Case presentation
Case 1: A 22-month-old male with a seven-day history
of intermittent fever, rhinorrhea, cough, poor appetite,
cervical lymphadenopathy, and fatigue presented to an outside hospital.
He was positive for SARS-CoV-2 and was noted to be neutropenic and
anemic and transferred to our hospital.
On arrival, he was tachypneic, tachycardic, and febrile (39.1°C),
but otherwise hemodynamically stable with an oxygen saturation
of 98-100%. The physical exam findings were significant for cervical
lymphadenopathy. A complete blood count (CBC) showed leukopenia (1.4 x
103/mL) with marked neutropenia (absolute
neutrophil count of 0), normocytic anemia (hemoglobin 7.1 g/dL) with
mild anisopoikilocytosis, and thrombocytosis (435 x
103/mL). There is an increase in C-reactive
protein (20.1 mg/dL) and ferritin (459 ng/mL, reference range 22-322
ng/mL). A biopsy of the marrow and the enlarged lymph node was done due
to the lack of clinical improvement and persistence of anemia and
neutropenia. The bone marrow aspirate showed normal trilineal
hematopoiesis and a marked increase in polytypic plasma cells
(~31%) (Figure 1 A-D ). There was no increase
in blasts. A lymph node biopsy did not reveal any pathology. The patient
was treated conservatively and got discharged with a negative COVID-19
test.
Two months later, the patient returned with febrile seizure and was
positive for respiratory syncytial viral (RSV) infection and was managed
symptomatically and discharged. At that time, he was negative for flu
and SARS-CoV-2. He again returned after four days with fever and
cervical lymphadenopathy. An infectious work-up this admission was
negative. CBC showed a new finding of blasts in addition to persistent
neutropenia. A second bone marrow biopsy was performed revealing B-acute
lymphoblastic leukemia (B-ALL) with 54% B-lymphoblasts (Figure 2A-C).
No plasmacytosis was noted.
Case 2: This is a 4-year-old girl presenting with daily fever
(101-103F) for 3 weeks along with knee pain, back pain, decreased
appetite, decreased activities and fatigue. She was treated empirically
with antibiotics for urinary tract infection, however with no relief and
was brought to the ER. She did not have any significant past medical
history apart from asymptomatic COVID-19 infection five months back with
complete recovery. She was up-to-date on her vaccinations and was
unvaccinated for COVID-19. On physical examination she had fever
(100.8F), conjunctival and skin palor, palpable hepatomegaly with no
splenomegaly and no abdominal tenderness. Her other exam findings were
normal and there was no palbable lymphadenopathy. The CBC showed
normocytic anemia (Hb: 8.3g/dL), leukopenia (0.6 x
103/mL) with marked neutropenia (absolute neutrophil
count of 0.1) thrombocytopenia (23K/mm3) and
circulating blasts (Figure 2D). A bone marrow examination was performed
showing aplastic trilineage hematopoeisis with increased blasts (Figure
2E) with a B-ALL immunophenotype, PAX5+/TDT+ (Figure 2F-G)/CD34+ (not
shown).
Discussion: In this case series, we noticed two unique findings
along the course of the patients’ illnesses. First, the unusual
plasmacytosis in the marrow during active COVID-19 infection in the
first patient and the second, is predilection of development of B-ALL
following COVID-19. The peripheral blood findings in the setting of an
acute COVID-19 infection as described previously,1-3include lymphocytopenia, neutropenia, left shifted neutrophilia, and
leukoerythroblastosis. Few bone marrow studies in COVID-19 positive
patients have been reported, mostly from autopsy
studies.4-6 Hemophagocytosis is the most common
finding reported in the bone marrow of these patients, who presumably
had more severe COVID-19 complications. Two studies demonstrated an
increased bone marrow plasma cells in a series of COVID-19
autopsies.4-5 However, the authors did not quantify
the degree of plasmacytosis nor were the plasma cells assessed for
clonality. In our first case, no hemophagocytosis was noted on the bone
marrow aspirate, and a prominent bone marrow polytypic plasmacytosis was
seen, an especially unusual finding in a child.
Limited marrow examination studies in infected patients, have failed to
definitively attribute the presence of increased plasma cells in this
patient to COVID-19 infection. However, the plasmacytosis, elevated
CRP, increased ferritin, and IgA and IgE hypergammaglobulinemia are
suggestive of a hyperinflammatory reaction. Hemophagocytosis and
associated cytokine storm-like clinical presentation are the more
commonly described hyperinflammatory reaction in severe COVID-19
infection.7 In a similar context, prior studies have
showed the presence of excess number of plasma
cells in bronchoalveolar lavage fluid of patients with
severe COVID-19.8-9
It has also been shown that reactive plasmacytosis can be seen in
certain viral infections which can even mimic a plasma cell neoplasm in
their initial presentation.10-12 A recent study showed
that presence of circulating peripheral plasma cells in the context of
COVID-19 infection is associated with a lower mortality
rate.13 In our case, we did not find any circulating
plasma cells in the peripheral blood.
Moreover, there is no known association between acute B-ALL and
COVID-19, and COVID-19 infection precipitating the development of B-ALL
has not been described in the literature. The diagnosis of B-ALL in our
two patients is a second separate malady and may be unrelated to the
patients’ prior COVID-19 infections. It has been hypothesized, however,
that an infectious agent can precipitate development of B-ALL in a
genetically susceptible individual.14-16. The most
common translocation occurring in pediatric B-ALL is ETV6-RUNX1[t(12;21)].15-16 In this context, Greaves proposed
a two-hit model for childhood acute leukemia. Briefly, as per this
model, the ‘first-hit’ happens in-utero with the generation of a
preleukemia clone which harbors leukemia-associated genetic changes. A
subsequent ‘second-hit’ occurs during early childhood possibly by
infectious agents such as viruses, which ultimately favors the
proliferation of the abnormal clones leading to development of acute
leukemia.14-15 Our first patient had COVID-19
infection followed by a RSV infection two months later. Either of these
infections or both could potentially contribute as a ‘second hit’ and
played a role in developing B-ALL. Our first patient’s cytogenetics
study showed a complex abnormal karyotype with trisomies 1,10, 11, 12,
17 and 22 and tetrasomies 4, 8, and 21. FISH study showed pathologic
alterations in the known pre-leukemic genes such as RUNX1 and/orETV6 . The second patient’s FISH detected trisomy 4 8, 14, 10 and
17, and four copies of RUNX1 (at 21q22, corresponding with
trisomy 21), in addition and deletion of CDKN2A . These
observations together may suggest the role of COVID-19 as a
“second-hit” in development of B-ALL, but this is a very preliminary
observation and based on only two cases, and further observations are
required to explore this association.
To the best of our knowledge, our case report is the first to show
marked polyclonal plasmacytosis in an alive COVID-19 patient. This
report also found development of B-ALL in patients following COVID-19
infection. The development of B-ALL in these patients may or may not be
associated with prior COVID-19 infection but keeping in mind the two-hit
model of B-ALL, this merits further investigation to characterize their
role.