Approach to primary immunodeficiencies: Clinical sciences

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Introduction0:00–0:28

Primary immunodeficiencies are inherited conditions that are characterized by defects in one or more components of the immune system.
Patients with immunodeficiencies have increased susceptibility to infection and are at risk for autoimmune and inflammatory conditions.
As well as malignancies. Primary immunodeficiencies can be categorized according to characteristic history and exam features as well as characteristic pathogens.
Now, if a pediatric patient presents with a chief concern, suggesting a primary immunodeficiency first, perform an ABCDE assessment to determine if they are stable or unstable.

Unstable0:28–0:58

If unstable, stabilize the airway breathing and circulation, then obtain IV access. Put your patient on continuous vital sign monitoring and provide supplemental oxygen if needed.
Finally administer IV antibiotics and consider IV immunoglobulin. Next.
Obtain a focused history and physical examination and look for signs suggesting severe combined immunodeficiency or skid.

SCID0:58–2:19

SCD is a primary T cell deficiency associated with severe humoral and cellular immune deficits, which is considered a life threatening medical emergency.
Affected. Patients are typically six months or younger and experience frequent atypical or opportunistic infections caused by bacteria, fungi, viruses or parasites, caregivers commonly report chronic diarrhea and if newborn screening is available results may confirm SCD.
The physical exam, often reveals oral ulcers, decreased or absent lymphoid tissue and possibly mucocutaneous candidiasis.
You might also notice signs of Oman Syndrome, including scaly skin alopecia and edema. With these findings consider SD and obtain a CBC with differential serum immunoglobulin levels.
Flow cytometry for T and B cells. And A chest X ray labs typically reveal decreased lymphocytes and immunoglobulin levels and decreased T and B cell counts or function.
While the xray is likely to demonstrate a small or absent thymus. These combined findings confirm SCD now that we have discussed unstable patients.

Stable2:19–3:26

Let's return to the ABCDE assessment and take a look at stable ones. Your next step here is to obtain a focused history and physical exam.
The patient or caregiver will typically report recurrent severe or opportunistic infections. Patients may also have an abnormal newborn screen, a personal history of an autoimmune disorder or a family history of immunodeficiency.
Additionally, the growth chart might reveal poor growth and suboptimal weight gain. Here's a clinical pearl.
During your evaluation. Remember to rule out secondary causes of immunodeficiency including HIV infection, malnutrition, physiological or psychosocial stress malignancy and medications like corticosteroids or chemotherapy.
At this point, you should consider a primary immunodeficiency and order a CBC with differential and serum immunoglobulin levels, then assess for characteristic features that suggest an associated syndrome.

DiGeorge3:26–5:14

Now, your patient might have a midline facial defect such as cleft lip or palate hypertelorism or features that suggest charge syndrome, including coloboma, heart defects, atresia of the co a restricted growth or development, genital hypoplasia and ear anomalies.
If this is the case, consider Digeorge syndrome, patients with degeorge may have frequent opportunistic infections as well as seizures or a conotruncal heart defect.
The physical exam typically reveals characteristic facial features such as a long face hypertelorism and a broad nose labs often demonstrated decreased lymphocyte count and possibly decreased iga or IgM levels.
Since the thymus produces T cells, it's important to order flow cytometry for T cells and a genetic analysis to look for the classic chromosomal deletion.
Lastly, you order a serum calcium level, a chest X ray to assess the thymus and a neck ultrasound to assess the parathyroid glands.
Flow cytometry typically reveals a decreased T cell count with normal function and genetic analysis confirms a 22 Q 11 deletion.
You'll often see a decreased serum calcium level, an absent or hypoplastic thymus on chest X ray, an absent or hypoplastic parathyroid glands on ultrasound.
With these results diagnosed to George Syndrome. Here's a clinical pearl.
The severity of immunodeficiency in degeorge syndrome depends on thymic function. Children with mild thymic hypoplasia have few infections.
While those with complete Digeorge syndrome and an absent thymus experience profound t cell deficiency and severe lifethreatening infections.
Ok. Let's switch gears and discuss patients with oculocutaneous albinism.

