Q:

11/10/2015
The patient is a 19 year-old Caucasian woman with a history of recurrent infections including pneumonia (Mycoplasma, Pseudomonas, strep), staph skin infections, pancreatic insufficiency (two low/normal pancreatic elastase levels and low fecal fat), recurrent sinus infections and "food intolerances". She had a cystic fibrosis genetics screen (106 mutations) which was negative. She also had two sweat chloride tests (at two different CF accredited centers) which were negative. The patient also reports a history of shortness of breath but had normal CT chest without evidence of bronchiectasis. PFTS c/w mild restrictive ventilatory defect. Sputum cultures in past reportedly grew out Pseudomonas. Sputum cultures recently c/w normal respiratory flora, enteric gram negative rods, fungal culture negative, AFB smear and culture negative. In addition, the patient reports that she has a history of a large, thick umbilical cord that was delayed in being detached. The patient's sibling had a similar large, thick umbilical cord. The patient's sister also had encephalitis at the age of 18 months which required extensive occupational rehabilitation. Her sister also has a history of recurrent upper respiratory infections but no pneumonias and no other infections.

The patient also complains of rhinitis, nasal congestion, itchy eyes, postnasal drip and itchy ears.

DATA: September 4, 2015: HIV 1 and HIV 2 negative

August 27, 2013: IgG 747, IgA 140, IgM 127; flow cytometry for T and B cells:
total white blood cell 8400,
total lymphocyte count 1856,
total T lymphocytes 865;
percentage T-lymphocyte 47 (normal is 61–87 percent);
helper–inducer T cells 495 (normal is greater than 600 cells per microliter);
helper inducer T-cell percentage 27 (normal is 32–65 percent);
suppressor cytotoxic T cells 321,
suppressor cytotoxic T-cell percentage 17,
natural killer cells 812 (normal 74–254);
NK cells percentage 44 (normal 4–14 percent)
total B lymphocytes 179%
% of B Lymphocytes 10%

June 29, 2015: White blood cell 7.2, hemoglobin 14.0, hematocrit 40.0, MCV 91.7, platelets 170, mean platelet volume 11.1 (normal 7–11 0.0); normal differential of white blood cells; sodium 139, potassium 4.4, chloride 103, CO2 30, BUN 16, creatinine 0.73, GFR greater than 60, BUN to creatinine ratio 21.9, glucose 83, calcium 9.8, total protein 7.2, albumin 5.1, globulin 2.1, total bilirubin 0.5, AST 23, ALT 15, alkaline phosphatase 81, magnesium 2.0, phosphorus 4.0, LDH 179, total IgE 13.0, free retinol vitamin A) ( 32.3 (normal is 32.5-78); hemoglobin A1c 4.86;
CF analysis 106 mutations: None detected;

October 20, 2015: lymphocyte proliferation studies:
low-normal lymphocyte response to Candida and tetanus;
normal lymphocyte response to PHA, Con A, pokeweed mitogen

I would be very grateful for your thoughts on both of these cases. I want to make sure I don't miss a mild version of a RAG1 deficiency/ Unc 119/MaGT1/Idiopathic CD4 penia. Should I order comprehensive CF gene screens on these patients if other immunodeficiency work-up is negative? At what point would you call any of these Idiopathic CD4 lymphocytopenia

A:



I do not think your patient has a leaky RAG syndrome or other form of combined immunodeficiency. Pancreatic insufficiency is associated with decreased fecal elastase but the stool for fat should be increased, not decreased. You also do not mention if there is a history of diarrhea and weight loss. Nutritional deficiencies, including zinc and caloric reduction, could lead to an increase of infectious problems and lymphopenia. I will assume there is no weight loss and that the pancreatic function is not severely decreased. You also do not mention if there is any imaging of the pancreas that is abnormal. Pancreatic insufficiency could be a result of IgG4 disease from either inflammatory, mass effect or autoimmune pancreatitis. There is also an increase in allergic symptoms as well as shortness of breath with either a restrictive changes or inflammatory lung disease in IgG4 disease. Peripheral IgG4 is increased in 80-85% of affected subjects. Zinc deficiency can be associated with pancreatic disease. Zinc deficiency can result in lymphopenia and impaired lymphocyte proliferation. Alpha-1-antitrypsin deficiency and hemochromatosis could be associated with pancreatic dysfunction and recurrent infection. Finally, complement defects could explain recurrent infection in both your patient and the meningitis of her sibling.

My recommendations are to:
1. Serum or erythrocyte zinc
2. Consider imaging of the pancreas if pancreatic insufficiency is supported by fecal elastase decrease or fecal fat increase.
3. IgG subclasses to be certain IgG4 is not increased
4. Alpha-1-antitrypsin
5. CH50, AH50 and mannose binding lectin
6. Hemoglobin A1C
7. Ferritin and transferrin saturation for hemochromatosis
8. Functional antibody assessment with pneumococcal antibodies followed by non-conjugated pneumococcal vaccine and repeat pneumococcal titers in 6 weeks.

I would not repeat CF genetic screening or obtain another sweat test. I would monitor lymphocyte count and lung function. Consider high resolution CT of chest to evaluate for bronchiolitis or bronchiectasis if lung function shows any decrease with time. I would not recommend genetic screening for immunodeficiency at this time as I do not think the presentation is consistent with a RAG deficiency or other primary immunodeficiency.

I hope this information is of help to you and your patient.

All my best.
Dennis K. Ledford, MD, FAAAAI

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