[CIS PIDD] [cis-pidd] Hemophilia, HLH, chronic lung disease, abnormal NK function

[CIS-PIDD]

Subject is an almost 8 year old male with hemophilia A (Factor VIII deficiency) since birth, treated with rhFVIII. There was no significant infectious history until 2013 (age 4 yrs.) when Mycobacterium sp. was cultured from central venous line (CVL) used for factor replacement. In 2014 (age 5 yrs.) he developed intermittent high fevers and other symptoms leading to a diagnosis of hemophagocytic lymphohistiocytosis (HLH). He was treated on protocol HLH-94 with dexamethasone, etoposide and cyclosporine A. Decreased CD107a degranulation was demonstrated (lab results below) but genetic analysis of 14 HLH-associated genes (Cincinnati) was non-diagnostic. His HLH went into remission, but he developed multinodular pulmonary disease. Normal CXRs were documented in 2013. Lung biopsy revealed caseating granulomas and he was started on TB therapy. Eventually M. fortuitum was cultured and he was switched to ciprofloxacin and azithromycin. At around the time of HLH treatment, he was found to have a FVIII inhibitor and was treated on an immune tolerance protocol of higher doses of FVIII. Since completing HLH therapy, he continues in remission, but a variety of micro-organisms continue to be isolated from his CVL, including M. fortuitum, Corynebacterium pseudodiphtheriticum, Acinetobacter sp., S. viridans, and S. epidermidis. The CVL has been replaced four different times. He continues with diffuse pulmonary disease, CT demonstrates multiple nodules, patchy ground glass opacities, tree-in-bud formation. He remains on prophylaxis with trimethoprim-sulfa.
Additional systems review

*        Spontaneous subdural bleed at age 6 mos. with seizures, complete recovery, seizure free

*        Recurrent left knee pain and swelling

*        Episodes of rash around the time of HLH presentation, but not recently

*        Sporadic mild elevation of blood glucose but never reached a level of concern
Lab summary

*        CBC-no persistent abnormalities

*        IgG 1120, IgA 152, IgM 1100 (2014)

*        ANA neg (2014)

*        HIV 1/2 neg (2014)

*        sIL2R 16,342 (2014), 837 (2015)

*        EBV 266 copies/mL (2014), negative (2015), EBV serology-evidence of prior infection

*        CD107a degranulation 8% (nml 11-35) (Cincinnati 2014); repeat 11% (2016)

*        Lymphocyte subsets-CD3 2596, CD4 1251, CD8 1019, CD16/56 279, CD19 523 (2016)

*        Quantiferon gold-positive, with positive mitogen control (2016)

*        NK function 6 LU30 (nml 7-125) (Quest 2016)

*        Neutrophil oxidative burst 97% (DHR, Quest 2016)

*        SAP/XLP1 expression by flow 94-98% (90-100)

*        XIAP/XLP2 expression 96-98% (>89)

Questions (for starters):

*        Are the abnormalities in NK function clinically significant?

*        Could persistent NK abnormalities be due to HLH therapy?

*        Does he have a primary NK cell abnormality?

*        Was his HLH acquired or intrinsic?

*        Is FVIII deficiency related to his other problems (excluding the CVL issues)?

Suggestions?


Anthony J. Infante, MD, PhD
Professor, Department of Pediatrics
Associate Chairman for Research & Academic Affairs
Chief, Division of Immunology & Infectious Diseases
University of Texas Health Science Center at San Antonio
7703 Floyd Curl Drive MC7802
San Antonio, TX 78229-3900
infantea at uthscsa.edu<mailto:infantea at uthscsa.edu>
tel.210-567-0510
fax 210-567-6305
Admin. asst. Stella Wise 210-567-5250
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