Clinical Radiology 72 (2017) 534e542

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Clinical Radiology
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Pictorial Review

Humoral primary immunodeficiency diseases:

clinical overview and chest high-resolution
computed tomography (HRCT) features in the
adult population
L. Cereser a, *, R. Girometti b, P. d’Angelo b, M. De Carli c, A. De Pellegrin d,
C. Zuiani b
a
Institute of Diagnostic Radiology, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
b
Institute of Diagnostic Radiology, Department of Medicine, University of Udine, Udine, Italy
c
Second Unit of Internal Medicine, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
d
Department of Pathology, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy

article in formation
Humoral primary immunodeficiency diseases (hPIDs) are a heterogeneous group of hereditary
Article history: disorders resulting in abnormal susceptibility to infections of the sinopulmonary tract. Some of
Received 16 November 2016 these conditions (e.g., common variable immunodeficiency disorders [CVID]) imply a number
Received in revised form of non-infectious thoracic complications such as non-infectious airway disorders, diffuse lung
10 March 2017 parenchymal diseases, and neoplasms. Chest high-resolution computed tomography (HRCT) is
Accepted 21 March 2017 a key imaging tool to characterise and quantify the extent of underlying thoracic involvement,
as well as to direct and monitor treatment. The aims of this review are to provide a brief
clinical overview of hPIDs and describe the related chest HRCT imaging features in the adult
population, with a special focus on CVID and its complications.
Ó 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Introduction (ESID).3 Patients with PIDs are often diagnosed in child-

Primary immunodeficiency diseases (PIDs) are a het-
erogeneous group of conservatively defined hereditary
disorders, affecting the development of the immune sys-
tem, its function, or both.1,2 PIDs are recognised as rare
conditions, with a prevalence of 6 in 100,000 inhabitants
according to the European Society for Immunodeficiencies
* Guarantor and correspondent: L. Cereser, Institute of Diagnostic
Radiology, Azienda Sanitaria Universitaria Integrata di Udine, Piazzale Santa
Maria della Misericordia, 15 33100 Udine, Italy. Tel.: þ39 0432 559266;
fax: þ39 0432 559867.
E-mail address: lcereser@sirm.org (L. Cereser).
hood, due to unusual, persistent, and recurrent infections
that manifest early in life4; >40% of diagnoses are made
during adulthood.5 Classification of PIDs is regularly
renewed, due to continuous new evidence of genetic de-
fects implicated in their pathogenesis. Currently, all known
conditions have been catalogued into nine major groups,
according to the most pronounced and fundamental
immunological defect.6
Antibody deficiencies, also known as humoral PIDs
(hPIDs), constitute the most common group of PIDs, ac-
counting for approximately 50% of all diagnoses.7 Patients
with hPIDs suffer from increased susceptibility to infections
of the sinopulmonary tract from encapsulated bacteria and

