ORIGINAL ARTICLE

Clinico-laboratory Profile and Outcomes of Megaloblastic

Anemia presenting as Severe Pyrexial Illness mimicking
Tropical Infection
Vineet Behera1*, Rajiv Kumar2, Chaturbhuj Agrawal3, Rajan Kapoor4, Navjyot Kaur5, Velu Nair6
Received: 22 May 2022; Revised: 07 November 2022; Accepted: 14 December 2022

A b s t r ac t • Patients with other causes of macrocytosis

such as hypothyroidism, drugs, chronic
Background: Anemia-causing fever has been described in patients with megaloblastic anemia.
Although the exact mechanism of this is unknown, high-grade fever is relatively less reported. liver disease, and others.12
Materials and methods: This prospective observational study included all new cases of Study Procedure
megaloblastic anemia presenting with febrile illness (>101°F) during a 3-year period. Patients
with existing anemia, comorbidities, and other causes of macrocytosis were excluded. A detailed All cases presenting with high-grade pyrexial
evaluation for megaloblastic anemia and workup for excluding tropical infections was done. The illness detected to have megaloblastic
patients were treated with parenteral vitamin B12, folic acid, and other hematinics. anemia, and qualifying the inclusion and
Results: Around 24 cases of megaloblastic anemia presenting with high-grade fever were exclusion criteria were included in the study.
included, with 14 (58.3%) males, mean duration of fever 7.7 days (4–18 days), and 09 (37.5%) Requisite consent was obtained from all
having temperature >103°F. The mean hemoglobin (Hb) was 8.15 g/dL (3.7–11.1 g/dL), the mean patients. Appropriate clearance was taken
corpuscular volume (MCV) was 111 ± 7.8 fL, 18 (75%) had unconjugated hyperbilirubinemia, from the Institutional Ethics Committee. The
the mean lactate dehydrogenase (LDH) was 814 ± 24 IU/L, and 21 (87.5%) had low B12 or folate clinical and laboratory profile of the cases was
levels. Most showed good therapeutic response to B12 or folic acid with defervescence in 1–5 days studied. Serum vitamin B12, folate levels, and
(mean 2.6 days) and improvement in lab parameters in 1 week. The study population was divided bone marrow examination was done.
into those with temperature ≥103°F, and temperature <103°F it was seen that there was a significant Detailed evaluation was done in the
association (p < 0.05) with leucocyte count of ≤3000/cumm, and MCV ≥110 fL, in patients with
study population which included complete
temperature ≥103°F.
blood count [leucocyte count, platelet
Conclusion: Megaloblastic anemia should be considered in the differentials of a patient presenting
count (Plt), and red blood cells (RBC)
with a febrile illness with no clinical localization and a negative initial fever workup. Early
identification and prompt therapy of this easily treatable disorder are very essential. indices] with PBS (including reticulocyte
count, anemia typing, and features of
Journal of the Association of Physicians of India (2023): 10.5005/japi-11001-0222 hemolysis) and immunechromatographic
card test for vivax/falciparum malaria,
latex agglutination for enteric fever (Widal
B ac kg r o u n d Inclusion Criteria
test), serum immunoglobulin M (IgM)/

M egaloblastic anemia is a common illness The diagnosis of megaloblastic anemia was

