A Review On Guidelines For Management and Treatment of Common Variable Immunodeficiency

Expert Review of Clinical Immunology
ISSN: 1744-666X (Print) 1744-8409 (Online) Journal homepage: https://www.tandfonline.com/loi/ierm20
A review on guidelines for management and

treatment of common variable immunodeficiency
Hassan Abolhassani, Babak Torabi Sagvand, Tahaamin Shokuhfar, Babak

Mirminachi, Nima Rezaei & Asghar Aghamohammadi
To cite this article: Hassan Abolhassani, Babak Torabi Sagvand, Tahaamin Shokuhfar, Babak
Mirminachi, Nima Rezaei & Asghar Aghamohammadi (2013) A review on guidelines for
management and treatment of common variable immunodeficiency, Expert Review of Clinical
Immunology, 9:6, 561-575, DOI: 10.1586/eci.13.30
To link to this article: https://doi.org/10.1586/eci.13.30
Published online: 10 Jan 2014.
Submit your article to this journal
Article views: 15191
View related articles
Citing articles: 8 View citing articles
Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=ierm20
CME Review
For reprint orders, please contact reprints@expert-reviews.com
A review on guidelines for

management and treatment
of common variable
immunodeficiency
Expert Rev. Clin. Immunol. 9(6), 561–575 (2013)
Hassan Abolhassani1, Common variable immunodeficiency (CVID) is the most common symptomatic primary
Babak Torabi immunodeficiency in adults. As symptoms of CVID are usually heterogeneous and unspecific,
Sagvand1, Tahaamin diagnosis and follow-up of CVID can be challenging. In light of this, a broad review of advances
in management and treatment of CVID is performed here in order to reach a distinct protocol.
Shokuhfar1, Babak
However, it should be noted that owing to the nature of the disease, it can only be treated
Mirminachi1, Nima symptomatically but not cured. There is little evidence to guide appropriate or universal guidelines to
Rezaei1,2 and Asghar improve the current status of management of the disease. The most satisfactory treatments of CVID
Aghamohammadi*1 could be achieved by the use of immunoglobulin replacement, antibiotics, immunosuppressants and
1
Research Center for hematopoietic stem cell transplantation. This review is written based on the importance of clinical
Immunodeficiencies, Pediatrics Center surveillance of asymptomatic CVID cases and early recognition of different clinical complications.
of Excellence, Children’s Medical
Moreover, for each complication, appropriate interventions for improving outcomes are mentioned.
Center, Tehran University of Medical
Sciences, Tehran, Iran
2
Molecular Immunology Research
Keywords: clinical phenotypes • common variable immunodeficiency • management • prevention • screening
Center; and Department of • treatment
Immunology, School of Medicine,
Tehran University of Medical Sciences,
Tehran, Iran Medscape: Continuing Medical Education Online
*Author for correspondence:
Tel.: +98 216 642 8998
This activity has been planned and implemented in
Fax: +98 216 692 3054
aghamohammadi@tums.ac.ir accordance with the Essential Areas and policies of the
Accreditation Council for Continuing Medical Education through the joint sponsorship of
Medscape, LLC and Expert Reviews Ltd. Medscape, LLC is accredited by the ACCME to provide
continuing medical education for physicians.
Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA
Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent
of their participation in the activity.
All other clinicians completing this activity will be issued a certificate of participation. To par-
ticipate in this journal CME activity: (1) review the learning objectives and author disclosures;
(2) study the education content; (3) take the post-test with a 70% minimum passing score and
complete the evaluation at www.medscape.org/journal/expertimmunology; (4) view/print certificate.
Release date: 30 May 2013; Expiration date: 30 May 2014
Learning objectives
Upon completion of this activity, participants will be able to:
• Analyze the clinical presentation of CVID
• Assess the practice of exogenous IgG administration to patients with CVID
• Evaluate pulmonary complications of CVID and their management
• Evaluate other potential complications of CVID
www.expert-reviews.com 10.1586/ECI.13.30 © 2013 Expert Reviews Ltd ISSN 1744-666X 561

Review Abolhassani, Torabi Sagvand, Shokuhfar, Mirminachi, Rezaei & Aghamohammadi CME
Financial & competing interests disclosure

Editor
Elisa Manzotti
Publisher, Future Science Group, London, UK.
Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.
CME Author
Charles P Vega, MD
Associate Professor and Residency Director, Department of Family Medicine, University of California, Irvine.
Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.
Authors and Credentials
Hassan Abolhassani
Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
Disclosure: Hassan Abolhassani has disclosed no relevant financial relationships.
Babak Torabi Sagvand
Disclosure: Babak Torabi Sagvand has disclosed no relevant financial relationships.
Tahaamin Shokuhfar
Disclosure: Tahaamin Shokuhfar has disclosed no relevant financial relationships.
Babak Mirminachi
Disclosure: Babak Mirminachi has disclosed no relevant financial relationships.
Nima Rezaei
Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences; Molecular
Immunology Research Center and Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Disclosure: Nima Rezaei has disclosed no relevant financial relationships.
Asghar Aghamohammadi
Disclosure: Asghar Aghamohammadi has disclosed no relevant financial relationships.
Common variable immune deficiency (CVID) as a heterogeneous hypogammaglobulinemia are considered as criteria for diagno-
group of primary immune deficiencies is characterized by insuf- sis of CVID (Figure 1) [24–26] . Furthermore, approximately 2% of
ficient serum levels of immunoglobulins (Igs), reduced response to CVID patients may represent clinical or laboratory features that
specific antigens and higher incidence of repeated infections [1–4] . suggest a known severe combined primary immunodeficiency
Autoimmune disorders, lymphoproliferative disorders and gastric (e.g., opportunistic fungal or viral infections, very low numbers of
complications also have an increased incidence in patients with T cells and/or monocytes). Although this phenomenon is rare, this
CVID [5,6] . The prevalence of this predominantly antibody defi- is important because such patients may need stem cell grafts [27] .
