Diffuse Hyper Pigmented Subcutaneous Nodules as a Primary Manifestation of Disseminated Bacillus Calmette-Guerin Disease in Young Infants

Abstract

Introduction: There are increasing reports of serious adverse events of bacillus Calmette-Guerin (BCG) vaccination in infants with unrecognized primary immunodeficiency disorders (PIDs) in our country. Among these adverse events skin manifestations occur less frequently and are less noticed. Case Presentation: We report on an 11-months-old boy with prolonged fever and diffuse hyper pigmented subcutaneous nodules. Due to lymphopenia, oral thrush and severe adverse reaction to BCG vaccination, the possibility of primary immunodeficiency was considered for him and immunological investigations were done. Conclusions: Subcutaneous nodules in the absence of a local reaction at the site of BCG vaccination may be the sole manifestation of disseminated BCG disease.

Full text

Arch Pediatr Infect Dis. 2015 October; 3(4): e24744. DOI: 10.5812/pedinfect.24744
Published online 2015 August 24. Case Report
Diffuse Hyperpigmented Subcutaneous Nodules as a Primary
Manifestation of Disseminated Bacillus Calmette-Guerin Disease in
Young Infants
Sedigheh Rafiei Tabatabaei 1; Ali Amanati 2,*; Abdollah Karimi 1; Kourosh Goudarzipour 3;
Zahra Chavoshzadeh 1; Maryam Kazemi Aghdam 4; Mohammad Bagher Haghighi 5
1Pediatric Infections Research Center, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
2Professor Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran
3Pediatric Congenital Hemathologic Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
4Pediatric Pathology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
5Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
*Corresponding author: Ali Amanati, Professor Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran, Amir Oncology Hospital; Address:
Fars - Shiraz - Farhang Shahr - against Kosar pool, Fax: +98-7136325655, Postal code: +98-7187915998, E-mail: ali_amanati_1356@yahoo.com
Received: October 21, 2014; Accepted: November 4, 2014
Introduction: There are increasing reports of serious adverse events of bacillus Calmette-Guerin (BCG) vaccination in infants with
unrecognized primary immunodeficiency disorders (PIDs) in our country. Among these adverse events skin manifestations occur less
frequently and are less noticed.
Case Presentation: We report on an 11-months-old boy with prolonged fever and diffuse hyperpigmented subcutaneous nodules. Due to
lymphopenia, oral thrush and severe adverse reaction to BCG vaccination, the possibility of primary immunodeficiency was considered
for him and immunological investigations were done.
Conclusions: Subcutaneous nodules in the absence of a local reaction at the site of BCG vaccination may be the sole manifestation of
disseminated BCG disease.
Keywords:Mycobacterium Bovis; Skin; Immunologic Deficiency Syndromes
Copyright © 2015 Pediartric Infections Research Center. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCom-
mercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial us-
ages, provided the original work is properly cited.
1. Introduction
Disseminated bacillus Calmette-Guerin (BCG) disease
has been estimated to occur at a rate of 1.35 per million
doses of administered vaccine (varies among different
populations) with a high case-fatality rate of 80 to 83% (1-
4). There are increasing reports of serious adverse events
of BCG vaccination in infants with unrecognized primary
immunodeficiency disorders (PIDs) in our country (5-12).
Reticuloendotelial system (lymphadenopathy and hepa-
tosplenomegaly), blood, bone marrow, lung and osteoar-
ticular involvement are known sites of disseminated BCG
disease. Skin manifestations occur less frequently and
are less noticed (3, 4, 13, 14). Nodules in the absence of a lo-
cal reaction at the site of the BCG vaccination may be the
sole manifestation of disseminated BCG disease (2, 15).
2. Case Presentation
An 11-month-old boy was referred to the pediatric infec-
tious ward for assessment of prolonged fever and rash.
The patient had been immunized for his age according to
the national immunization program. He had a 32-month-
old healthy brother. His fever had begun three months
before admission. He had no significant signs and symp-
toms other than intermittent fever for a few weeks after
the primary illness. Few weeks later, diffuse cutaneous
lesions appeared primarily in lower extremities. His le-
sions presented as macules which progressed to subcuta-
neous nodules (Figure 1).
Figure 1. Diffuse Hyperpigmented Subcutaneous Nodules
He was admitted to the local hospital for having fever
and rashes. Initial investigations, prior to admission,
revealed hypochromic microcytic anemia, leukopenia,

