Acute leukaemias remain a very serious group of diseases often associated with major
complications and substantial morbidity and mortality. Diagnosis and appropriate anti‐leukaemic
therapy together with any needed supportive therapy should be started as soon as possible.
Any delay in diagnosis or treatment increases the probability of additional medical
complications, including hyperleukocytosis with related leukostasis, tumour lysis
syndrome and coagulopathies or myeloid extramedullary masses. In addition, patients
with acute leukaemias are highly susceptible to infectious diseases unrelated to the
disease itself, to treatment side effects and to individual risk factors.
Severe infectious diseases, such as the plague, cholera and yellow fever, have been
the cause of pandemics throughout recorded human history including in the past two
centuries. For example, 14 international conferences were held between 1851 and 1938
to coordinate responses to major infectious outbreaks. Restrictive measurements including
quarantine and social distancing measures were established and guidelines for sanitary
management of contagious disease were developed.
1
These conferences aimed to maximize protection from disease with minimum effects on
trade and travel.
From its emergence in China, SARS‐CoV‐2 virus has spread all around the world, representing
the most serious health, economic and social crisis of the new millennium.
2
Since the beginning of the SARS‐CoV‐2 epidemic in Italy, the Italian Government has
implemented several restrictive measures to contain the spread of infection. Among
these measures, the lockdown implemented on 9 March 2020 has a positive impact on
disease propagation, in particular in the central and southern regions of Italy.
3
Unfortunately, the overwhelming information on the explosive growth of the number
of SARS‐CoV‐2 cases, the large number of virus‐caused deaths and the necessity to
avoid interpersonal contacts have combined to produce significant anxiety in the general
population. This anxiety has led to underdiagnoses of symptoms in patients with haematological
disorders other than fever and respiratory failures, postponement of haematological
laboratory and radiological tests and deferrals of medical and haematological examinations.
Delays in chemotherapy initiation often negatively affect prognosis, particularly
in young patients with low‐ or intermediate‐risk haematological disease. Moreover,
any postponement of diagnosis and treatment might result in patients progressing to
a high‐risk disease state and acquiring additional genetic abnormalities and hyperleukocytosis.
4
Here we report on eight cases of hyperleukocytosis observed from 17 March 2020 to
22 April 2020 in patients who went to the hospital emergency room after postponing
their medical check‐up for fear of SARS‐CoV‐2 infection. In four cases, the clinical
pictures were complicated by fever and pulmonary symptoms, the proximal reason for
the hospital visit due to the strong suspicion of a SARS‐CoV‐2 infection. One patient
had acute kidney failure and another presented with a bowel sub‐occlusion and spleen
infarction causing severe abdominal pain. Another patient was documented with a pulmonary
infection and femoral artery thrombosis causing intense pain and claudication. Signs
and symptoms of anaemia and asthenia were present in all cases. Each case was tested
twice or three times for SARS‐CoV‐2 before admission to the haematologic ward and
all were negative. Three cases had acute myeloid leukaemia (AML), one was determined
to have chronic myeloid leukaemia (CML) in the accelerated phase, one CML in blast
crisis (BC), one was confirmed to have acute lymphoblastic leukaemia (ALL) and one
was diagnosed with mantle cell lymphoma (MCL) in the leukaemic phase. All patients
arrived at the hospital with hyperleukocytosis (77–326 white blood cells [WBC]/µl)
21–45 days after the occurrence of symptoms that appeared following the implementation
of restrictive measures to delay the spread of SARS‐CoV‐2. To date, three patients
are on induction therapy started 17, 15 and 23 days after hospital admission and 27,
45 and 33 days, respectively, from the occurrence of symptoms or clinical signs. Three
other patients are on antibiotics and supportive therapy, and one patient died three days
after arrival at the hospital on salvage haemodialysis. The patient in CML (accelerated
phase) has just started on hydroxycarbamide (Table I). Although the age of two patients,
at 60 and 63 years respectively (one AML and one BC‐CML) makes them potentially eligible
for intensive treatment, significant pre‐existing co‐morbidities postponed the start
of treatment (still not started), and suggested a less intensive treatment regimen.
Table I
Clinical and biological characteristics of patients diagnosed with haematological
disorders.
