[CIS PIDD] [cis-pidd] poor healing, chronic osteomyelitis, immunologic laboratory abnormalitie

[Yu, Karl [BSD] - PED]

Professors, colleagues,

(I apologize if you are seeing this a second time -- there was a hiccup the first time I sent this out)

I have enjoyed meeting many of you in Houston.

I am hoping that I may get some immunology advice on a fairly difficult case.

I am taking care of a 15 y/o M with neurofibromatosis type 1, an intellectual developmental delay, and otherwise without a significant recurrent infection history, who 8 months ago sustained a gunshot wound to his lower spine, and has since been rendered paraplegic, and in need of intermittent catheterization for neurogenic bladder.  Beginning 4 months ago, his clinical course was complicated by a burn injury that required skin allografting, sepsis due to an ESBL+ Klebsiella pneumoniae bacteremia, and deep soft tissue infections with the same ESBL+ Klebsiella, E coli, Enterococcus faecalis, Poprionobacterium acnes and a sulbactam and meropenem-resistant Acinetobacter baumanii requiring operative management.  He had initially improved on anti-infective therapy, but was readmitted after inflammatory markers showed a substantial increase.  Now, we have diagnosed him with a culture-negative (bacterial, fungal, AFB) septic hip and femoral head osteomyelitis (s/p repeat surgical exploration), a vancomycin-resistant enterococcal urinary tract infection, followed by a candidal urinary tract infection.  He remains on anti-infective therapy with only intermittent improvement on inflammatory markers.  I have unfortunately been relying heavily on laboratory markers as the patient has not mounted a fever since his admission, and cannot give any indication of pain below the waist.  We are also managing hypercalcemia (per Ped Endocrinology likely due to immobilization, borderline high cortisol, FS, LSH, PRL; normal E2, TFTs, testosterone), anemia (mixed; iron-deficiency and chronic disease), deep vein thrombosis (on enoxaparin), recurrent hypomagnesemia and hypokalemia, and depression (started on olanzapine by Ped Psychiatry).

I had been attributing poor healing and protracted disease to this patient's relatively poor nutrition due to diet and continued refusal for NG feeds or G-tube placement.  His pre-albumin ranges from 5 - 16 mg/dL, 1,25-OH2-Vitamin D at < 8 pg/ml.  However, a very experienced Pediatric/Adolescent Rehabilitation Medicine physician has advised me that this patient's slow recovery is, in her experience, beyond the range of expected -- even for malnourished and paraplegic teenagers.  This has led me to investigate if there might be an occult immunodeficiency that may be complicating recovery.

Exam is significant for weight loss (premorbid mass 63 kg.  currently 43 kg).  Slight gynecomastia.  No hepatosplenomegaly or abnormal lymphadenopathy.  Operative site (L anterior hip) clean/dry/intact.  Skin allograft sites healing.  (+) decubitus ulcers at stages 1 and 2 that appear uninfected.

Labs thus far:

WBC 6700/uL.   N53%, L38%, M6%, E3%.  Platelets 439,000/uL
ALC 2189/uL.  CD3+4+ 37%, CD3+8+ 23%, CD16/56+3- 8%, CD19+ 17%.
CD3+4+ CD45RA:CD45O at 14% v. 19%
ESR persistently >= 120 mm/h
CRP ranging 15-165 mg/L.  currently 58
Liver function tests normal except low LDH at 99, high ferritin at 523 ng/ml

Aspergillus blood antigen <0.5 index (negative)
Fungitell (1,3-beta-d-glucan) < 31 pg/ml (negative)
Histoplasma and Blastomyces antibodies negative
HIV antibody negative
Pathology (femoral bone biopsy): acute-on-chronic osteomyelitis. bacterial/fungal stains negative.
Blood cultures negative, including for AFB.

IgG 1772 mg/dL (high), IgA 294, IgM 285.  IgE 65.
Present titers to tetanus toxoid, Hemophilus, and S pneumoniae (16 of 23 serotypes >= 1.3 ug/ml, patient is s/p Prevnar-13 only)
Negative titers to varicella
dihydrorhodamine-123 testing normal
lymphocyte mitogen testing normal against PWM and PHA
Quantiferon Gold indeterminate with nil tube at 0.05 IU IFN-gamma/ml, TB tube at 0.05, mitogen (PHA) tube at 0.21 (low/near-absent) -- repeated 0.05 / 0.05 / 0.14


My questions for the group:
#  Has anyone had any experience with patients with neurofibromatosis type 1 patients having difficulty in dealing with infection and/or wound healing?  I have found one case in the literature with neurofibromatosis co-presenting with CVID.  That's it.
#  Can malnutrition by itself (I have never placed this patient on immunosuppressant therapy) explain an absent IFN-gamma mitogen response in the Quantiferon test, or would this abnormality be sufficient basis to pursue an IFN-gamma/IL-12 defect workup?
#  Are there any other possible diagnoses and diagnostics that we should entertain?

Your advice is appreciated.  Thank you.

  -  Karl

Karl O. A. Yu, M.D., Ph.D., FAAP
Clinical Instructor and Research Fellow, Pediatric Infectious Diseases
Comer Children's Hospital  |  University of Chicago
5841 South Maryland Avenue, MC 6054, Chicago, IL 60637
tel  773.702.9281   |   fax  773.702.1196   |   pager  773.702.6800 @ 3285


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