http://dx.doi.org/10.1016/j.crad.2017.03.018
0009-9260/Ó 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
 L. Cereser et al. / Clinical Radiology 72 (2017) 534e542
viruses. In some of these conditions (e.g., in common variable
immunodeficiency disorders [CVID]) a number of non-
infectious complications, such as autoimmune or granulo-
matous diseases, and enhanced risk of malignancy can occur.8
Chest high-resolution computed tomography (HRCT) is
regarded as the key imaging tool to confirm, characterise,
and quantify the extent of thoracic manifestations of hPIDs,
including infections, non-infectious airway disorders,
diffuse lung parenchymal diseases, and neoplasms.2,9e11 In
patients with pulmonary disease, HRCT also plays an
important role in the multidisciplinary monitoring of the
response to therapy.10,12
The aims of this review are to provide a brief clinical
overview of hPIDs and to describe the related chest HRCT
imaging features in the adult population, with a special
focus on CVID and its complications.
Clinical overview
Classification and epidemiology
hPIDs comprise a heterogeneous group of diseases,
mostly characterised by reduced serum immunoglobulin
levels, with an abnormal number and/or function of B cells.6
Selective IgA deficiency is the most common hPID, affecting
approximately 1:700 individuals worldwide. About one-
third of patients are symptomatic, presenting with recur-
rent infections, autoimmune diseases, or allergies.1,13
CVID is the most frequent symptomatic hPID, with a
prevalence of 1:25,000e50,000 persons.14 The term CVID
includes several clinical and laboratory phenotypes that
may be caused by distinct genetic and/or environmental
factors. It is characterised by low levels of IgG and IgA and/
or IgM, with poor or absent responses to immunisation and
poor specific antibody production.15 The combination with
frequently associated T-cell abnormalities (occurring in up
to 50% of patients) most likely contributes to the hetero-
geneous (“variable”) clinical manifestations of this disor-
der.16 CVID affects males and females equally, usually has a
later age of onset than other hPIDs, and is most frequently
diagnosed in adults aged 20e40 years.8,17
Clinical manifestations and complications
Respiratory symptoms involving the upper and lower
airways are the most common features of hPIDs. Most
frequently involved pathogens are Streptococcus pneumo-
niae and Haemophilus influenzae, as well as opportunistic
agents, particularly in the subset of patients with CVID and
low levels of CD4þ T cells.8,18
In patients with CVID, a wide spectrum of both systemic
and organ-specific non-infectious diseases has also been
reported, leading to the definition of distinct phenotypes,
which include autoimmunity, polyclonal lymphocytic infil-
tration, enteropathy, and lymphoid malignancy.19 The most
frequently involved site is the lung, followed by the gas-
troenteric tract and the liver.18
Increased risk of malignancy harbouring in hPIDs (1.8- to
13-fold increase) is well documented.20 In particular, up to
535
15% of patients with CVID develop malignancy, mostly
gastric carcinoma and lymphoma. Lymphoma is usually
non-Hodgkin’s type, predominantly of B-cell in origin and
extranodal, the majority affecting the lung; lymph node
involvement is also common.21,22 It manifests mostly in the
fourth to seventh decades of life.21 General signs and
symptoms (e.g., fever, poor general condition, night sweats)
are frequently absent; respiratory involvement with chronic
cough and/or dyspnoea may occur.23 As a consequence,
vigilance for malignancies is a major aim for clinicians who
manage patients with hPIDs.8,17
Granulomatous and lymphocytic lung disease (GLILD)
Patients with CVID are prone to developing a restrictive
interstitial lung disease with granulomatous and lympho-
proliferative pattern on biopsy (i.e., lymphoid hyperplasia,
follicular bronchiolitis, and lymphocytic interstitial pneu-
monitis [LIP]), termed GLILD.24 The heterogeneity of histo-
pathological findings of GLILD may account for its
incomplete characterisation, exploiting the complexity of
differential diagnosis with other interstitial lung diseases
displaying combined granulomatous, inflammatory, and
fibrotic features.25 Although GLILD is more common in pa-
tients with CVID (occurring in 10e25% of cases), recent
studies show that similar pulmonary abnormalities can also
manifest in other types of PIDs.21,26
Pathogenesis of GLILD is not clearly understood, with
some ascertained risk factors (i.e., hypersplenism and pol-
yarthritis) and a possible role played by B-cells, T-cells, vi-
ruses (e.g., EpsteineBarr virus, human immunodeficiency
virus [HIV], and human herpesvirus 8), as well as by in-
flammatory and immunoregulatory cytokines (e.g., tumour
necrosis factor alpha [TNF-a] and lymphotoxin-a).27,28
GLILD can be considered as the pulmonary expression of
a multisystemic lymphoproliferative disorder that clinically
manifests with dyspnoea, splenomegaly, diffuse adenop-
athy, and granulomatous inflammation in various organs;
moreover, an increased risk of developing B cell lymphomas
has been reported.24,25,29
Once the diagnosis of GLILD has been made, corticoste-
roids are the most commonly used medications, with gen-
eral improvement in clinical symptoms. Nevertheless, the
induced remission is not long lasting, and relapse of the
disease with cessation of therapy is not uncommon.27,30
Some authors report successful use of cyclosporine (active
against T cells expansion), biologics eliminating B-cells
(rituximab), and combination chemotherapies.30e32
Diagnosis
Early diagnosis of hPIDs enables establishment of
appropriate management, with the aim of reducing serious
morbidity and early mortality.20 Due to the great variability
in presentation (recurrent respiratory infections, along
with inflammatory, autoimmune, or neoplastic diseases),
the appreciation of hPIDs is often limited in daily practice,
leading to delayed diagnosis.33 Recently revised criteria for
the clinical diagnosis of CVID were provided by Ameratunga
et al. and ESID.34,35
536 L. Cereser et al. / Clinical Radiology 72 (2017) 534e542
Figure 1 Lung parenchymal scarring in an 83-year-old male patient
with CVID. HRCT image reformatted on the coronal plane shows
irregular bands at the level of left lower lobe, with traction effect on
the fissure (arrow).
Patient management
Immunoglobulin-replacement therapy (either intrave-
nous or subcutaneous), at regular intervals throughout life,
is the most proved medical intervention for most forms of
hPIDs.4,8 Patients are recommended to undergo baseline
HRCT at the time of diagnosis.2 As recurrent airways in-
fections and related complications are the most frequent
manifestations of hPIDs, imaging is also required for regular
monitoring in patients at risk.2 Concerning the use of HRCT
during follow-up, radiologists and clinicians should keep in
mind the balance between the potential benefit of sequen-
tial imaging and the risk linked to cumulative radiation
exposure, especially in younger individuals and stating the
Figure 2 Infectious pneumonia in a 53-year-old female patient with
selective IgG1 deficit. HRCT image on the axial plane shows consoli-
dation on the right lower lobe, with surrounding ground-glass opacity.
Haemophilus influenzae was isolated following bronchoalveolar lavage.
Figure 3 Infectious bronchiolitis in a 36-year-old male patient with
CVID. Transaxial maximum intensity projection (MIP) image shows
centrilobular nodules and tree-in-bud opacities in the right middle lobe.
Haemophilus influenzae was isolated following bronchoalveolar lavage.
well-known radiosensitivity of patients with CVID.36
Although a precise timeline for sequential imaging over
time is yet to be determined, it may be reasonable to repeat
HRCT as dictated by the patient’s clinical situation, although
a progression of pulmonary disease without overt clinical
deterioration is possible.2 To monitor therapy in patients
with CVID and pulmonary disease, the alternate use of HRCT
and lung function tests (including carbon monoxide diffu-
sion) may represent a balanced management strategy.37
Chest HRCT imaging features
HRCT findings in patients with hPIDs may be subtle and
should be carefully investigated. Normal examinations in
patients with CVID have been recently reported in only
4e6% of cases.38,39
Figure 4 Opportunistic lung infection in a 73-year-old female patient
with selective IgG3 deficit. HRCT image on the axial plane depicts
bronchiectasis associated with peribronchial alveolar consolidation in
the middle lobe and, to a less extent, in the lingula. Concomitant tree-
in-bud opacities in the lower lobes are also depicted. Mycobacterium
fortuitum was isolated following bronchoalveolar lavage.
 L. Cereser et al. / Clinical Radiology 72 (2017) 534e542 537