ciency should not be thought of as being rare (1:10,000–50,000) Heterogeneity in CVID refers to variability in immunological
and CVID is the most common symptomatic human primary and genetic defects and diversity in clinical symptoms described
immunodeficiency [7–9] . The onset (early or late) and clinical man- in this group of patients [19,28,29] . The main immunological defect
ifestations (distinct phenotypes) of the disease have heterogenous is failure of B-cell Ig production, although abnormalities have
presentations [10–12] . This variability in clinical phenotype and been described in all other components of the immune system
late onset of disease may lead to delay in CVID diagnosis [13,14] . [30,31] . Only some CVID cases are due to monogenic Mendelian
The molecular basis, both immunologically and genetically, of diseases and homozygous mutations in that some genes have been
CVID is still unclear despite huge amounts of evaluation in this reported in some CVID families [17,18,32] .
field since 1953 [15] . However, during the last 10 years, 10–15% of The clinical spectrum of CVID is broad. The main clinical man-
the patients with a history of CVID manifestations are classified ifestations are recurrent infections occurring in the respiratory tract,
in other primary immunodeficiency categories because of specific GI tract, skin and soft tissues [4,33,34] . However, inflammatory com-
identified gene mutations including ICOS, CD19, CD20, CD81, plications occur in varying proportions and include autoimmunity,
CD21 and LRBA1 [16–23] . Decreased serum level of IgG, IgA chronic lung disease, bronchiectasis, gastrointestinal (GI) disease
and/or IgM (at least 2 standard deviations below the mean for the with or without malabsorption, systemic or localized granuloma-
age group), hyporesponsiveness to specific antigens, minimum age tous disease, liver disease, splenomegaly, lymphadenopathy with or
of 4 years, absence of lymphoid malignancy during the first 2 years without lymphoma and other malignancies [26,35] . By using data of
of diagnosis and genetic exclusion of other known etiologies for clinical manifestations and complications from 334 CVID patients
562 Expert Rev. Clin. Immunol. 9(6), (2013)

CME Management of common variable immunodeficiency Review
from seven European centers, five different clinical phenotypes CMV, Clostridium difficile, Helicobacter pylori, HBV, HCV and
were considered for these patients [13] . In the revised phenotyping so on. Giardiasis is the most prevalent GI infection, especially
criteria, lymphoid malignancies were excluded [36] . in those with undetectable serum IgA levels [54] . H. pylori is
Over the last few years, advances have been made in the man- an important pathogen in CVID, resulting in chronic active
agement of CVID, improving outcomes in the patients; these gastritis involving antrum and corpus, achlorhydria, gastric
include Ig replacement, antibiotics for treatment and preven- adenocarcinoma and gastric lymphoma [55,56] .
tion of infections and appropriate therapy for noninfectious The CNS (meningoencephalitis is especially caused by
complications [37] . Enterovirus spp.), joints, bones (especially due to Mycoplasma
IgG replacement is the mainstay of treatment of CVID [35] spp.), skin and eyes are also affected by CVID and their involve-
and it has been shown that long-term Ig replacement therapy ment might be the first and sole presentation of CVID [57] . Fibrotic
for CVID has reduced the rate of infections and their long-term bladder can develop due to recurrent urinary tract infections due
complications [38–41] . However, despite the reduction in the rate of to Ureaplasma urealyticum [25,36] .
bacterial infections by use of IgG replacement in CVID patients, Viral hepatitis (especially HCV transmitted by intravenous Ig
these patients are still more susceptible to complications because [IVIG] administration) and severe Herpes zoster infection have been
of a dysregulated immune response that attracts the caregiver’s reported in large numbers of patients [4] . Because of recent devel-
attention. Here, the authors review the recent advances in CVID, opments in Ig preparation including careful selection of donors,
specifically the clinical features, and focus on the management plasma antibody screening and effective procedures of viral inacti-
and treatment of CVID. Other specific classifications based on vation, the rate of these infections are now very rare in the western
immunological property of CVID cases (including Freiburg, world [58] . CMV is involved in many inflammatory complications
Paris, EUROclass and severe T-cell defect classification) exist,
however their importance for clinical management are under eval-
uation [42–46] . Moreover, the authors review the recent advances
on the management and treatment of CVID.
CVID
Clinical manifestations of CVID
The clinical manifestations of CVID constitute six major
categories including: infections, pulmonary complications,
LRBA1
granulomatous or polyclonal lymphocytic infiltrative diseases,
autoimmunity, GI diseases and neoplasias (Table 1) . These can
be established in different periods of life, from childhood to late CD20
adulthood, with a bimodal age distribution, demonstrating two
peaks between 1 and 5 years and 18 and 25 years [3,4,47] . CD19, CD21, CD81
Management of infectious complications

ICOS
Virtually all CVID patients encounter chronic or recurrent infec-
tions, particularly sinusitis, otitis, bronchitis and pneumonia
[47–49] . Approximately 90% of CVID patients have encountered HIGM
at least one episode of chronic sinusitis and 70% have suffered
recurrent otitis media before diagnosis [50–52] . Previously, there had XLP
been a history of at least one episode of pneumonia before diagno-
sis in 75–85% of the CVID patients as well as multiple episodes
XLA
in many others [38,41] . The majority of morbidities and mortalities
of CVID is due to long-term sequelae of recurrent r espiratory tract
infections including chronic sinusitis, hearing loss (due to tym- SCID
panic membrane perforation) and bronchiectasis [4] . Encapsulated
(Haemophylus influenzae, Streptococcus pneumoniae) or atypical
(Mycoplasma spp.) bacteria are the major causative agents for recur-
rent infections of both the upper and the lower respiratory tract
[4,35,53] . Failure of antigen-specific IgG production, which increases
susceptibility to encapsulated bacteria, seems to be responsible for
Figure 1. Differential diagnosis for common variable
recurrent rhinoviral infections in CVID [51] . immunodeficiency with definite single defect gene.
The GI tract is the second organ that is involved in infections CVID: Common variable immunodeficiency; HIGM: Hyper IgM
in 10–40% of the CVID cases. Various pathogens can cause syndrome; ICOS: Inducible T-cell costimulator; SCID: Severe
GI infections in CVID patients including: Giardia lamblia, combined immunodeficiency; XLA: X-linked
Campylobacter jejuni, Salmonella spp., Cryptosporidium parvum, agammaglobulinemia; XLP: X-linked lymphoproliferative disease.
www.expert-reviews.com 563
Table 1. Abstracted guideline for management of common variable immunodeficiency complications.
