Abstract:
We present the case of a 35-year-old male with no past medical history
who presented with pancytopenia and melena and was found to have PNH in
the setting of acute COVID-19 infection. Other infectious, autoimmune,
and malignant etiologies were ruled out. It is unclear if this was an
acquired PIG-A mutation or an expansion of a preexisting mutation in the
setting of COVID-19 infection. Emerging evidence shows that the
SARS-CoV-2 spike protein directly activates complement by engaging the
alternate complement pathway which could indicate this is an acquired
PIG-A expanded mutation. To our knowledge this is the first case of
COVID-19 infection presenting as PNH.
A 35-year-old African-American man with history of migraines presented
to the emergency room with headaches and melena associated with fatigue
and inappetence for two weeks. He was initially admitted to the
intensive care unit for suspected gastrointestinal bleed given severe
pancytopenia. He denied any fevers, chills, cough, myalgias, dyspnea,
difficulty breathing, diarrhea, anosmia, or ageusia. He was transfused
two units of packed red blood cells and transferred to general medical
floor as he was hemodynamically stable. At home he was taking ibuprofen
800mg daily for one week due to his headaches. Physical exam was
unremarkable.
Initial laboratory tests showed white blood cell count (1.70K/uL),
absolute neutrophil count (0.82K/uL), absolute lymphocyte count
(0.65K/uL), hemoglobin (5.0g/dL), platelet count (12K/uL), with normal
prothrombin time, partial thromboplastin time, international normalized
ratio, D-dimer, fibrinogen, and normal renal and hepatic function.
Computed Tomography of chest/abdomen/pelvis revealed bilateral lower
lobe opacities.
COVID-19 by nasopharyngeal polymerase chain reaction (PCR) was positive
on Day 1. Viral studies, including parvovirus, human immunodeficiency
virus, cytomegalovirus, Epstein-Barr, varicella zoster, hepatitis B and
C, were negative. Iron studies, vitamin B12, folate, Coombs, and
urinalysis were normal. Exhaustive Rheumatological testing was
unremarkable including complement 3 / 4/ 5 levels, Aldolase, cyclic
citrullinated peptide antibody, anti-nuclear factor antibody, anti-smith
antibody, anti-RNP antibody, anti-double stranded DNA antibody, anti-SSA
and anti-SSB antibody, scleroderma and centromere antibodies. Abnormal
laboratory studies included undetectable haptoglobin (<20
mg/dL), with elevated lactate dehydrogenase (794 U/L), ferritin (503
ng/dL), and erythrocyte sedimentation rate (38 mm/hr). Blood smear
showed poikilocytosis and large granular lymphocytes (LGL) [Figure
1]. Peripheral T-Cell receptor (TCR) gene rearrangement showed
clonality in TCRβ and TCRγ [Figure 2]. Peripheral flow cytometry
revealed normal myeloid and lymphocyte immunophenotype with increased
natural killer-like T-cells (20%). Serum protein electrophoresis was
normal with increased serum kappa/lambda free light chain ratio (2.09;
normal 0.26-1.65), normal by day 17. Serum and urine immunofixation
showed no monoclonality. Bone marrow biopsy showed trilineage
hematopoiesis with maturation. Glycosylphosphatidylinositol-linked
antigen testing revealed “classical Paroxysmal Nocturnal Hemoglobinuria
(PNH)” showing RBC-Complete Antigen (Ag) Loss 4.34% (Reference Range
(RR) 0.00-0.01), Granulocytes 42.55% (RR 0.00-0.01), Monocytes 45.84%
(RR 0.00-0.05) [Figure 3]. Due to his persistent headaches a
Magnetic Resonance Imaging (MRI) of the brain was performed which showed
nonspecific patchy elliptically shaped areas of restricted diffusion and
low marrow signal within the left parietal calvarium, cervical vertebral
bodies, posterior elements, and clivus with minimal if any associated
enhancement. The patient empirically received high-dose pulse steroid
and intravenous immunoglobulin without improvement. He was discharged
home to start eculizumab as outpatient.
Here we present the case of a patient with new onset PNH in the setting
of acute COVID-19 infection without any of the typical symptoms
associated with the disease caused by severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2). PCR testing was positive on days 1 and 7 of
hospitalization, and subsequently tested negative on days 13 and 14.
COVID IgG and IgA antibodies were negative on days 2 and day 4,
confirming this was an acute infection. To our knowledge, this is the
first report of a case of COVID-19 presenting with isolated pancytopenia
from PNH without any of the commonly associated symptoms from the acute
infection. Review of the literature shows the report of a single case of
a patient with a known history of PNH developing acute flare possibly
precipitated by COVID-19 infection.1
There is a known association with LGL clonal expansion in PNH, though
unlikely relevant unless persistently cytopenic post PNH
therapy.2 There was an increase in NK-like T cells,
CD57+/CD3+ comprising 10.3% of the total population with different
subtypes such as CD57+/CD8+ comprising 5.9% of the total population. An
increase in these populations can be seen in conditions such
inflammatory disease, viral infections, following treatment with
chemotherapy or transplant patients and in large granular lymphocyte
leukemia. T-cell rearrangement studies showed discrete bands in both
TCR-beta and TCR-gamma analysis, suggesting a clonal T-cell population.
However, the clinical significance of these findings is unclear in the
setting of pancytopenia and the acute COVID-19 infection.
PNH is an X-linked acquired somatic mutation of the phosphatidylinositol
glycan class A (PIG-A) gene that can cause bone marrow failure,
complement mediated hemolysis, and thrombophilia.5This mutation causes impaired expression of CD55 and CD59 (complement
regulators) which causes dysregulated complement activation.5
Yu et al demonstrated that SARS-CoV-2 spike proteins activate complement
by engaging the alternative complement pathway. 3 This
activation can cause complement mediated damage such as endothelial
injury, hemolysis, and contribute to end organ damage.4 Prior to this admission, the patient had not sought
medical care in years, thus prior laboratory data for the patient is not
available. It is possible that he had subclinical PNH that was
discovered only during the acute COVID-19 infection when he became
symptomatic. It is unclear if the acute COVID-19 infection caused an
acquired PIG-A mutation or expanded an existing PIG-A mutation.