Figure 5 (a) Bronchiectasis in the same patient at in Fig 4 and (b) in a 70-year-old female patient with CVID. HRCT images on the axial plane
show mild cylindrical dilatation of peripheral bronchi in the lingula (arrow in a) and more prominent, varicose and cystic bronchiectasis,
extending to the pleural surface and nearly replacing the middle lobe (b).

Airways and pulmonary infections
HRCT appearance of airways and pulmonary infections in
patients with hPIDs does not significantly differ from that in
immunocompetent patients. Differences may be related to
more extensive lung involvement or co-existence of signs of
scarring from previous recurrent infections, including
parenchymal lines, reticular abnormalities, and bronchiec-
tasis (more than 50% of cases; Fig 1).9,12 Although scarring
signs are not specific, they are useful to prompt careful
search for more subtle findings to confirm diagnosis or
assess disease progression.
In the acute phase, bacterial pneumonia manifests in the
form of segmental or lobar consolidation (Fig 2), possibly
with cavitation and related hilar and mediastinal adeno-
pathies.10,12 Poorly defined centrilobular nodules associated
with branching linear and nodular opacities (i.e., tree-in-
bud sign) are the typical HRCT findings of infective bron-
chiolitis, frequently sustained by encapsulated bacteria or
viruses (Fig 3).10