known to have protean manifestations
involving various organ systems.1,2 There
are case reports of megaloblastic anemia
presenting as catastrophic acute anemia, and
severe pyrexial illness mimicking infections,
such as malaria, leptospirosis, dengue, rickettsia,
or other bacterial infections. 3–8 Low-grade
fever is known to occur in megaloblastic anemia
but a high-grade pyrexial illness mimicking
a tropical infection is anecdotal and not
known.9–11 We studied all cases of megaloblastic
anemia who initially presented with acute
pyrexial illness mimicking a tropical illness, and
assessed the clinicopathological profile and
outcomes in them.
M at e r i a l s and Methods
Study Design and Population
This was a prospective obser vational
study conducted in a tertiary care hospital in
Western India over a period of 3 years. All cases
of acute high-grade febrile illness who were
detected to have new onset megaloblastic
anemia were included in the study.
immunoglobulin (IgG) for Leptospira, serum
defined as anemia (Hb < 11 g/dL in females
IgM/ IgG/NS1 for dengue, TORCH titers,
and <12 g/dL in males) with any one of the
IgM/IgG for rickettsia, blood and urine
following:
culture, microscopy and staining tests of
• Mean corpuscular volume (MCV) > 110 fL
• Peripheral blood smear (PBS) showing 1
Associate Professor Medicine & Nephrologist,
hyp er-se gmente d neutrophils,
Department of Nephrology; 2Professor,
macroovalocytes, or other typical features Department of Medicine & Hematology,
of megaloblastic anemia. INHS Asvini, Mumbai, Maharashtra, India;
• Bone marrow picture suggestive of 3
Consultant, Department of Medical
megaloblastic anemia. Oncology, Bahrain Specialist Hospital,
• Low serum vitamin B12 or folic acid Manama, Bahrain; 4Professor, Department
levels. of Medicine & Hematology, Army Hospital
(Research & Referral), Delhi; 5Associate
• Moderate to high-grade fever (core body
Professor, Department of Medicine &
temperature >101°F) for at least 3 days. Cardiologist, Command Hospital Air Force,
• Patients ≥ 18 years. Bengaluru, Karnataka; 6Professor and Chief
Consultant, Department of Hematology, Apollo
Exclusion Criteria Comprehensive Blood & Cancer Centre,
Ahmedabad, Gujarat, India; *Corresponding
• Patients who had proven infections, Author
malignancies, or other abnormalities as How to cite this article: Behera V, Kumar R,
an underlying cause of fever. Agrawal C, et al. Clinico-laboratory Profile
• Patients with preexisting anemia, and Outcomes of Megaloblastic Anemia
megaloblastic anemia, or hematological presenting as Severe Pyrexial Illness mimicking
Tropical Infection. J Assoc Physicians
dis order s like ap las tic an emia or
India 2023;71(5):70–74.
myelodysplastic syndrome.

© The Author(s). 2023 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/
by-nc/4.0/). Please refer to the link for more details.
 Megaloblastic Anemia presenting as Severe Pyrexial Illness

stool, urine and sputum, antinuclear antibody of megaloblastic anemia during the study serum B12 and folate levels revealed low
(by immunofluorescence), X-ray chest and period. Six cases had evidence of infection B12 levels in 9 (37.5%), low serum folic acid
ultrasound abdomen were done to evaluate or other causes of macrocytosis and hence levels in 6 (25%), and combined deficiency
for the causes of fever. If any of these tests were excluded. The remaining 24 cases were in 6 (25%), while three patients (12.5%)
were positive, or any other cause of fever included in this study as given in Flowchart 1. had normal levels of both. Bone marrow
was detected, the patients were excluded The average age of patients was 33.9 years examination showed cellular reactive bone
from the study. No antibiotics, antimalarials, (range 17–69 years),14 (58.3%) being males marrow with megaloblastoid changes in all
or other antimicrobials were given. In case and 16 (66.70%) patients were Hindus. A patients.
