The current pandemic of the novel coronavirus SARS-CoV-2 infection has
affected over 6 million humans around the planet. The clinical
manifestations of Coronavirus disease 2019 (COVID-19) are diverse,
ranging from asymptomatic or mild flu-like symptoms to atypical
pneumonia, severe respiratory distress syndrome, systemic inflammation,
immune dysregulation and dyscoagulation.
Inborn errors of immunity (IEI) are a heterogenous group of more than
430 rare congenital disorders with increased susceptibility to
infection, autoimmunity, atopy, hyperinflammation and cancer. Autosomal
recessive ARPC1B deficiency is an actinopathy, as are DOCK8 deficiency
and the Wiskott-Aldrich Syndrome. Defective actin polymerization affects
hematopoietic cells, impairing their migration and immunological
synapse1, which results in a combined immune
deficiency characterized by leukocytosis, eosinophilia, platelet
abnormalities and hypergammaglobulinemia; and clinically, by eczema and
food allergy, infections caused by bacteria, fungi and viruses,
vasculitis, and bleeding diathesis2.
Here, we describe a male infant patient with known ARPC1B deficiency who
was hospitalized for COVID-19 pneumonia and improved without requiring
intensive care or mechanical ventilation.
An 8-month-old infant was brought to the emergency department with
high-grade fever. His family history is remarkable for one brother who
died as a newborn from intracranial bleeding, and an 11-year-old sister
with the same genetic defect who underwent hematopoietic stem-cell
transplantation twice without success, and is currently on
antimycobacterial treatment, antimicrobial prophylaxis and regular
subcutaneous immunoglobulin. The patient was first seen at age 1-month
old for eczema and rectal bleeding attributed to cow milk protein
allergy. At age 4 months, he developed bronchiolitis caused by
respiratory syncytial virus (RSV) and oral candidiasis. Laboratory
workup revealed leukocytosis (17,500-33,600/mm3), eosinophilia
(5,600-20,100/mm3) and a marginally high (467,000) platelet count; as
well as high serum IgG (737 mg/dL) and IgA (165 mg/dL) with normal IgM
(37.7 mg/dL). CD8+ T lymphocytes were low at 3% (257 cells) and B cells
were elevated at 48% (4,116 cells). Whole exome sequencing identified a
homozygous 46 base-pair deletion in exon 8 of ARPC1B(chr7:99,392,784 hg38; p.Glu300fs).
Upon his arrival to the emergency department he was febrile with
tachycardia and signs of septic shock requiring rapid fluid
resuscitation. He showed no respiratory or gastrointestinal signs. He
also had a post-traumatic ulcerated lesion under the tongue with dark
discoloration, which raised a concern for fungal infection. Intravenous
antibiotics (ciprofloxacin) with antifungal coverage were started within
the first hour, and a dose of intravenous immunoglobulin (IVIG) at
1g/kg. Blood counts revealed leukocytosis, neutrophilia, and mild
eosinophilia without lymphopenia, while platelets were initially found
within normal limits. A day later, blood culture had grownPseudomonas aeruginosa .
During his second day of hospitalization, the patient persisted febrile,
tachycardic and tachypneic, with oxygen desaturation into the low 80s.
Chest X-ray showed nonspecific bilateral interstitial opacities in the
perihilar regions (Figure 1 ). Real-time Polymerase chain
reaction (RT-PCR) for SARS-Cov2 came back positive, and he was then
transferred to a COVID-19 isolation area. The potassium hydroxide (KOH)
test for oral thrush was negative for yeast cells, after which
amphotericin was switched to fluconazole. Supplemental oxygen was
discontinued on day 6 of hospitalization, when mild thrombocytopenia and
a prolonged thromboplastin time (aPTT) (but normal fibrinogen and
ferritin serum levels) were reported. After completing 14 days of
antimicrobial treatment, the patient was discharged without ever
requiring intensive care unit admission or mechanical ventilation.
The behavior of COVID-19 in patients with IEI might help dissect the
immune response to SARS-Cov2. A few cases of adults with COVID-19 and
predominantly antibody deficiencies have been
reported3,4; some of them developed acute respiratory
distress syndrome (ARDS), while some had a milder course of illness.
Based on what we know, innate immune defects in genes involved in type 1
interferon response (such as IRF7, IRF9, TLR3) are the most likely
candidates to result in severe disease and death in patients with
flu-like virus infection5. In a few cases of fatal
influenza A (H1N1), variants in genes associated with familial
hemophagocytic lymphohistiocytosis (FHL) and a decreased cytolytic
function of NK cells, were also reported6.
Our patient was on monthly supplemental IVIG treatment, and he received
an additional dose during his hospital stay. This, and his young age,
might have ameliorated the clinical course7. He had a
favorable evolution, despite the known susceptibility to viral infection
and immune dysregulation in ARPC1B deficient
patients1. There were no signs of severe infection,
ARDS, hyperinflammation or of “cytokine storm” unleashed by
SARS-CoV-2. Despite his having a combined immune deficiency, our patient
fully recovered without the need of additional supportive measures other
than IVIG, supplemental oxygen and antibiotic treatment directed against
the documented bacteremia.
Although pediatric cases of COVID-19 are fewer compared to adults, some
severe presentations and deaths among children have been reported. The
presence of a restricted repertoire of IgG (since infants have no
previous exposure to coronaviruses) might play a role in the better
outcome seen in pediatric patients. Antibody-dependent enhancement has
been implicated in the development of severe COVID-19 in the
elderly8. Additionally, lung cells from children and
women show a lower expression of membrane-bound ACE-2, which may also be
protective against severe pneumonia.
Conceivably, some immune defects could protect patients with certain
IEIs from mounting a full uncontrolled inflammatory response against
SARS-Cov2. The cytoskeleton is a regulator of gene transcription,
coupling cell mechanics with the activity of NF-κB. Coronaviruses are
thought to alter the cytoskeleton architecture to facilitate viral
replication and output9. Thus, ARPC1B deficiency and
other actinopathies might limit SARS-CoV-2 replication. Furthermore, Th2
cytokines modulate ACE2 (angiotensin-converting enzyme 2) and TMPRSS2
expression in airway epithelial cells10, and children
with allergies (asthma and/or allergic rhinitis) have a lower expression
of ACE211. Patients with ARPC1B deficiency often have
allergic diseases; their Th2-biased response could help explain the
milder presentation seen in our patient. Insights from protective
mechanisms in children, with and without certain immune defects, could
facilitate the identification of therapeutic targets.
Lina Maria Castano-Jaramillo1, MD
Marco Antonio Yamazaki-Nakashimada1, MD
Selma Cecilia Scheffler Mendoza1, MD, MS
Juan Carlos Bustamante-Ogando2, MD, MS
Sara Elva Espinosa-Padilla2, MD, PhD
Saul O. Lugo Reyes2, MD, MS.
From the (1) Clinical Immunology Service, and the (2) Immunodeficiencies
Research Unit, at the National Institute of Pediatrics, Mexico City,
Mexico.
Conflict of interests: None
Ethical statement: The patient and his family gave written informed
consent for the diagnostic procedures and for publication of the case
report.
KEY WORDS: Primary immune deficiency, inborn errors of immunity,
combined immune deficiency, ARPC1B deficiency, actinopathy, children,
COVID-19, SARS-Cov-2, allergy, pneumonia, sepsis.