You have recieved your COVID19 immunizations but nonetheless are still practicing
telemedicine.
You are shown a picture of a 3-year-old boy who has recalcitrant cutaneous and
lymph node infection with Klebsiella oxytoca (see Panel A below). The infection has not responded to tetracycline (a drug generally
not given to children under the age of 8 because of its detrimental effects on dentition)
despite the factor that in vitro tests indicate the organism is sensitive to achievable blood levels.
The child's past medical history includes an episode of osteomyelitis of a wrist
bone at the age of 6 months. The causative organism was never isolated, but he responded
to a two week course of intravenous oxacillin.
You are told that the child's vital signs are normal and that his physical examination
is unremarkable except for the klebsiella infection.
Except for a leukocytosis of 12,000 (80% neutrophils, 20% lymphocytes) and an
elevated CRP, his laboratory studies, including his blood glucose, BUN, creatinine,
calcium, magnesium, liver function tests, TSH and urinalysis, are within the normal
range.
What is your diagnosis, what test(s) would you order to confirm your suspicions,
and what treatment, if any, do you advise?
DIAGNOSIS: Chronic granulomatous disease (CGD).
CGD is a primary X-linked or autosomal recessive immunodeficiency caused by
a mutation in any one of the components of the phagocyte nicotinamide adenine dinucleotide
phosphate (NADPH) oxidase complex. Neutrophils, monocytes and macrophages utilize
the NADPH oxidase complex to generate reactive oxygen species (ROS) to destroy phagocytosed
pathogens. ROS generated by NADPH oxidase also mediate formation of NETS which trap
extracellular organisms; hence, NET formation is abnormal in patients with CGD. In
addition, neutrophils from patients with GCD have decreased expression of toll-like
receptors (TLR)5 and TLR9, further impairing the patients' innate immune system. These
defects result in phagocytes which are unable to effectively kill intracellular and
some extracellular microorganisms.
GCD occurs at a frequency of one out of every 200,00 live births in the USA.
In North America the majority of infections are caused by 5 pathogens - Staphylococcus aureus, Aspergillus spp., Nocardia spp., Burkholderia spp., and Serratia spp. In addition to bacterial and fungal infections, patients with CGD are at increased
risk of forming pulmonary, gastrointestinal and genitourinary granulomas. This may
be due to impaired phoshatidylserine-dependent recognition and removal of apoptotic
cells (efferocytosis) and uncontrolled inflammasome activity.
Without antimicobial prophylaxis, patients with CGD have an estimated rate of
1 life-threatening infection every 10 months. Trimethoprim-sulfamethoxazole (TMP-SMX),
5 mg/kg/day, has been used routinely for the prevention of bacterial infections in
CGD for over 40 years. Advantages of this antimicrobial agent include its ability
to concentrate in phagocytes and to spare bowel anaerobic flora. The presented case
responded to TMP-SMX treatment and prophylaxis. Immunotherapy with interferon-gamma
has also been used to treat CGD.
The diagnosis in the presented case was established by performing a nitroblue
tetrazolium (NBT)test (see Panel B below).
Panel A. Chronic cutaneous and lymph node infection with Klebsiella oxytoca.
Panel B
A. A normal NBT test in which nitrobluetetrazolium has been converted to formazan (dark
blue staining areas). B. The absence of NBT conversion in a CGD patient.
Dihydrorhodamine flow cytometry is currently the standard diagnostic test for CGD.
Bonus Question: Why are all eyes blue at birth ? Note: a complete expanation is required to receive credit.
Bonus Answer: Pigment in the iris is produced by melanocytes which, at birth, contain little or
no melanin. Brown eyes are produced when melanocytes are stimulated by the sympathetic
nervous system to produce melanin. Hence, brown-eyed patients with long standing Horner's
syndrome (ptosis, miosis, and anhydrosis) may lose pigment in the affected eye (hypochronic
iridis)(see picture, below).