antimicrobials were started before presenting total of 10 (41.6%) patients consumed a The infec tious disease workup,
to this center, it was stopped. strict vegetarian diet. All patients presented autoimmune workup, radiological evaluation,
The study population was treated for with an acute febrile illness ranging from and cultures were negative in all patients.
megaloblastic anemia with an injection of vitamin 4 to 18 days (mean duration 7.7 days), with Eight (33.4%) of the patients were pure
B12 1000 µg given intravenous/intramuscular 09 (37.5%) having temperature ≥103°F, and vegetarian (milk only) and etiology could
every alternate day, oral folic acid 5 mg once 14 patients (58 %) having chills or rigors with not be ascertained in four (16.5%) patients.
daily, and oral B complex once daily. A packed fever. All patients had features of anemia like Five (20.5%) patients showed gastritis on an
RBC (PRBC) transfusion was given if indicated. dyspnea, fatigue, or palpitations, as given in upper gastrointestinal endoscopy, as shown
Oral or parenteral iron therapy was also added Table  1. Clinical evaluation revealed icterus in Figure 2. About a quarter of all patients
if concomitant iron deficiency was detected. The in 12 patients (50%), splenomegaly and/or had been given anti-infective agents before
subsequent therapeutic response was noted in hepatomegaly in 11 (45.8%), and features of the diagnosis of megaloblastic anemia
terms of number of days to become afebrile, peripheral neuropathy in 4(16.7%), as shown intravenous antibiotics in five (20.8%) and
reticulocyte response, and improvement in in Table 1. Hyperpigmentation of the tongue, antimalarials in one (4.1%) patient.
other parameters. knuckles (Fig. 1), or elbows was a striking
finding seen in 11 (45.8%) patients. Response to Therapy
Statistical Analysis The patients were treated with parenteral
Statistical analysis of the data was carried Laboratory Findings and Evaluation vitamin B12 and oral folate as per the protocol.
out using appropriate statistical packages I nv e s t i g a t i o n s r e v e a l e d a m e a n H b PRBC support was given to five patients
(Statistical Package for the Social Sciences
of 8.15 g/dL (range 3.7–11.1 g/dL), leucopenia, (20.8%) who had features of congestive
version 19). Data was reported as mean ± and thrombocytopenia in 19 (79.1%) patients. heart failure or severe anemia (average
standard deviation (SD). For purpose of MCV was increased in all patients with the of 1.6 PRBC units transfused). The response
comparison, frequency, percentage, and mean (±SD) being 111 ± 7.8 fL (maximum to therapy was closely monitored. The
paired t-tests were used. A p-value of 128 fL), as given in Table  2. The peripheral patients showed a satisfactory improvement
< 0.05 was considered statistically significant.
smear was characterized by macrocytosis with defervescence of fever and a sense
Changes in different parameters between in 19 (79%), hyper-segmented neutrophils of well-being occurring within 1–5 days
the two fever groups were done using the in 20 (83.3%), and other features such as (mean 2.6 days) after initiating therapy. The
student’s t-test for paired observations. macroovalocy tes, Howell Jolly bodies, investigations after one week showed a mean
poikilocytosis, or basophilic stippling. The improvement of Hb of 1.42 g/dL after 1 week,
R e s u lts biochemistry tests revealed unconjugated a fall in mean MCV by 3 fL, a fall in mean LDH
hyperbilirubinemia in 18 (75% cases), by 180 IU/L, and an appropriate reticulocyte
Demographic and Clinical prerenal azotemia, and hypoalbuminemia in response. A serial follow-up showed gradual
Characteristics 5 (20.8%) cases each. LDH was an important normalizing of total leucocyte count (TLC),
A total of 30 cases were presented to this marker being raised in most patients with the platelet count, and bilirubin levels. There was
center with high-grade fever and evidence mean LDH being 814 ± 24 IU/L. Estimation of no mortality in this study.

