave of HIV infected
VACCINATION
Immunization Practices - Pediatric
Vaccination Recommendations

method of inducing immunity against serious or potentially fatal

infectious diseases for which there is no effective treatment

protection of vaccinated children but also of community by reducing

the spread of infectious diseases = collective immunity

worldwide, the prevalence of poliomyelitis was reduced by 99%,

deaths were reduced by diphtheria, tetanus, pertussis, measles,
eradicated smallpox
Infectious diseases preventable by vaccination
TB meningitis and TB miliary:

• Prevalence still high, 15000 patients in 2014 in Romania ,

over 1200 deaths (2011-2012)
• This, along with the even greater number of asymptomatic
/ oligosymptomatic cases, show a high degree of risk for
infection with mycobacteria.
• Prevalence of symptomatic tuberculosis infection in BCG
vaccination, although it does not appear to provide
significant protection against infection or tuberculosis
pulmonary (the most common form), is effective in
preventing the two most serious forms of the disease -
tuberculous meningitis and miliary TB - forms in which
mortality andrisks of sequelae at survivors are increased,
especially in children.
Infectious diseases preventable by vaccination
Difteria:

• Produced by Corynebacterium diphtheria,

pharyngeal infection with incubation for 2-5 days,
5-10% mortality
• Exotoxin inhibits protein synthesis, has local toxic
and necrotic effects:
• Formation of membranes
• Edema
• Compromised airways
• Cardiac - myocarditis
• Neurological –neuritis
• tetanus
produced by Clostridium tetani, induces:
• a localized infection (watch out for tetanus wounds! deep, fractured, crushed, with
devitalized edges, with retained foreign bodies), or
• generalized (late stages or neonatal tetanus, by umbilical cord contamination),
• with a 7-day incubation period (7-21 in generalized form).
• The toxin produced migrates along the axons and it reaches the CNS, where it
blocks the action of inhibitory neurons, producing involuntary painful muscle
contractions, which causes severe pain and can lead to fractures, airway
compromise, death.

• Except for the localized form, mortality is high (> 70% in neonatal tetanus).
Convulsive cough
• produced by Bordetella pertussis or parapertussis
• Respiratory infection after incubation 3-12 days
• It has three phases of evolution:
• The bluish phase - similar to any cold
• The paroxysmal phase - intense coughs that last for minutes, followed by
noisy inspiration
• Infants less than 6 months of age are at higher risk of exhaustion and
apnea
• Convalescence phase - cough lasting a few weeks, significant
leukocytosis, mortality 1-3%

Polio - enteric infection with incubation time 4-10 days until neurological
signs appear
• 95% of the infected have only general signs - enteritis, pharyngitis
• 5% develop neurological affection with or without paralysis, those with
central lesion, lethal potential
• Hepatitis B - one of the main causes of cirrhosis but also of liver cancer
• Transmission by sexual contact or by blood products
• incubation - 1-6 months

• Haemophilus influenzae type B - HiB - the main cause of bacterial meningitis

in children
• other severe manifestations - sepsis, cellulitis, septic arthritis, epiglottis,
• pneumonia
• Meningitis mortality - 5%, epiglottitis - 5-10%, despite treatment

• Measles - eruptive virosis caused by measles virus, with an incubation time of

7-14 days
• Fever, intense oculo-nasal catarrh
• Enantum - sign Koplik
• exanthema
• Mortality 0.1-0.2%
• Multiple complications: croup, pneumonia, encephalitis
• Sequelae - loss of vision, subacute sclerosing panencephalytis
rubella - incubation 14 - 21 days, teratogenic
risk

Mumps - incubation 16-18 days, fever, altered

general condition, swollen parotid glands
Complications - aseptic meningitis, orchitis,
pancreatitis

Otitis and pneumococcal pneumonia -

pneumococcus is the main cause of otitis media
and pneumonia - low frequency by vaccination
Sepsis, meningitis - uninfluenced vaccination
frequency unfortunately
Other common diseases, not included in the
national vaccination program
• Rotavirus

• Meningitis and meningococcal sepsis

• chicken pox

• Viral hepatitis A

• Papillomas and uterine cancer

Romanian Ntional Schedule of Vaccination
Varsa recomandata Vaccinul Comentarii

Primele 24 ore Hepatita B Maternitate

4-7 zile BCG Maternitate
2 luni Hexavalent (DTPa-VPI-Hib-Hep B) Medic familie/simultan
Vaccin pneumococic conjugat