Type of clinical Prevention Screening Treatment
complication
Infectious Ig replacment; prophylactic Patients’ awareness; sputum High dose Ig; threaputic antibiotics
antibiotics; vaccination monitoring; routine visits
Pulmonary Control of infection; high dose Ig Spirometry; HRCT; routine visits Endoscopic sinus surgery; inhaled
corticosteroids; anti-inflammatory
antibiotics; IL-2 therapy; B2 agonists;
leukotriene receptor antagonists; lung
transplantation
Lymphoproliferative Lymph nodes biopsy; spirometry; Systemic corticosteroids;
imaging; routine visits hydroxychloroquine;
immunosuppressive agents
Autoimmunity Ig replacment? CBC, diff, PBS; thyroid Corticosteroids; anti-CD20
examination and thyroid monoclonal antibodies; TNF-α
function; routine visits inhibitors
Gastrointestinal Control of infection, Upper and/or lower endoscopy Immunomodulators; TNF-α inhibitors
autoimmunity and and yearly ultrasonography;
lymphoproliferative routine visits
complications
Neopelasis Helicobacter pylori eradication; Routine cancer screening; Routine chemotherapy; rituximab
decreasing unnecessary screening by endoscopy; bone protocols; surgical modalities;
irradiation marrow examinations allogeneic stem cell transplantation
CBC: Complete blood count; diff: Differentiation of cell blood count; HRCT: High-resolution computed tomography; Ig: Immunoglobulin; PBS: Peripheral blood smear.
of a selected group of CVID patients with special immune cell Although long-term IVIG infusion is an effective treatment
phenotypes [59] . Enteroviral infection is also currently rare in for prevention of recurrent infections in CVID patients, it can
western CVID patients, however this microorganism being main- be complicated by systemic adverse reactions. These side effects
tained probably due to lack of high-dose treatment and may lead may occur up to 72 h after the infusion [73,74] .
to meningoencephalitis with poor prognosis [60] . The minority of The majority of IVIG side effects are mild, transient and
these patients are prone to meningoencephalitis, which usually has a self-limited and do not require discontinuation of therapy [58] .
poor prognosis [61] . Human parechovirus type 1 and norovirus were Predisposing factors responsible for adverse reactions include
also reported in CVID patients that had severe enteropathy [62] . infection [75] , rate of infusion, other comorbidities or patient-
related factors such as age (≥65 years), cardiovascular impair-
Prevention ment, renal dysfunction, thromboembolic risk and the presence
Lifelong Ig replacement therapy (injection of human antibodies of diabetes mellitus, pre-existing renal disease, hypovolemia, sep-
harvested from plasma donations) is the mainstay of the thera- sis, anti-IgA antibodies and increase of interval since last infu-
peutic approach for stopping the cycle of recurrent infections in sion [76] . One study showed that side effects of IVIG were not
CVID patients. Both intravenous (3–12% IVIG) and subcutane- significantly correlated with pregnancy [77] . There are different
ous (10–20% subcutaneous Ig [SCIG]) routes provide sufficient types of Ig products regarding the concentration of antibodies
amounts of Ig [58,63] . IVIG is used more commonly than SCIG and other plasma proteins such as sodium content, sugar content,
and reduces both the rate of acute and chronic infections and osmolarity and IgA content. The selection of Ig product must be
their long-term secondary medical conditions in CVID [38,40,64] . individualized based on clinical condition of the patient and Ig
Although the purpose of Ig replacement therapy is to prevent product-related factors. For patients with congestive heart failure
infections, the amounts of administered Ig and individualized and elderly patients, Ig products with 10% concentration and
dosing can vary depending on baseline level of IgG and presence lower sodium content are more suitable [78] .
of chronic lung or GI damage [65] . Furthermore, the optimum Monitoring for adverse reactions to IVIG and SCIG must be
trough level of IgG is not universal and clinical response may performed during therapy. Depending on the type of adverse
be a better indicator for dose adjustments in CVID cases [66–68] . reactions, different managements should be considered.
Based on this goal, universal IVIG routine protocols recommend A very important issue to consider is determination of patients
typically starting the dose at 400–600 mg/kg every 3–4 weeks, with anti-IgA. Some tests that detect IgG anti-IgA seem to be
while SCIG is usually started by dosage at 100–200 mg/kg fol- helpful in predicting adverse reactions. By contrast, some authors
lowed by 160 mg/kg every week. In infants and young children, disagree with the significant importance of anti-IgA antibodies
5–7 ml of SCIG per site is well tolerated; in adults, the volume and they consider it as a rare problem in CVID. Furthermore,
per site is generally 15–20 ml [69–72] . many expert centers do not measure these antibodies because

there is little correlation between levels and reactions. However, by antibodies of IVIG and are not recommended in CVID. In
low-IgA preparations or SCIG should be used in CVID cases who contrast, antibody against seasonal influenza virus is not presented
generate anti-IgA antibodies against routine IVIG. After preven- in IVIG, therefore yearly recommendation for inactivated influ-
tion of all predisposing factors for adverse reactions, premedication enza vaccine administration is acceptable. Moreover, for indirect
including paracetamol (500–1000 mg), oral diphenhydramine protection, close-contact relatives of patients should be vaccinated
(25–50 mg), corticosteroids/acetaminophen/anti-inflammatory against influenza [91,92] .
drugs should be considered prior to treatment for patients who
experience adverse reaction following IVIG infusions. If persistent Follow-up
headache symptoms are observed, the patient can switch to SCIG Pay attention to educate patients (and parents of children) about
to eliminate the problem and no further premedication is needed alarming signs of infections and the necessity of holding sputum
[79,80] . Despite this idea, many physicians do not agree with this pots themselves before starting antibiotics which is the main step
strategy and they manage headache critically [76] . for early detection of infections. Beside patients, raising the aware-
Most patients tolerate IVIG and SCIG well if administered by ness of medical and social caregivers for appropriate approach to
an expert nurse. Avoiding infusion during active infection and recurrent infection is critical. Clinical visits and physical examina-
changing the preparation in those rare patients with repeated reaction for early detection of infections in CVID cases that warrant
tions usually solves the problem. Moreover, hydration of patient immediate treatment should be carried out every 3–6 months.