Flowchart 1: Consort diagram of the study

Journal of the Association of Physicians of India, Volume 71 Issue 5 (May 2023) 71

 Megaloblastic Anemia presenting as Severe Pyrexial Illness

Table 1:  Demographic and clinical characteristics of study population Table  2:  Biochemical parameters of the study
Serial no Variable Total (N = 24) population
n (% of N) Serial Baseline investigations Mean ± SD
Demographic features no
1 Male sex 14 (58.3%) 1 Hb (g/dL) 8.15 ± 1.3
2 Mean age (in years) 33.9 (range 17–69) 2 TLC (/cumm) 2988 ± 1252
3 Pure vegetarian 08 (33.4 %) 3 Plt (/cumm) 78708 ±
4 Hindu religion 16 (66.7%) 3888
Clinical symptoms 4 Absolute neutrophil 1749 ± 804
count
5 Fever - total cases 24 (100%)
Fever < 103ºF 15 (62.5%) 5 MCV (fL) 111 ± 7.8
Fever ≥ 103ºF 09 (37.5%) 6 Serum urea (mg/dL) 36.3 ± 9.6
6 Duration of fever (days) 7.7 (range 4–18) 7 Serum creatinine (mg/dL) 0.9 ± 0.3
7 Chills or rigors 14 (58.3%) 8 Serum sodium (meq/L) 138.3 ± 7.8
8 Gastrointestinal symptoms 06 (25%) 9 Serum potassium 4.08 ± 0.9
9 Encephalopathy 03 (12.5%) (meq/L)
10 Use of antimicrobials 13 (54.1%) 10 Serum albumin (mg/dL) 4.12 ± 0.6
Clinical signs 11 Serum bilirubin (mg/dL) 2.85 ± 1.2
11 Hypotension 09 (37.5 %) 12 Direct bilirubin (mg/dL) 1.59 ± 1.1
12 Tachycardia 07 (29.1%) 13 AST (IU/L) 59.6 ± 29.2
13 Tachypnea 07 (29.1%) 14 ALT (IU/L) 52.4 ± 24
14 Pedal edema 06 (25%) 15 Lactate dehydrogenase 814.4 ± 24
(IU/mL)
15 Icterus 12 (50%)
16 Serum vitamin B12 level 246.5 ± 5.4
16 Pigmentation (knuckles, tongue, and skin) 11 (45.8%)
17 Serum folate level 6.52 ± 1.9
17 Hepatomegaly/splenomegaly 11 (45.8%)
ALT, alanine aminotransferase; AST: aspartate ami-
18 Ejection systolic murmur 10 (41.63%)
notransferase; IU, international units
19 Bilateral crackles 03 (12.5%)
20 Features peripheral neuropathy 04 (16.6%)
Discussion
Megaloblastic anemia was first described
by Addison in 1849 and since then this
disease has fascinated physicians due to
myriad presentations.13,14 Megaloblastic
anemia generally presents as insidious onset
gradually progressive symptomatic anemia
with hepatosplenomegaly, neurological
features, gastrointestinal manifestations,
hyperpigmentation, panc y topenia,
unconjugated hyperbilirubinemia, and other
features of ineffective erythropoiesis.15,16 The
presentation may vary from asymptomatic
chronic illness to an acute rapidly progressing
disease.13
Acute rapidly progressing megaloblastic
anemia is rare and has been described in
Figs 1A and B: Pigmentation of (A) knuckles; (B) tongue in megaloblastic anemia association with inhalational nitrous oxide
exposure, high dose trimethoprim, in dialysis
patients, alcoholics, and debilitated patients on
Factors Associated with High-grade to those with temperature <103ºF were more parenteral nutrition.17-19 Agents such as nitrous
Fever likely to have Hb ≤ 8 g/dL, leucocyte count oxide or trimethoprim cause destruction
The study population was divided into two ≤ 3000/cumm (p = 0.02), Plt ≤ 80,000/cumm, or severe suppression of methylcobalamin
groups based on the intensity of fever — MCV ≥ 110 fL (p = 0.01), LDH ≥ 700 IU/L and serum leading to acute megaloblastic anemia.
those with a temperature of ≥103°F and with bilirubin ≥ 2 mg/dL. There was a significant Fever is known to occur in megaloblastic
a temperature of <103°F. The number of association (p < 0.05) seen with leucocyte count anemia but it is usually mild with only minimal
patients with hematological or biochemical ≤ 3000/cumm and MCV ≥ 110 fL, indicating elevation of temperature (100°F). Studies
20