Chediak-Higashi5:14–6:03

This finding should make you consider Shadyac Higashi syndrome affected patients typically have frequent staph aureus infections, photophobia and prolonged bleeding.
The exam usually reveals nystagmus, sparse silvery hair and possibly gingivitis and hepatosplenomegaly. Labs might show decreased neutrophils.
A normal platelet count and normal immunoglobulin levels. Your next step is to perform a right or peroxidase stain on a peripheral blood smear or bone marrow biopsy.
If this demonstrates large Granules or inclusions in all nucleated blood cells, diagnose Shadyac Higashi syndrome. Now, let's discuss patients with ataxia.

Ataxia-Telangiectasia6:03–6:45

This finding should make you think of ataxia, telangiectasia affected patients experience chronic sinopulmonary infections and severe progressive ataxia history might also reveal malignancies like lymphoma or leukemia.
And the exam demonstrates oculocutaneous telangiectasias and neuropathy. Lab findings show absent iga possibly with decreased IgG or elevated IgM.
Next, perform genetic analysis if it identifies an ATM gene mutation, diagnose ataxia telangiectasia. All right, let's move on to patients with eczema.

Eczema6:45–7:00

Eczema is associated with Hyper IgE syndrome and Wiskott Aldrich Syndrome to differentiate the two assess for coarse facial features if present, consider hyper IgE syndrome.

Hyper-IgE7:00–7:33

These patients have frequent staph aureus and candida albicans infections as well as recurrent skin abscesses and pneumonia with pneumatocele.
On physical exam. You may notice eczema and skin abscesses without signs of inflammation.
Labs typically demonstrate elevated eosinophils markedly high IgE levels and normal GG IG A and I GM levels with these findings diagnose hyper IgE syndrome.

Wiskott-Aldrich7:33–8:27

On the other hand, if your patient has eczema with out course facial features, consider Wiskott Aldrich Syndrome due to an X linked recessive inheritance.
These patients are usually biologically male, most have recurrent sinopulmonary infections caused by streptococcus pneumoniae and other encapsulated bacteria.
Many also have prolonged bleeding which is often noticed during circumcision as well as bloody diarrhea and possibly Epstein barr virus related malignancies.
Exam findings typically include eczema and purpura while labs show low platelets decreased I GM elevated IGA and IgE and possibly decreased IgG.
Next order a genetic analysis. If there's a mutation of the Wiskott Aldrich Syndrome protein or WASP gene, you've confirmed the diagnosis of Wiskott Aldrich syndrome.
Ok. Let's switch gears and look at patients who have no features suggesting an associated syndrome.

No Associated Syndrome8:27–8:41

In this case, assess for a history of infections caused by characteristic bacterial pathogens. Let's begin with extracellular encapsulated bacteria such as streptococcus pneumoniae, haemophilus, influenzae and Neisseria meningitidis.

Encapsulated Bacteria8:41–8:55

Next, assess the predominant types of infections your patient has experienced if history reveals invasive meningococcal disease, consider complement disorders.

Complement Disorders8:55–10:05

These patients often have a history of joint pain and some have systemic lupus erythematosus exam. Findings include angioedema and possibly joint swelling or tenderness.
If the labs demonstrate a normal CBC and immunoglobulin levels, perform activity assays of CH 50 which measures the classical complement pathway and ah 50 which measures the alternative pathway if there is decreased ch 50 or ah 50 activity diagnose A complement deficiency.
Here's a clinical pearl. You can check for complement deficiency by using screening panels like ch 50 or a 50 or by measuring individual components including C three C four or mannose binding lectin.
And here's a high yield fact, since the spleen is a lymphoid organ that filters bacteria. Patients with asplenia are also susceptible to infections with encapsulated bacteria.
So make sure these individuals receive pneumococcal and meningococcal vaccines. On the other hand, if your patient experiences sinopulmonary or possibly gastrointestinal infections, consider B cell or antibody defects.

B cell or Antibody Defects10:05–10:19

Next, examine your patient to assess for lymphoid tissue. If you detect no palpable lymph nodes and small or absent tonsils.