(before, after and during treatment), preparation of Ig product Sputum monitoring and analysis must be performed for all cases
before infusion and using a heating pad or warm blanket because with productive cough. Chronic viral infection is often very dif-
of chilling or local swelling are other strategies to facilitate intra- ficult to diagnose without a sophisticated virology laboratory.
venous replacement therapy [81–83] . Besides preference of SCIG in Although with current legislation on the control of Ig products
patients with major adverse events compared with IVIG, this type and viral inactivation, no case of viral transmission by Ig admin-
of replacement reduces fluctuations in serum IgG concentrations, istration has been reported since 2000, the HCV viral genome
does not require venous access, prepares rapid infusions, decreases (HCV RNA) must be checked for regularly in all patients already
risk of fluid overload or hyperosmolarity, is prescribed home-based receiving IVIG. Very recently, detection of κ-deleting recombina-
self-administration requiring minimal skills, improves quality of tion circles provides a tool for neonatal screening of B-cell forma-
life and saves travel time, reduces utilization of the healthcare sys- tion defects before presentation of infections, but the sensitivity
tem and eliminates missing work or school. However, local reac- and specificity of this modality should be evaluated in CVID
tions to SCIG are unacceptable for patients with general edema cases [93,94] .
or lack of subcutaneous tissue. Discomfort associated with the
needle stick of SCIG can be minimized with local anesthetic Treatment
creams [58,71] . Early treatment of infections at the first signs and symptoms
The second line in prevention of infection in CVID patients should be considered an integral part of the treatment of CVID
is antibiotic prophylaxis, especially in the cases with bronchi to prevent secondary structural damage. In each type of infec-
ectasis, frequent infections (generally more than three per year) tion, samples must be collected before oral or intravenous anti
or disruptive infections (hospital admission, prolonged period off biotic therapy if possible. Although culture and sensitivity results
work, secondary complications such as empyema) [84] . However, help clinicians choose the most effective drugs, this should not
this effect of prophylactic antibiotics in CVID patients has not lead to delayed empiric therapy. The effective empiric therapy
been rigorously assessed [85] . Previous microbiology results, serial for sinopulmonary infections in patients not taking prophylactic
sputum testing and antibiotic sensitivity of cultured organisms drugs (amoxicillin, macrolide or levofloxacin) differ from cases
determine the choice of antimicrobial prophylaxis [86] . Daily use taking prophylactic drugs (amoxicillin clavulanate, macrolide or
of trimethoprim– sulfamethoxazole or macrolides, which provide ciprofloxacin [90]). Initial treatment in GI microorganisms, the
substantial anti-inflammatory effects, provide more benefit than second most important group of infections, is determined on the
much greater doses of Ig therapy in patients with persistent lung basis of culture results and biopsy findings and usually includes
diseases [14,87] . Other regimes for prophylaxis consist of azithro- antibiotics, restoration of nutrients and rehydration.
mycin 250 mg three times/week, cotrimoxazole 960 mg three The use of antiviral agents, such as gancliclovir, pleconaril or
times/week, amoxicillin 500 mg two times/day and ciprofloxacin ribavirin, appears to be safe and sometimes effective but should
250 mg two times/day [88–90] . By contrast, some authors suggest be evaluated in controlled clinical trials [60,95] .
that the use of prophylactic antibiotics should be avoided because It should be noted that active infection plays a role in increas-
of an increased risk of infection with fungi or other resistant ing the risk of adverse reaction to IVIG, therefore combination
organisms. However, resistant organisms can be treated if they of antibiotic therapy and Ig replacement must be planned in
arise by changing of antibiotics according to an algorithm of these cases. A prolonged course of treatment should be consid-
alternative antibiotics [87] . ered in cases with relapse of infections. Because of the nature of
Immunization by polysaccharide vaccines may be effective the disease, resistant common organisms and unusual organisms
in selected CVID patients with normal class-switched memory (Pseudomonas spp., Mycobacterium tuberculosis and opportunistic
B cells. Activated vaccine (MMR and varicella) may be neutralized infections) should be reviewed when treatment fails.
Management of pulmonary complications fluticasone or nebulized gentamicin for reduction of sputum

As the most frequent manifestation of CVID, pulmonary diseases production [109,110] , using an oral quinolone and aerosolized
are present in most patients at the time of diagnosis and they colimycin or tobramycin for aggressive eradication of colonized
significantly increase morbidity and mortality in CVID patients Pseudomonas spp. [111,112] , NSAIDs [113] and mucolytics [114] . Of
[47,51] . Recurrent pulmonary infections with pyogenic bacteria interest, patients with bronchiectasis required IVIG higher than
among CVID patients can culminate in permanent pulmonary 600 mg/dl to achieve the same IgG level compared with patients-
disorders such as air-trapping, ground-glass attenuation, paren- without bronchiectasis [115,116] . Clinical response, lung function
chymal opacification, reticular fibrosis, bronchial wall thickening, and sputum sampling should be performed for respiratory health
atelectasis and bronchiectasis (obstructive and restrictive) [48,51] . monitoring after starting the treatment.
These complications can develop in various periods of life but are In CVID patients with pulmonary diseases, new therapeutic
slightly milder among pediatric patients than in adult cases [51] . Of approaches focus on IL-2 therapy [117–120] , short and long-acting
the aforementioned complications, bronchiectasis subsequent to inhaled B2-agonists in bronchiectasis [121,122] and leukotriene
recurrent pneumonia is more prominent and develops in approxi- receptor antagonists [113] . Although most bronchiectatic CVID
mately a third of patients [4,96] . Despite regular and adequate patients tend to have generalized lung damage, selected cases with
treatment in response to the immune dysregulation that occurs highly localized disease may benefit from surgical procedure [123] .
in CVID, affected patients may develop inflammatory diseases, Lung insufficiency due to progressive intractable pulmonary
which could result in more pulmonary complications, especially disease necessitates continuous oxygen treatment and/or heart or
bronchiectasis, in this group of patients [47,97] . lung transplantation, although overall outcomes of this modality
are variable in CVID cases [53,124–126] .