Figure 6 Bronchiectasis and mucoid impaction in a 54-year-old female patient with selective IgG3 deficit. (a) HRCT image reformatted on
the sagittal plane shows bronchiectasis in the right lower lobe, with extensive mucous impaction, appearing as branching opacities (straight
arrow). Bronchial wall thickening in the upper lobe is also present (curved arrow). (b) Transaxial minimum intensity projection (MinIP) image
demonstrates an area of hypo-attenuation (regarded as hyperinflation due to collateral air drift) and decreased vascularity surrounding the
bronchiectases with mucous impaction (arrow).
538 L. Cereser et al. / Clinical Radiology 72 (2017) 534e542

Figure 7 Air-trapping in a 54-year-old female patient with CVID. (a) Inspiratory HRCT image on the axial plane barely shows a pattern of subtle
mosaic attenuation in lower lobes. (b) End-expiratory scan at the same level clearly enhances air-trapping, corresponding to lung parenchymal
areas with less than normal increase in attenuation and lack of volume reduction, with lobular pattern.

Opportunistic infections, although more frequent than in be advised if a history of chronic bronchitis or pneumonia
the general population, rarely occur (they are reported to exists, regardless of the presence of symptoms.47
complicate CVID in less than 10% of patients), probably
because adequate T-cell function is preserved in many Bronchial wall thickening
cases.21,40 Fungi, Pneumocystis jirovecii, cytomegalovirus, Bronchial wall thickening is a non-specific and poten-
and Mycobacterium spp. can be encountered as main caus- tially reversible feature, considered as an early sign of
ative pathogens (Fig 4).12,41 inflammation. This finding can occur in isolation or in as-
sociation with bronchial dilatation (Fig 6).44,49 Not sur-
Non-infective airway disorders prisingly, most studies reported bronchial wall thickening
as a frequent HRCT finding in patients with CVID, being
Signs of structural damage of airways, such as bron- present in 40e75% of cases.38,39,46
chiectasis, bronchial wall thickening, and air-trapping, Subjective visual inspection is regarded as the usual
are supposed to be the consequence of the cumulative method for estimation of wall thickness, stating acceptable
effect of infections, although they can also develop levels of inter-reader agreement.50 The application of an
subclinically.39 appropriate HRCT lung window setting, particularly in
terms of width (i.e., setting up values not lower than 1,000
Bronchiectasis HU and not greater than 1,400 HU), is crucial in order to
Bronchiectasis plays an important role in the develop- avoid substantial over- and underestimation.51
ment of recurrent and persistent respiratory infection and
inflammation processes.42 Thus, early detection is essential
to institute prompt treatment, aimed to prevent respiratory
infections and, in turn, the progression of lung structural
changes.39
HRCT is the current radiological technique of choice to
establish the diagnosis of bronchiectasis, which relies on
the visual inspection of typical direct and indirect signs.43
Direct findings include bronchial dilatation (i.e., when
bronchoarterial ratio is greater than 1:1), lack of bronchial
tapering, and visibility of airways in the peripheral lung
zones (Fig 5).44 Indirect findings include bronchial wall
thickening (that can facilitate the visualisation of dilated
small airways in the lung periphery), fluid- or mucus-filled
bronchi (Fig 6), atelectasis (Fig 5b), and tree-in-bud opaci-
ties.44 As CVID patients are more prone to chronic and se-
vere bacterial pulmonary infections than other hPIDs,
bronchiectasis is regarded as the most frequent HRCT
Figure 8 OP in a 58-year-old female patient with CVID. HRCT image
finding, being reported in 40e95% of cases.38,45,46 The right
on the axial plane shows an irregular area of consolidation with air
middle lobe and lower lobes have been described as the bronchogram in the right upper lobe. The bronchial aspirate revealed
most common locations.9,46 no causative microorganisms. At follow-up after corticosteroid
In patients with CVID, the association between low CD4þ treatment (without antibiotics administration) the lesion dis-
T cell counts and bronchiectasis has recently been demon- appeared, while other similar areas of consolidation appeared in the
strated. In such patients, repeated HRCT examinations may contralateral lung (not shown).
 L. Cereser et al. / Clinical Radiology 72 (2017) 534e542 539