Rafiei Tabatabaei S et al.
Arch Pediatr Infect Dis. 2015;3(4):e247442
neutropenia and increase in acute phase reactants, in-
cluding erythrocyte sedimentation rate (ESR) and C-
reactive protein (CRP). Further evaluation confirmed
leukopenia, neutropenia and increase in ESR and CRP, yet
no definite diagnosis was achieved and the patient was
referred to our hospital. He was admitted initially to the
hematology/oncology ward to rule out malignancy and
was then transferred to the infectious ward for further
investigations. In primary physical examination he was
ill and febrile. He looked pale and edematous. Abdomi-
nal distention was notable. Generalized hyperpigmented
subcutaneous nodules were seen on his entire body. No
significant lymphadenopathy was noted. Detection of
hepatosplenomegaly was impossible because of abdomi-
nal distension. Hemoglobin electrophoresis was normal.
Conventional blood culture was negative. Bone marrow
aspiration/biopsy was performed without conclusive re-
sults. In bone survey, no evidence of lytic or sclerotic le-
sions was seen except for diffuse subcutaneous masses.
Punch biopsy from skin nodules was also performed.
Pathological examination revealed non-necrotizing
granulomatous inflammation. In Ziehl–Neelsen staining
many acid fast bacilli were seen (Figure 2).
Immune status work up was also performed and the
possibility of primary immunodeficiency was consid-
ered. The flow cytometry immunophenotyping analysis
of peripheral blood has been summarized in Table 2. In
the immunoglobulin profile study only a low level of
IgA was noted. Nitroblue-tetrazolium (NBT) test was also
done which was more than 95%. Early morning gastric
washing was performed twice, which was positive for tu-
berculosis complex-PCR and acid-fast bacilli both times.
No active infiltration of lung fields were reported by the
chest x-ray, cardio thoracic ratio was in normal ranges,
costophrenic angles were clear and soft tissue and bone
densities of the thorax were unremarkable.
Figure 2. Skin Biopsy
Ziehl–Neelsen staining revealed numerous acid fast bacilli, both intracel-
lularly and extracellularly.
Extensive work was done to rule out other possible viral
and parasitic opportunistic infections (Table 1).
Spiral chest computed tomography scan without con-
trast showed bilateral peribronchial infiltrations with
collapse at the right lower and upper lobs. Band shape
atelectasis was seen in the left lower lob. Bilateral sub-
pleural ground glass opacities were also seen in depen-
dent parts of both lungs (Figure 3). Anti-mycobacterium
bovis treatment was begun with isoniazid, rifampin, eth-
ambutol, ciprofloxacin and clarithromycin. After a week,
amikacin was added to his regimen. Two weeks after
drug therapy the fever subsided and the nodules became
smaller.
3. Discussion
Discussion about differential diagnosis of fever and
rashes could be found in review articles and guidelines
elsewhere. Nonetheless, neoplastic skin manifesta-
tion of hematologic malignancy especially Langer-
hans cell histiocytosis should always be kept in mind.
Table 1. Summary of Virological and Parasitological Workup a
Virus Marker Antibody Type Result Comment
Anti-toxoplasma
Antibody
IgG 24.9 Reactive
IgM 0.25 Non-reactive
Anti CMV Antibody IgG 9.3 Borderline
IgM 0.25 Non-reactive
Anti HCV Antibody IgM Non-reactive
Anti EBV Antibody
(VCA)
IgG 1 Non-reactive
IgM 0.4 Non-reactive
HIV PCR Negative
HIV Antibody Negative
Anti leishmania Anti-
body (IFA)
Negative
a Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; HCV,
hepatitis C virus; HIV, human immunodeficiency virus; IFA, indirect
immunofluorescent-antibody test.
Table 2. Flow Cytometry Immunophenotyping Analysis of
Peripheral Blood
Markers Patient results (%) Absolute Count Gate
CD3 3 < 1 Lymphocyte
CD4 < 1 < 1 Lymphocyte
CD8 3 < 1 Lymphocyte
CD19 68 < 1 Lymphocyte
CD20 61 < 1 Lymphocyte
CD16 18 < 1 Lymphocyte
CD56 2 < 1 Lymphocyte
CD4/CD8 0.33 Lymphocyte