Prevention
Prophylaxis and treatment of upper and lower respiratory tract infec- Management of polyclonal lymphocytic infiltrative
tions with greater doses of Ig (600 mg/kg/month) and regular sup- complications
pressive antimicrobials are the best means for controlling progression Approximately 10–25% of CVID patients encounter various
of lung disease, however, randomized clinical trials are needed for lymphoproliferative and granulomatous diseases and the mean age
the exact proof [68,98] . Reducing contact with fungal sources should at onset of these complications is 20–40 years. Granulomatous
be noted by patients, especially Aspergillus spp.-infected areas [99] . lesions can affect any organ in the progression of CVID, but
the most common site is the lung, presenting with a pattern of
Follow-up interstitial lung disease (granulomatous lymphocytic interstitial
Although there is no consensus for monitoring lung damage in lung disease [GLILD]) [48,103,127,128] .
CVID patients, pulmonary lung function tests (spirometery and The frequency of multisystemic involvement is unknown and
carbon monoxide diffusion; at baseline and every 1–2 years) and probably underestimated [129] . All CVID patients with pulmo-
high-resolution computed tomography (gold standard test; at nary granulomatous diseases suffer from shortness of breath and
baseline and every 4–5 years) are the best recommended exami- persistent cough. Although physiological functions are normal
nations. Plain chest X-ray radiography is of limited value in in patients with pulmonary granulomas, it is not excluded that
CVID; however, it should be considered if the patient is febrile, these patients would have eventually developed abnormal tests
has pleuritic pain and signs of consolidation, effusion or collapse. over time [48] . Lymphoid interstitial pneumonitis (LIP) is another
Moreover, because of the probability of radiosensitivity in some involvement of the pulmonary system in lymphoproliferative dis-
CVID cases, lower intervals with other X-ray procedures should orders without evidence to be related to any known pulmonary
be avoided as screening leads to excessive radiation exposure over infection and it is associated with other connective tissue disorders
time [48,51,100–102] . Biopsy and pathological investigation should [36] . LIP and GLILD complications have a poor outcome and
be carried out if large or persistent nodules are found in the many unanswered questions about the pathogenesis and appropri-
lungs, which may change our therapeutic strategy to treat for ate therapeutic intervention of both complications remain [130] .
polyclonal lymphocytic infiltrative disease-like granulomatous The lymphoproliferative and granulomatous diseases in CVID
infiltrates [53,103] . seem to be related to severe depletion of switched memory B cells
and CD4 + native T cells [131] . Splenomegaly and malignancies
Treatment are also more frequent in this subgroup of CVID patients [48] .
Endoscopic sinus surgery may be required in cases of chronic Expansion of CD8 + cells and lack of CD4 + cells has already been
sinusitis. Obstructive airway diseases of CVID patients can be shown to be associated with the granuloma formation in tis-
managed with inhaled corticosteroids [99] . There are several sues [132–134] . Genetic predisposition may have a role in different
studies that report methods for preserving and improving lung aspects of granulomatous diseases in CVID patients.
function in pulmonary complicated CVID cases, including
postural drainage, inspiratory muscle training and pulmonary Prevention
rehabilitation programs [104,105] , advocating higher IgG trough Ig replacement therapy has no effect on polyclonal lymphocytic
levels (700–800 mg/dl) [27] , using anti-inflammatory effects of infiltrative diseases as a preventive agent for inflammatory process
macrolides with azithromycin [106–108] , inhaled corticosteroids that is made by an immune dysregulation mechanism [40,135] .

Follow-up include the presence of anti-IgA antibodies [154] , autoimmune

Biopsy via open lung or transbronchial surgery may be required for neutropenia [36] , pernicious anemia [140,150] , juvenile rheuma-
large and persistent lymph nodes. Signs of interstitial lung disease toid arthritis, systemic lupus erythematosus, psoriasis, auto
including dyspnea and reduced exercise tolerance should be consid- immune thyroiditis, autoimmune hepatitis, primary biliary
ered in regular visits. Restrictive ventilatory pattern in pulmonary cirrhosis, insulin dependent diabetes, sicca syndrome, vitiligo
function test and parenchymal nodules or ground glass opacities and vasculitis [25,36,155,156] .
in high-resolution computed tomography may alert physicians
to consider pulmonary lymphoproliferative diseases. However, Prevention
other imaging modalities (e.g., MRI, endoscopy) for assessment No preventive modalities are presently available, however, IVIG
of progression of granulomatous diseases may be indicated. treatment has led to reduction of incidence of the autoimmune
diseases especially within cases with ITP and AIHA [153] .
Treatment
The optimum therapeutic option for CVID-related lympho Follow-up
proliferative diseases is not clear, and this complication remains General medical vigilance and hematologic laboratory monitoring
a major clinical challenge. High doses of systemic corticosteroids with intervals of 3–6 months is the way for monitoring of hema-
(10 mg a day or 20 mg every other day or twice-daily inhaled tologic autoimmunity. Some clinical immunologists recommend
beclomethasone) is the first choice for interstitial lung disease annual thyroid examination and thyroid function testing as part
with restrictive ventilatory defect due to lymphoproliferative of routine follow-up in CVID patients.
disease such as pulmonary granulomas and LIP, but their long-
term use is limited because of the risk of infections [136,137] . Treatment
For long-term therapy, hydroxychloroquine is prescribed with Common treatment protocols for autoimmunity are used simi-
dosage of 200–400 mg a day (range: 3.5–6.5 mg/kg) [138–140] . larly in CVID cases. In case of hematologic autoimmunity,
Steroid-sparing immunosuppressive agents have also been rec- managements are based on intravenous corticosteroids (1 g of
ommended in special situations when inflammation is predo methylprednisolone in mild disease) or anti CD-20 monoclonal
minantly pulmonary, including cyclosporine A (125 mg a day) antibodies (rituximab in severe disorders) [36,157,158] . Persistent
[135] , methotrexate [141] , azathioprine, mycophenolate mofetil autoimmunity can be handled by high Ig immunomodulatory
and 6-mercaptopurine [136] . All mentioned therapeutic modali- effects (1 g/kg/week) for a short time.