X-linked Agammaglobulinemia10:19–11:14

Consider X linked agama globulinemia. Since inheritance is X linked recessive.
Most patients are biological males who present around six months of age with chronic fungal infections and occasionally autoimmune colitis.
Laboratory results included decreased neutrophil count even during times of active infection and decreased immunoglobulins across the board including IGA IgG, IgM and IgE.
Next, perform flow cytometry for B cells and if they're absent, diagnose X linked agammaglobulinemia. Here's a high yield fact, transplacentally acquired IgG antibodies protect infants from infection during the 1st 3 to 4 months of life.
But once they disappear, patients with impaired humoral immunity, experience frequent infections. Ok.

CVID11:14–11:40

Let's move on to patients with normal lymphoid tissue. Here, assess for cutaneous granulomas and if present, consider common variable immunodeficiency or CVI.
These patients might have a history of lymphoma or autoimmune disease and the exam may reveal hepatosplenomegaly if labs show decreased IgG with or without decreased IGA or IgM diagnose CVI.
Now, if your patient doesn't have granulomas, assess for opportunistic infections such as PG O VCI pneumonia, histoplasmosis or cryptosporidiosis.

Hyper-IgM11:40–12:20

A history of opportunistic infections should make you consider hyper IgM syndrome patients or caregivers often report diarrhea, possibly in combination with fractures, osteopenia or inflammatory bowel disease.
As for labs, you'll typically see elevated I GM with decreased GG IG and I GE next, perform a genetic analysis if there's a CD 40 LG gene mutation, diagnose hyper IgM syndrome.
On the other hand, if there is no history of opportunistic infections, consider iga deficiency. These patients have frequent giardia infections and diarrhea and some have celiac disease or inflammatory bowel disease.

Selective IgA deficiency12:20–12:43

If labs reveal very low or absent iga with normal IgG and IgM diagnose selective iga deficiency. Ok.

Leukocyte adhesion deficiency12:43–13:30

Let's move on and look at patients who have polymicrobial infections caused by aerobic and anaerobic bacteria. In this case, consider leukocyte adhesion deficiency.
Caregivers report delayed separation of the umbilical cord, possibly with omphalitis as well as frequent skin and mucosal infections.
During the exam. Look for ulcers without pus and evidence of gingivitis.
Labs show markedly elevated leucocytes even in the absence of infection with normal immunoglobulin levels. Next, obtain flow cytometry for neutrophil adhesion, glycoproteins such as CD 11 B and CD 18.
If these are decreased diagnose leukocyte adhesion deficiency. Finally, if the primary pathogens are catalyzed positive bacteria like staph aureus, Serratia, Klebsiella, Aspergillus and nocardia, consider chronic granulomatous disease or CGD.

CGD13:30–14:26

Here, patients have granulomas of the skin and solid organs as well as recurrent pneumonia, abscesses and osteomyelitis.
They might also experience gastric or ureteral outlet obstruction due to granuloma formation. During the exam, look for gingivitis, folliculitis, lymphadenitis and possibly perirectal abscesses or fistulas.
Lab findings include a decreased neutrophil count and normal immunoglobulin levels. Next, perform flow cytometry using the dihydrorhodamine test also called oxidative burst assay.
If this shows decreased phagocytic oxidase activity diagnose CGD. All right.

Review14:26–15:40

As a quick recap. If you suspect a primary immunodeficiency in an unstable patient, provide acute management and consider skid, which usually presents when the patient is about six months old for those with features.
Suggesting an associated syndrome. Think to George syndrome with midfacial defects and charge syndrome.
Shadya Kashi syndrome is linked to oculocutaneous albinism, ataxia, telangiectasia to ataxia and hyper IgE syndrome and Wiskott Aldrich Syndrome to eczema.
For patients without features of an associated syndrome. Consider specific causative pathogens with encapsulated bacterial infections.
Consider complement deficiency or B cell or antibody defects like X linked agama globulinemia, CVI hyper IgM syndrome and selective iga deficiency.
Keep in mind that patients with X linked agammaglobulinemia are typically six month old. Biological males.
On the other hand, for polymicrobial infections, consider leukocyte adhesion deficiency and for catalase positive bacterial infections.
Think of CGD