Rafiei Tabatabaei S et al.
3
Arch Pediatr Infect Dis. 2015;3(4):e24744
Figure 3. Spiral Chest Computed Tomography Scan Without Contrast
Showed Bilateral Subpleural Ground Glass Opacities in Dependent Parts
of Both Lungs
These manifestations together with hepatosplenomegaly
can closely mimic those of hematological malignancies
(16). Our aim for the present report however, was
to emphasize on rare manifestation of BCG adverse
events in immunocompromised infants with PID.
Pediatricians should be mindful of the fact that these
complications are not uncommon in immunodeficient
patients in our region (5-12). Notably, presence of acid
fast bacilli within the cytoplasm (intracellularly) is
an uncommon yet interesting phenomena (16). Our
patient fulfilled all diagnostic criteria of disseminated
BCG infection, including presence Mycobacterium bovis
BCG substrain on his skin as indicated by PCR, showing
typical histopathological changes with granulomatous
inflammation and positive tuberculosis complex-PCR
in gastric washing, having systemic symptoms and
more than two areas of involvement beyond the site of
BCG vaccination (hepatosplenomegaly, pulmonary and
skin involvement) (3, 17). Patients with unrecognized
primary immunodeficiency frequently experience severe
complications of live bacterial or viral vaccines (for
example BCG and rotavirus) in early infancy. Unusual
vaccine adverse events could be the first signs of primary
immune deficiencies (2, 3, 8, 12, 17); some authors have
estimated the incidence of primary immune deficiencies
from unusual systemic adverse events of live vaccines
in early infancy (2). These complications may partly be
the consequence of lack of standard newborn screening
programs for primary immunodeficiency. Additionally,
inattention to dubious infant death in the family history
may also contribute to the late diagnosis and treatment of
primary illness. Skin lesions like diffuse hyperpigmented
maculopapular rash and subcutaneous nodules could
be the primary manifestations of disseminated BCG
disease in patients with PID. The cumulative incidence
of PID according to a more recent report of Iranian
Primary Immunodeficiency Registry (IPIDR) is about
9.7 per 1,000,000 individuals during the last seven
years. Among different types of PID, severe combined
immunodeficiency was the most common specific
disorder (in about 21.1%; consisting of 154 cases from a
total of 731 PID patients). This means a ratio of about
one fifth from the total cases of PID who are at increased
risk for serious adverse events of BCG vaccination at
birth. In fact, more than one third of patients with PID
should be considered susceptible to BCG because of
susceptibility of infants and children with congenital
phagocytic disorder (with prevalence of about 17.4%)
to develop systemic BCG disease (18). According to this
report systemic BCG disease was found in 17 cases (2.3
%) as the first presentation of PID, during the last seven
years (2006 to 2013) (18). Considering the numerous
recent reports of serious systemic adverse events of BCG
vaccination (5, 7, 10-12, 19-21) and also based on experience
in our referral tertiary center, the probability of greater
incidence of these side effects as a result of primary
immune deficiency comes to mind. Thus, an additional
local surveillance system designed to evaluate serious
adverse events after live viral and bacterial vaccines at
infection wards may be helpful to establish a databank
and develop research protocols for clinical evaluation,
diagnosis, and management of these adverse events in
infants with PID in Iran.
Acknowledgements
The authors would like to acknowledge the assistance
of the infectious, pathology and hematology/oncology
ward’s staff.
Authors’ Contributions
Abdollah Karimi and Sedigheh Rafiei Tabatabaei de-
signed the study. Mohammad Bagher Haghighi contrib-
uted to the acquisition of data. Ali Amanati performed
the data interpretation and drafted the manuscript.

Rafiei Tabatabaei S et al.
Arch Pediatr Infect Dis. 2015;3(4):e247444
Kourosh Goudarzipour contributed to the hematological
work. Maryam Kazemi Aghdam contributed to the inter-
pretation of pathology. Zahra chavoshzadeh contributed
to the immunologic work.
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