Gender (M/F)
Age (years)
Date of diagnosis
Swabs for COVID‐19 testing after diagnosis (number/result)
Diagnosis
Molecular and/or cytogenetics
WBC/μl at baseline
Estimated days of symptoms before going to the emergency room
Symptoms before diagnosis
Comorbidities associated with HL at diagnosis
Follow‐up
F
57
03/17/2020
2/negative
Blast crisis in chronic myeloid leukaemia
P190 BCR/ABL
t(9;22)
299 000
23
Weakness, diffuse purpura, conjunctivitis
Acute kidney failure (creatinine value: 8–6 mg/l)
Death after two days of salvage haemodialysis
F
65
03/18/2020
2/negative
Acute myeloid leukaemia
NPM1
46XX
326 000
27
Fever unresponsive to antibiotics, hypoacusia
Infective lung nodule (9 × 5 cm), severe respiratory insufficiency
On induction chemotherapy after 3 weeks of i.v. antibiotics and antifungal therapy
M
71
03/22/2020
2/negative
Mantle cell lymphoma
t(11;14)
190 000
45
Low‐grade fever, night sweats, intermittent abdominal pain
Bowel sub‐occlusion, spleen infarction
On chemotherapy after 2 weeks of surgical surveillance
M
74
04/03/2020
3/negative
Acute lymphoblastic leukaemia
46XY
137 000
33
Weakness, persistent low‐grade fever, sore throat
Acute kidney failure (creatinine value: 4·6 mg/l), gram positive sepsis
On induction chemotherapy after 2 weeks of salvage haemodialysis and 2 weeks of i.v.
antibiotics
M
65
04/09/2020
2/negative
Acute myeloid leukaemia
FLT3 ITD and FLT3 TKD
46XY
86 000
35
Persistent low‐grade fever, pain on right lower limb associated with initial claudication
Pneumonia, superficial thrombosis of femoral arteries
On treatment with i.v. antibiotics and anticoagulant therapy (chemotherapy not yet
started)
F
65
04/14/2020
3/negative
Acute myeloid leukaemia
FLT3 ITD and NPM1
46XX
95 000
42
Fever unresponsive to antibiotics, persistent cough
Interstitial pneumonia
On treatment with i.v. antibiotics (chemotherapy not yet started)
F
63
04/20/2020
2/negative
Blast crisis in chronic myeloid leukaemia
P190 BCR/ABL
t(9;22); +8 in 4 metaphases
77 000
21
Fever unresponsive to antibiotics
Pneumonia
On treatment with i.v. antibiotics (chemotherapy not yet started)
F
51
04/22/2020
2/negative
Accelerated phase in chronic myeloid leukaemia
P210 BCR/ABL
t(9;22)
175 000
33
Weakness, fever unresponsive to antibiotics
Pneumonia
On treatment with i.v. antibiotics (chemotherapy not yet started)
M, male; F, female; WBC, white blood cells; HL, hyperleukocytosis; i.v., intravenous.
John Wiley & Sons, Ltd
This article is being made freely available through PubMed Central as part of the
COVID-19 public health emergency response. It can be used for unrestricted research
re-use and analysis in any form or by any means with acknowledgement of the original
source, for the duration of the public health emergency.
The fear of diseases, a well‐known psychological phenomenon which most people experience
at least once during their lives, is the consequence of a complex mix of cultural,
epidemiological, familial, social and psychological factors. During history, various
human populations have faced naturally occurring or human‐made disasters, but nothing
in our lifetimes compares to the 2020 health crisis. Over the last century, comparable
events include the Spanish flu pandemic of 1918 and subsequent epidemics such as polio,
HIV, ebola, SARS and swine flu that were more virulent, but smaller in scale and in
duration, and less disruptive globally. The HIV epidemic bears some similarity to
SARS‐CoV‐2, but the key psychological factors causing the delay in diagnosis and treatment
are different in the two situations. In the case of HIV, guidelines recommending HIV
testing every 3–6 months were not followed by the majority of high‐risk individuals.
These results highlighted the importance of HIV stigma as the principal barrier to
HIV testing due to fear of affective, social, healthcare and behavioural consequences.
5
In contrast, the main objective during the present pandemic has been to avoid SARS‐CoV‐2
infection and individuals who are psychologically or socially more fragile may have
exaggerated their implementation of containment measures.