Figure 9 GLILD in a 40-year-old female patient with CVID. (a, b) HRCT images on the axial plane show peribronchial nodules with air-
bronchogram (arrow in a) and patchy areas of consolidation and ground-glass opacity along with reticulation and mild bronchiectasis, with
lower lung zones predominance (b). (c) Histology (haematoxylin and eosin stain at 100 magnification) of a transbronchial biopsy (TBB) shows a
bronchiolarealveolar parenchyma with a substantial amount of inflammatory cells mainly consisting of lymphocytes in pseudolobular archi-
tecture and aggressive features towards the epithelial components.

Air-trapping bronchogram (with slightly dilated bronchi), lower lobe

Air-trapping is a well-established sign of small airway predominance, peripheral or peribronchial patchy distri-
disease and a significant determinant of airflow obstruc- bution, with a tendency to migrate over time (Fig 8).54
tion.38 An early involvement of small airways disease in the
process leading to bronchiectasis has been hypothesised.52 GLILD
Hence, a supplementary low-dose expiratory scan is By definition, the term GLILD encompasses different
recommendable in order to detect this finding (Fig 7). In granulomatous, lymphoid (i.e., lymphoid hyperplasia,
CVID, the detection rate of air-trapping on HRCT is reported follicular bronchiolitis, and LIP), and inflammatory lesions
between 45 and 63% of cases.38,39,46 (i.e., OP).25 The possible coexistence of these histopatho-
logical entities in the same patient (what is more, in vari-
Diffuse lung parenchymal diseases able proportion) accounts for the great heterogeneous
appearance of GLILD on HRCT.55
Organising pneumonia
Organising pneumonia (OP) is a non-specific pulmonary
reaction pattern to different pathogenic processes, which
respond to corticosteroid therapy. OP rarely occurs in hPIDs,
manifesting as a consequence of either lung injury
(e.g., recurrent infections), or a postulated immunological
cause.53
HRCT typical appearance varies from ground-glass
opacities to consolidation, with polygonal shape, air