ties are used in case reports or limited studies and their results TNF-α inhibitors might be used in overlapped phenotypes
for extrapolation to CVID should be tested in clinical trials. of autoimmunity (e.g., infliximab for Crohn’s disease and
Monoclonal antibodies as TNF-α inhibitors, such as etanercept etanercept for rheumatoid arthritis) and polyclonal lymphocytic
[132,142] and infliximab [143–146] , can be used in the case of gen- infiltration [142,159] .
eralized granulomatous lesions combined with autoimmunity,
but no systematic clinical trials have investigated their efficacy Management of GI complications & enteropathy
and safety. Opportunistic infections like Pneumocystis jirovecii The GI tract constitutes the largest human immune organ and is
pneumonia may result when patients are under treatment for therefore expected to be affected by CVID [55,160–162] . Virtually
lymphoproliferative diseases [52,115] . 60% of CVID patients present with diarrhea and 10% develop
Hepatomegaly and lymphadenopathy have also not been digestive complications such as idiopathic malabsorption associ-
proven for treatment recommendations. Splenectomy should ated with weight loss [163] . Other gut symptoms such as discomfort
be avoided because its efficacy in the treatment of cytopenia and bloating are also common [25] . Inflammatory GI disorders are
is controversial and this surgery predisposes patients to severe extremely frequent in CVID patients [164] . Approximately 20%
infections [4,147,148] . of CVID patients have GI symptoms not related to infectious
causes [4] . Classical Crohn’s disease is probably not seen in CVID,
Management of autoimmune complications although it has a high incidence in X-linked agamamglobuline-
Autoimmune-associated disorders, reported in 20–25% of mia. Celiac (gluten-sensitive) disease does occur but is very rare.
CVID patients, are caused by immune dysregulation due to CVID-related enteropathy is a sprue-like illness with villus atro-
failed or circumvented specific autoreactivity checkpoints during phy and crypt hyperplasia in biopsy but shows no improvement
the B-cell development process [149] . This dysregulation cul- by gluten-free diet [165] . Inflammatory bowel disease (ulcerative
minates in production of multiple autoantibodies against vari- colitis, ulcerative proctitis or Crohn’s disease), which can cause
ous self-antigenic targets [150] . Autoimmune thrombocytopenic stricture, lymphocytic colitis and collagen enterocolitis, is more
purpura (ITP) and autoimmune hemolytic anemia (AIHA) are prevalent in CVID patients than the normal population [166] .
the most common types of autoimmune consequences, occur- Intestinal lymphangiectasia, nodular lymphoid hyperplasia and
ring in 5–8% of the all registered CVID patients [4,151] . These nonspecific malabsorption have also been reported [4] . Defective
disorders present in some patients before the diagnosis of CVID. cellular immunity, rather than antibody deficiency alone, appears
Thus, CVID must be considered as a differential diagnosis in to predispose patients to such symptoms [164] . Up to 10% of
adult-onset ITP and AIHA [152,153] . Other autoimmune disorders CVID patients may suffer from liver dysfunctions (abnormal
liver function tests, predominantly increased alkaline phosphatase of surveillance for malignancy, especially lymphoma and gastric
and nodular regenerative hyperplasia) caused by infections (e.g., cancer [48] . Risk of gastric cancer, especially gastric adenocarci-
HBV and HCV), autoimmunity (e.g., autoimmune hepatitis, noma, may be increased by H. pylori infections and chromosomal
primary biliary cirrhosis) and granulomatous diseases [84,160,167] . radiosensitivity [177,179] . Chronic viral infections with CMV and
Previous studies suggested that nodular regenerative hyperplasia human herpesvirus 8 may predispose CVID patients to develop
has different etiology, including circulating immune complexes NHL [176] .
or light chain deposits in the sinusoidal walls [168] . Unexplained
liver disease with portal hypertension occurs in 5–10% of the Prevention
patients. Autoimmunity (69.2%) and lymphocyte abnormalities H. pylori antigen screening in feces and appropriate endoscopy
(78.6%) were observed more frequently in CVID patients with with examination for this microorganism and its eradication
hepatic dysfunctions [169–173] . may prevent gastric cancer [180] . Moreover, decreasing unneces-
sary exposure of CVID patients to irradiation can reduce risk of
Prevention iatrogenic cancer due to chromosomal radiosensitivity [177] .
No effective preventive modalities are presently available for GI
complications. However, prevention of primary hepatic complica- Follow-up
tions (viral hepatitis, autoimmunity and granulomatous diseases) First of all, age-appropriate cancer screening of general healthy
helps progression of CVID cases from regenerative hyperplasia population (colonoscopy, prostate examination, cervical smears
leading to portal hypertension, cholestasis and hepatic dysfunc- and mammograms) should be programmed for all CVID patients
tion. It remains to be proven whether fast treatment of intestinal more tenuously. CVID-specific screening by endoscopy for find-
infections improves outcomes for CVID patients [14] . ing mucosal changes should be performed in symptomatic cases.
Histopathological investigation of enlarged nodes via excision
Follow-up of the whole lymph node and periodic complete blood counts
Screening for GI complications is more unclear, unless attention and differential white blood cell counts are important means for
is paid to the patient complaints (diarrhea refractory to antibiotic screening of lymphoid malignancy [181] . Bone marrow examina-
treatments) and clinical symptoms (especially weight loss) that are tions for lymphoma screening, however, are not positive, except
key alarm signs [14] . Biannual upper and/or lower endoscopy and in the most advanced cases.
yearly ultrasonograohy may help screening for GI symptomatic
CVID cases. Treatment
Management of neoplasia in CVID is similar to routine chemo-
Treatment therapy protocols for cancerous patients as well as standard rituxi-
The management of severe inflammatory enteropathy in CVID mab protocols. Surgical modalities such as total gastrectomy are
is based on low-dose immunomodulators (azathioprine or lifesaving for early diagnosed cancers [177] .