abnormalities between both groups was that the presence of these abnormalities is have shown that fever occurs in about 40% of
compared, as shown in Table 3. It was seen that more likely to be associated with megaloblastic patients with megaloblastic anemia, caused
patients with temperature ≥103ºF, as compared anemia presenting with a high fever. by a deficiency of either vitamin B12, folic

72 Journal of the Association of Physicians of India, Volume 71 Issue 5 (May 2023)

 Megaloblastic Anemia presenting as Severe Pyrexial Illness

Megaloblastic anemia presenting in this

fashion can mimic various illnesses especially
tropical infections like malaria, leptospirosis,
dengue, rickettsial infections; hematological
m a li g n a n ci e s , h e m o l y ti c a n e m ia , o r
autoimmune conditions.10 Moreover, high
fever with leucopenia, can also be due to
febrile neutropenia in some cases. This
leads to extensive workup and a battery
of investigations for the above-mentioned
conditions which are costly, and cause patient
inconvenience. Moreover, the patients are
often empirically given antimicrobial agents
like broad-spectrum antibiotics, antimalarials,
and antivirals which may be unnecessary.
The timely diagnosis of megaloblastic
anemia prevents the unnecessary battery of
Fig. 2: Etiology of megaloblastic anemia presenting with fever investigations to exclude the abovementioned
conditions, prevents unnecessary fear of
Table 3:  Comparison of hematological and biochemical parameters in megaloblastic anemia with
conditions like malignancy, can restrict the
temperature ≥103ºF and <103ºF (by Chi-squared test, two-tailed p-value given, p-value < 0.05
unnecessary use of antimicrobial agents,
considered statistically significant)
and helps in the timely initiation of B12/folate
Serial no Parameter Temperature ≥103ºF Temperature <103ºF p-value therapy in this easily treatable condition.
N=9 N = 15 A high index of suspicion and early
n (%N) n (%N)
identification of megaloblastic anemia
1 Hb (g/dL) becomes imperative in such a situation
Hb ≤ 8 04 (44.4%) 05 (33.4%) p = 0.52 especially if there is a history of a purely
Hb > 8 05 (55.6%) 10 (66.6%) vegetarian diet, gastrointestinal symptoms,
2 TLC (/cumm) neurological abnormalities, or pigmentation
TLC ≤ 3000 07 (77.8%) 04 (26.6%) p = 0.02 of knuckles or tongue.15 A macrocytic picture,
TLC > 3000 02 (22.2%) 11 (73.4%) typical PBS findings of hyper-segmented
3. Plt (/cumm) neutrophils and macroovalocytes with
Plt ≤ 80,000 06 (66.7%) 06 (40%) p = 0.22 leucopenia/thrombocytopenia, MCV ≥ 110 fL,
Plt > 80,000 03 (33.3%) 09 (60%) biochemical abnormalities such as raised LDH
4 MCV (fL) levels or unconjugated hyperbilirubinemia
MCV ≥110 08 (88.9%) 04 (26.4%) p = 0.01 are strong pointers to the diagnosis of
MCV <110 01 (11.1%) 11 (73.4%) megaloblastic anemia.13,15 The diagnosis
5 LDH (IU/mL) is clinched by a therapeutic response of
LDH ≥ 700 05 (55.6%) 07 (46.7%) p = 0.67 resolution of pyrexia and improvement in
LDH < 700 04 (44.4%) 08 (53.3%) patient condition following parenteral B12 and
6 Serum bilirubin (mg/dL) folate supplementation.
Bilirubin ≥2 06 (66.7%) 06 (40%) p = 0.22 The limitations of this study are that there
Bilirubin <2 03 (33.3%) 09 (60%)
is a rare possibility of this high-grade fever
Bold values are statistically significant (p < 0.05) being caused by an unknown self-limiting
infection like a mild viral illness or other
acid, or both.9 In a study by Tahlan et al.21, the within the bone marrow leads to systemic conditions, which could not be detected
incidence of low-grade fever in nutritional pyrexia.4,10,23 However, the exact cause of fever by the tests done by us. Secondly, it can be
megaloblastic anemia varied from 28 to 60%. in megaloblastic anemia is not established. argued that the response to therapy was
Persistent low-grade fever has been described Megaloblastic anemia presenting as an due to the antimicrobial agents used, in the
in 70% of the females with B12 and/or folate acute severe illness with high-grade fever is patients in whom it was used. But as some of
deficiency in a study from North India.22 The very rare but has also been reported in the these patients persisted to have fever despite
exact cause of pyrexia in megaloblastic anemia literature.3–11 The cause of such a rapid and antibiotic use till B12/folate replacement was
is not known. It may be due to a defect in acute presentation is not understood. It could started, and a group of patients who were not
oxygenation to the temperature regulatory be due to an acute worsening of an underlying given antibiotics also responded well showed
centers in the brain due to severe anemia, compensated disease, precipitated by a trigger that the defervescence is likely due to the use
causing hypoxia to these centers, resulting in such as an infection, comorbid illness, stress, of hematinics, and not antimicrobials.
their stimulation and causing fever.20 However, drugs, and surgery. But in our cases, there It is therefore recommended that
this hypothesis fails to explain the absence of was no clinical or laboratory evidence of any megaloblastic anemia be considered as a
fever in other etiologies with anemia as the of these conditions. Therefore, it is postulated differential diagnosis of tropical illness with
principal manifestation. It is also proposed that that it could be due to a severe manifestation high-grade fever, and clinical indicators as
megaloblastic anemia leads to hyperplasia of of the mechanisms causing fever, as discussed described above and routine investigations
the bone marrow and thus increased activity above. like a complete haemogram with PBS, LDH,

Journal of the Association of Physicians of India, Volume 71 Issue 5 (May 2023) 73

 Megaloblastic Anemia presenting as Severe Pyrexial Illness
and bilirubin be done in all these cases. In case
of doubt, a confirmatory evaluation like bone
marrow evaluation or serum levels of vitamin
B12 or folic acid can be done, and appropriate
treatment should be initiated concurrently
in all these cases to look for the therapeutic
response and avoid unnecessary evaluation
and antimicrobial agents.
C o n c lu s i o n
Megaloblastic anemia has protean
manifestations and can present with
high-grade fever mimicking an infectious
etiology. The exact mechanism of this severe
presentation is not clear and further research
is recommended in terms of larger trials
and studies to establish the mechanism of
the same. Our study demonstrates that in
the Indian context, megaloblastic anemia
should be considered in the differentials of
a patient presenting with a febrile illness
with no clinical localization, a negative initial
fever workup, and a hematological profile
classical of megaloblastic anemia. Early
identification and prompt therapy of this
easily treatable disorder are very essential to
prevent unnecessary investigations for various
tropical disorders and unnecessary usage of
antimicrobial agents.
74 Journal of the Association of Physicians of India, Volume 71 Issue 5 (May 2023)
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