Figure 11 Follicular bronchiolitis in the same patient as in Fig 9. HRCT

Figure 10 GLILD in a 60-year-old female patient with CVID. Trans- image on the axial plane show tiny, ill-defined peribronchial nodules
axial MIP image reveals multiple, small nodules with random distri- (arrows) in the left upper lobe. Polyclonal lymphocyte infiltration in
bution in both lungs. the walls of bronchioles was found at histopathology.
540 L. Cereser et al. / Clinical Radiology 72 (2017) 534e542
Figure 12 GLILD in a 44-year-old male patient with CVID. HRCT
image on the axial plane shows a nodular lesion in the right lower
lobe, appearing as a central ground-glass-like opacity with a sur-
rounding air-space consolidation (reverse halo sign). The finding is
suggestive of OP and disappeared after treatment with rituximab.
Nodules, consolidation, reticulation with mid- to lower-
zone predominance, and smooth interlobular septal thick-
ening are the most frequently reported HRCT findings
(Fig 9).45,56 Nodules can be either small (<5 mm), well-
defined, and randomly distributed, or larger, ill-defined,
and bronchocentric, with a slight predominance in lower
lobes (Fig 10).45,56 Multiple peripheral nodules with air
bronchograms and inconstant “halo sign” (i.e., ground-glass
opacity surrounding the nodule) have also been reported.57
A solitary nodule or area of consolidation is the most
frequent HRCT manifestation of focal lymphoid hyperpla-
sia.58 In follicular bronchiolitis, HRCT demonstrates small
(measuring up to 3 mm in diameter) centrilobular and
peribronchovascular nodules (Fig 11). Additional findings
Figure 13 Non-Hodgkin diffuse large B-cell lymphoma in a 59-year-old male patient with CVID (a, b). CT images on the axial plane show
mediastinal (a) and retroperitoneal (b) soft-tissue attenuating masses, with smooth margins, conforming to surrounding vessels.
include interlobular septal thickening, areas of ground-glass
opacity, and cysts.59 The HRCT findings of LIP in patients
with PIDs most often consist of patchy ground-glass opacity,
reflecting a diffuse interstitial infiltration. Poorly defined
centrilobular nodules and lung cysts may also associate,
reflecting peribronchiolar infiltration with lymphocytes and
plasma cells, and airway obstruction, respectively.60
The more course reticulation may account for pulmonary
interstitial fibrosis, which has been reported to be a com-
mon pathological finding.25 Interstitial fibrosis in GLILD
may resemble idiopathic interstitial pneumonia patterns
such as non-specific interstitial pneumonia (NSIP) and,
rarely, usual interstitial pneumonia (UIP).25
The presence of mildly enlarged lymph nodes in multiple
nodal stations (e.g., mediastinum, hila, axillae, and
abdomen) is another characteristic finding of GLILD.56
Rao et al.25 recently emphasised that OP is a frequent and
potentially prominent histological feature of GLILD (Fig 12).
As a consequence, as the OP reaction pattern (either cryp-
togenic or secondary to known noxae) is also a frequent
cause of lung parenchymal disease in CVID, it is important
not to underestimate the risk of incorrect characterisation
of histological findings when biopsy specimens are limited.
For this reason, it has been suggested to resort to open lung
or video-assisted thoracoscopic (VATS) biopsy over bron-
choscopy whenever possible.25
Thoracic neoplasms
A substantial overlap between thoracic benign lympho-
proliferative disorders (included in the condition of GLILD)
and malignancy in term of HRCT presentation exists.12
Indeed, pulmonary lymphoma may appear as multiple,
bilateral and bronchocentric consolidation or nodules.55
Lymphoma may also present in the classic form of a medi-
astinal soft-tissue attenuating mass or with involvement of
several lymph node groups, conforming to adjacent struc-
tures (Fig 13).10
Coexistence of hypogammaglobulinaemia and thymoma
defines Good syndrome (Fig 14). This is a rare condition
(estimated prevalence of 1:500.000), characterised by
increased susceptibility to autoimmunity and infections,
 L. Cereser et al. / Clinical Radiology 72 (2017) 534e542
Figure 14 Good syndrome in a 68-year-old female patient with CVID. (a) HRCT image on the axial plane with soft-tissue window setting depicts
a peripherally calcified oval mass in the anterior mediastinum. Thymoma was confirmed at surgery. (b) Panoramic magnification of thymectomy
showing a perfectly encapsulated lesion with coarse sepimentation and macrocalcification, consisting of a monomorphic spindle cells popu-
lation. The set of findings is consistent with the diagnosis of thymoma (type A acc. W.H.O 2015; Stage I acc. Masaoka/Koga).
mainly bacterial with a particularly invasive load.61 When
performing CT in patients with thymoma, radiologists
should carefully look for features of pulmonary scarring and
structural damage of airways (frequently overlooked in
everyday clinical practice): these subtle signs may testify to
previous recurrent infections and suggest the presence of
an associated immunodeficiency.
Conclusions
Pulmonary complications are significant determinants of
morbidity and mortality in adult patients with hPIDs.
Knowledge of the pleomorphic HRCT findings is crucial, in
order to correctly recognise different pathological condi-
tions. Signs of structural damage of airways, that are sup-
posed to be the consequence of the cumulative effect of
infections, are the most frequent imaging features. Inflam-
matory, granulomatous, and lymphoid lesions (encom-
passed in the term GLILD) should be suspected when HRCT
shows signs of diffuse lung parenchymal disease. Multiple,
bilateral and bronchocentric consolidations or lung nod-
ules, as well as large lymphadenopathies, should raise the
suspicion of lymphoma. Careful imaging interpretation and
reporting plays a major role in the multidisciplinary man-
agement of patients.
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