6-mercaptopurine) and TNF-α blockers (infliximab or etanercept) Because of the relation of presentation of malignancy and
[165,174] . Management in mild inflammatory bowel disease, how- impaired T-cell immunity in CVID, allogeneic stem cell trans-
ever, is the same as for immunocompetent patients. The use of plantation is now considered in these selected CVID cases.
long-term high-dose corticosteroids is controversial because of the However, it should be noticed that these potentially curative
increased probability of intestinal CMV infection [160,175] . approaches are experimental and should only be proposed for
therapy-refractory life-threatening complications (late-onset
Management of malignancy combined immunodeficiency subgroup) with careful process for
CVID patients are at higher risk of neoplasias (hematological or donor selection [182] . The best response of allogeneic stem cell
solid tumors) compared with normal population (over ten-times transplantation is seen in the patients with NHL resolving all
the risk) [176] . The most common type of malignancy is non- CVID-related consequences. Graft-versus-host disease should be
Hodgkin’s lymphoma (NHL), which is more likely to be of B-cell monitored in these patients [183] .
origin [177] . Lymphoid malignancies (including mucosa-associ-
ated lymphoid tissue lymphoma, marginal zone lymphoma and Prognosis & surveillance
T‑cell-rich B-cell EBV-associated lymphoma) are more prevalent Major indicators that affect poor CVID prognosis are structural
in younger patients [5,34,178] ; by contrast, CVID adults are more pulmonary damages, GLILD, severe autoimmunity, malignancy
susceptible to GI tract malignancies, especially adenocarcinoma and extent of end-organ damage, which all can be managed by
of the stomach [177] . It was estimated that 8.2% of CVID cases are therapeutic strategies [103] . Moreover, implementation of appropri-
susceptible for lymphoma, however, females and CVID cases with ate prevention, screening and treatment protocols during recent
higher levels of serum IgM are more prone to this secondary com- years improved mortality rate after 10 years of follow-up from
plication [26] . Polyclonal lymphocytic infiltration is a clinical pre- 20–40% [4,33] to 5–10% [13,34] . Respiratory tract insufficiency,
dictor associated with an increased risk of lymphoid malignancy especially cor pulmonale, serves as the most frequent cause of
[51] . Furthermore, in CVID patients, clinical and family histories death in CVID patients followed by lymphoma and liver fail-
of neoplasia should be taken accurately along with consideration ure. Despite clinical manifestations, low levels of IgG, poor

T-cell responses to antigens, and a low percentage of peripheral additional management, and higher doses of Ig replacement
B cells are laboratory factors that can predict lower survival rates therapy can be recommended in certain conditions.
in CVID.
Five-year view
Expert commentary It is to be hoped that underlying genetic defect(s) and precise
Ig replacement therapy, either subcutaneous or intravenous, is the pathophysiology of CVID will be identified in the near future,
mainstay of therapy in patients with CVID, while specific treat- considering multicenter international studies in this field, which
ment for certain complications associated with disease is needed. could provide novel possibilities for treatment of this disease.
In addition to recurrent infections, in which antibiotic prophylaxis Moreover, conducting some studies on safety and efficacy of cur-
might be added to Ig replacement therapy, further pulmonary rent treatments can help clinicians come to a consensus on treat-
problems as well as polyclonal lymphocytic infiltrative complica- ment of this disease, which definitely can improve the prognosis
tions, enteropathy, autoimmune diseases and malignancies require of the patients.
Key issues
• Education of patients, immunoglobulin replacement therapy, prophylactic and therapeutic antibiotics and complementary vaccinations
are the main means for tackling infectious complications of common variable immunodeficiency (CVID) cases.
• Pulmonary function tests and high-resolution computed tomography should be considered in all CVID patients to diagnose secondary
lung damages at the earliest time possible.
• Annual ultrasonography and endoscopy every 2 years are the best screening methods for individuals with suspected gut complication.
• Steroid-sparing immunosuppressive agents and TNF-α inhibitors may be useful therapeutic modalities in patients with
lymphoproliferative and autoimmune phenotypes.
• Beside routine protocols of chemotherapy, allogeneic stem cell transplantation may have an appropriate result in malignant CVID
patients.
References Northern Ireland. Ir. Med. J. 75(1), 16–19 14 Cunningham-Rundles C. How I treat
(1982). common variable immune deficiency. Blood
1 Notarangelo LD, Fischer A, Geha RS
8 Fasth A. Primary immunodeficiency 116(1), 7–15 (2010).
et al. Primary immunodeficiencies: 2009
update. J. Allergy Clin. Immunol. 124(6), disorders in Sweden: cases among children, 15 Janeway CA, Apt L, Gitlin D. Agamma-
1161–1178 (2009). 1974-1979. J. Clin. Immunol. 2(2), 86–92 globulinemia. Trans. Assoc. Am. Physicians
(1982). 66, 200–202 (1953).
2 Notarangelo LD. Primary immuno
deficiencies. J. Allergy Clin. Immunol. 9 Hammarström L, Vorechovsky I, Webster 16 Grimbacher B, Warnatz K, Peter HH. The
125(2 Suppl. 2), S182–S194 (2010). D. Selective IgA deficiency (SIgAD) and immunological synapse for B-cell memory:
common variable immunodeficiency the role of the ICOS and its ligand for the
3 Aghamohammadi A, Farhoudi A,
(CVID). Clin. Exp. Immunol. 120(2), longevity of humoral immunity. Curr.
Moin M et al. Clinical and immunologi-
225–231 (2000). Opin. Allergy Clin. Immunol. 3(6),
cal features of 65 Iranian patients with
10 Luzi G, Businco L, Aiuti F. Primary 409–419 (2003).
common variable immunodeficiency.
Clin. Diagn. Lab. Immunol. 12(7), immunodeficiency syndromes in Italy: 17 Grimbacher B, Hutloff A, Schlesier M
825–832 (2005). a report of the national register in children et al. Homozygous loss of ICOS is
and adults. J. Clin. Immunol. 3(4), associated with adult-onset common
4 Cunningham-Rundles C, Bodian C.
316–320 (1983). variable immunodeficiency. Nat. Immunol.