The rapid expansion of SARS‐CoV‐2 in Italy has led to the widespread adoption of screening
measures with two major aims: (i) to limit interpersonal contact and therefore viral
spread; and (ii) to avoid the collapse of hospitals, in particular intensive care
units, due to the exceptionally large volume of patients with SARS‐CoV‐2 or SARS‐CoV‐2‐like
symptoms. Accordingly, Italian health authorities have indicated that in cases of
fever, cough or mild signs of dyspnoea, patients should remain at home, remaining
isolated as much as possible until SARS‐CoV‐2 swab results are obtained. Unfortunately,
fear and anxiety about a disease such as SARS‐CoV‐2 is often overwhelming, causing
difficulties in assessing proper health status and undertaking corrective procedures.
Many haematological diseases, including acute leukaemia, have an asymptomatic onset,
or initial signs indistinguishable from those present in SARS‐CoV‐2 infections. The
majority of acute leukaemias, however, rapidly deteriorate with severe co‐morbidities,
and producing a rapid diagnosis and prompt organization of supportive care is crucial.
Complications are typically present in patients with acute leukaemia, particularly
in those who experience delays in diagnosis or start of treatment. The consequence
may be a worsening of the disease due to the acquisition of molecular abnormalities
or treatment with a less intensive schedule to avoid potentially fatal risks. A complete
haematological assessment at the time of onset of asthenia and/or fever would normally
be the course of action in order to identify the most appropriate treatment path and
potentially a more successful outcome of these haematological disorders (Table II).
Table II
Possible measures to prevent potential delays in haematological disease diagnosis
during the SARS‐CoV‐2 pandemic.
Primary measures
Family doctors
Telephone calls, telemedicine or digital platforms should be utilized to screen patients
for potential haematological symptoms such as persistent or low‐grade fever unresponsive
to antibiotics, cough, weakness, fatigue, weight loss, night sweats, bleedings, lymphadenopathies
and exposure history that potentially could identify patients with SARS‐CoV‐2 infection.
Appropriate personal protective equipment (PPE) should be provided to allow patients
to be seen at home especially in the elderly setting if required by critical clinical
conditions.
Home care services should be promptly activated or, if symptoms persist for >72 h,
refer patients to specific departments.
Home care services
Develop home care services with dedicated staff (e.g., nurses equipped with appropriate
PPE) capable of performing a SARS‐CoV‐2 swab and blood analysis including blood cell
count and assessment of coagulation parameters. These exams should be processed quickly,
within a few hours.
If alterations of blood cell count or coagulation parameters are noted, patients should
be immediately referred to a haematology department or seen by a specialist, regardless
of SARS‐CoV‐2 results
John Wiley & Sons, Ltd
This article is being made freely available through PubMed Central as part of the
COVID-19 public health emergency response. It can be used for unrestricted research
re-use and analysis in any form or by any means with acknowledgement of the original
source, for the duration of the public health emergency.
Little is known about the impact of SARS‐CoV‐2 on non‐haematological diseases. In
a study conducted in Hong Kong, the authors reported delays in seeking medical help
by seven ST elevation myocardial infarction (STEMI) patients. These delays, measured
in the time from symptom onset to first medical contact, were observed after the initiation
of SARS‐CoV‐2 control measures, compared to STEMI patients before the outbreak.
6
Another study in an Italian paediatric hospital research network reported 12 cases
of delayed access to hospital care during the week of March 23–27 across five hospitals.
7
These studies further show how public health emergencies can impact healthcare in
patients unrelated medical conditions.
As a result of the SARS‐CoV‐2 crisis, management authorities of all Italian hospitals
have produced regulations regarding suspension of outpatient visits for non‐urgent
situations, limiting therapies to those that cannot be postponed. Scientific societies
such as the Italian Society of Haematology (SIE) and the Italian Group for Marrow
Transplantation (GITMO) have suggested to proceed with the current haematological
treatment as long as possible, isolating inpatients from visitors and restricting
outpatients to waiting rooms and day hospitals. Our experience indicates that the
need for some haematological patients to be analysed in a hospital setting is at least
as urgent as a patient with a strong suspicion of SARS‐CoV‐2 infection, because any
delay in a diagnosis of acute leukaemia can have a deleterious effect on medium‐ or
long‐term survival. In this period of worldwide health crisis and unprecedented stress
on healthcare systems, haematologists should expect to continue to provide rapid diagnoses
and treatment options to those with more advanced forms of haematological diseases.
Author contributions
MM and PDF designed the study and wrote the paper. CM and PN collected clinical data.
IC and AP did the immunophenotype studies and diagnoses. PDF supervised the study.
All authors gave their final approval to the manuscript.