4 luni Hexavalent (DTPa-VPI-Hib-Hep B) Medic familie/simultan

Vaccin pneumococic conjugat

11 luni Hexavalent (DTPa-VPI-Hib-Hep B) Medic familie/simultan

Vaccin pneumococic conjugat

12 luni Rujeola-Rubeola-Oreion Medic familie

5 ani Rujeola-Rubeola-Oreion Medic familie
6 ani Vaccin tetravalent (DTPa – VPI) Medic familie
14 ani Vaccin diftero-tetanic>Vaccin difetro- Medic familie
tetanic – pertussis acellular

24 ani dT pt adulți Medic familie

Vaccines classification

Live attenuated vaccines

Inactivated vaccines

• Cellular inactivated vaccines

• Subunit vaccines
• Proteic subunit vaccines – purified antigens
• Capsular polyzacharides
• Toxoids

Combined vaccines (DTP)

Live attenuated vaccines
• Obtained by attenuating bacteria or virus
• They contain viable cells but poor virulence, unable to induce the
disease
• Capable of causing an immune response similar to natural infection
• More durable and more effective immunity than inactivated vaccines
stimulates all stages of the immune response

• Common side effects

• C-ind in people with immunodeficiency
• Strict storage conditions

• !!! Secondary mutations may return to virulence

• 2 VACCINES can be administered simultaneously or at 30 days interval
• After treatment with immunoglobulins, vaccination is postponed for 6-
10 months
Live attenuated vaccines - examples

• BACTERIAL
• BCG

• VIRUSES
• POLIO ORAL
• MMR
• rotavirus
• chicken pox
Inactivated vaccines
• Requires 3-5 doses for an effective immunogenic response
• cellular inactivated vaccines - made from microbial cultures inactivated
by heat or chemical agents (formaldehyde)
• They can not replicate in the host organism
• They do not cause the disease
• Subunit vaccines - acellular, chemical - are obtained by isolating
some cellular portions capable of inducing a protective immune
response. They are extracted by enzymatic digestion, hydrolysis,
microbial cells, can not replicate, can not cause disease
• protein subunit - putative antigens
• Capsular pure or conjugated polysaccharides (with carrier protein,
increase immunogenicity)
• Toxoids 3-5 doze pt un raspuns imunogen eficient
Inactivated vaccines
• Bacteria – pertussis

• Viruses - influenza, polio, hepatitis A, rabies

• Subunit: hep B, acellular pertussis, influenza, HPV,

• Pure-pneumococcal capsular polysaccharides (Pn23), meningococcus

• Capsular conjugated pneumococcal polysaccharides (PCV 7, 10, 13), H

influenzae B, meningococcus

• Toxoid - diphtheria, tetanus

Important information
• Acute minor illnesses with or without fever are not vaccination
contraindications
• Moderate or severe febrile illnesses are reasons for postponing
vaccination
• Live viral vaccines are NOT transmitted by breast milk
• Human milk does not interfere with immune response to vaccines and is
not a contraindication to vaccination
• The nursing mother can receive any vaccine without contraindications
• Most chronic diseases are NOT vaccination contraindications
• Premature babies should be vaccinated consistent with their
chronological and not gestational age without dose reduction
• Vaccination may possibly be avoided in children with progressive CNS
degenerative diseases
• Inactivated vaccines may be administered together with other vaccines
Vaccines content

• Suspension fluid - sterile water or serum, or complex liquids containing

proteins or other biological constituents

• Preservatives, stabilizers, antimicrobial agents

• gelatin, 2-phenoxyethanol
• Thimerosal - current is found in some influenza vaccines

• Adjuvants - Enhance the immune immune effect

• Aluminum in the form of salts - should be injected deeply to avoid
granulomas, necrosis
 Immune response
• Antibodies synthesis

• T cell dependent - strong and lasting immune response

• T cell independent - polysaccharides - stimulates LfB directly, weaker and
shorter response in the child under 2 years

• Antibody production begins at 7-10 days after administration

• Early - IgM, replaced by IgG reaching a peak 1 month after administration

 Contraindications, precautions

Child health status!

Chronic conditions that affect immunity!

Allergies - contraindications only in case of anaphylactic shock to

the previous vaccine, there are desensitization protocols
Autism - still debatable!

Information source: CDC, FDA

Immune mediated reactions to vaccines
The benefits of vaccination are:

• promotes health;
• have a high degree of coverage, protecting individuals,
communities and the entire population;
• have a rapid effect on the population;
• save lives and are cost-effective