Common variable immunodeficiency:
11 Chapel H, Geha R, Rosen F; IUIS PID 4(3), 261–268 (2003).
clinical and immunological features of 248
patients. Clin. Immunol. 92(1), 34–48 (Primary Immunodeficiencies) Classifica- 18 van Zelm MC, Reisli I, van der Burg M
(1999). tion committee. Primary immunodefi- et al. An antibody-deficiency syndrome
ciency diseases: an update. Clin. Exp. due to mutations in the CD19 gene.
5 Cunningham-Rundles C, Siegal FP,
Immunol. 132(1), 9–15 (2003). N. Engl. J. Med. 354(18), 1901–1912
Cunningham-Rundles S, Lieberman P.
12 Notarangelo L, Casanova JL, Fischer A (2006).
Incidence of cancer in 98 patients with
common varied immunodeficiency. J. Clin. et al.; International Union of Immunologi- 19 Lopez-Herrera G, Tampella G,
Immunol. 7(4), 294–299 (1987). cal Societies Primary Immunodeficiency Pan‑Hammarström Q et al. Deleterious
diseases classification committee. Primary mutations in LRBA are associated with a
6 Ko J, Radigan L, Cunningham-Rundles C.
immunodeficiency diseases: an update. syndrome of immune deficiency and
Immune competence and switched
J. Allergy Clin. Immunol. 114(3), 677–687 autoimmunity. Am. J. Hum. Genet. 90(6),
memory B cells in common variable
(2004). 986–1001 (2012).
immunodeficiency. Clin. Immunol. 116(1),
37–41 (2005). 13 Chapel H, Lucas M, Lee M et al. Common 20 Kuijpers TW, Bende RJ, Baars PA et al.
variable immunodeficiency disorders: CD20 deficiency in humans results in
7 Darragh PM. The prevalence and
division into distinct clinical phenotypes. impaired T cell-independent antibody
prevention of severe mental handicap in
Blood 112(2), 277–286 (2008).
responses. J. Clin. Invest. 120(1), 214–222 33 Hermaszewski RA, Webster AD. Primary heterogeneous disease. Blood 99(5),
(2010). hypogammaglobulinaemia: a survey of 1544–1551 (2002).
21 van Zelm MC, Smet J, Adams B et al. clinical manifestations and complications. 43 Wehr C, Kivioja T, Schmitt C et al. The
CD81 gene defect in humans disrupts Q. J. Med. 86(1), 31–42 (1993). EUROclass trial: defining subgroups in
CD19 complex formation and leads to 34 Quinti I, Soresina A, Spadaro G et al.; common variable immunodeficiency. Blood
antibody deficiency. J. Clin. Invest. 120(4), Italian Primary Immunodeficiency 111(1), 77–85 (2008).
1265–1274 (2010). Network. Long-term follow-up and 44 Piqueras B, Lavenu-Bombled C, Galicier L
22 Frank MM. CD21 deficiency, complement, outcome of a large cohort of patients with et al. Common variable immunodeficiency
and the development of common variable common variable immunodeficiency. patient classification based on impaired B
immunodeficiency. J. Allergy Clin. J. Clin. Immunol. 27(3), 308–316 (2007). cell memory differentiation correlates with
Immunol. 129(3), 811–813 (2012). 35 Bonilla FA, Bernstein IL, Khan DA et al.; clinical aspects. J. Clin. Immunol. 23(5),
23 Thiel J, Kimmig L, Salzer U et al. Genetic American Academy of Allergy, Asthma and 385–400 (2003).
CD21 deficiency is associated with Immunology; American College of Allergy, 45 Giovannetti A, Pierdominici M, Mazzetta
hypogammaglobulinemia. J. Allergy Clin. Asthma and Immunology; Joint Council of F et al. Unravelling the complexity of T cell
Immunol. 129(3), 801–810.e6 (2012). Allergy, Asthma and Immunology. Practice abnormalities in common variable
parameter for the diagnosis and manage- immunodeficiency. J. Immunol. 178(6),
24 Salzer U, Warnatz K, Peter HH. Common
ment of primary immunodeficiency. Ann. 3932–3943 (2007).
variable immunodeficiency – an update.
Allergy Asthma Immunol. 94(5 Suppl. 1),
Arthritis Res. Ther. 14(5), 223 (2012). 46 Malphettes M, Gérard L, Carmagnat M
S1–S63 (2005).
25 Yong PF, Tarzi M, Chua I, Grimbacher B, et al.; DEFI Study Group. Late-onset
36 Chapel H, Cunningham-Rundles C. combined immune deficiency: a subset of
Chee R. Common variable immunodefi-
Update in understanding common variable common variable immunodeficiency with
ciency: an update on etiology and
immunodeficiency disorders (CVIDs) and severe T cell defect. Clin. Infect. Dis. 49(9),
management. Immunol. Allergy Clin. North
the management of patients with these 1329–1338 (2009).
Am. 28(2), 367–386, ix (2008).
conditions. Br. J. Haematol. 145(6),
26 Resnick ES, Moshier EL, Godbold JH, 47 Aghamohammadi A, Abolhassani H,
709–727 (2009).
Cunningham-Rundles C. Morbidity and Moazzami K, Parvaneh N, Rezaei N.
37 Abolhassani H, Aghamohammadi A, Correlation between common variable
mortality in common variable immune
Abolhassani F, Eftekhar H, Heidarnia M, immunodeficiency clinical phenotypes and
deficiency over 4 decades. Blood 119(7),
Rezaei N. Health policy for common parental consanguinity in children and
1650–1657 (2012).
variable immunodeficiency: burden of the adults. J. Investig. Allergol. Clin. Immunol.
27 Fried AJ, Bonilla FA. Pathogenesis, disease. J. Investig. Allergol. Clin. Immunol. 20(5), 372–379 (2010).
diagnosis, and management of primary 21(6), 454–458 (2011).
antibody deficiencies and infections. Clin. 48 Park MA, Li JT, Hagan JB, Maddox DE,
38 Busse PJ, Razvi S, Cunningham-Rundles Abraham RS. Common variable immuno-
Microbiol. Rev. 22(3), 396–414 (2009).
C. Efficacy of intravenous immunoglobulin deficiency: a new look at an old disease.
28 Aghamohammadi A, Parvaneh N, Rezaei in the prevention of pneumonia in patients Lancet 372(9637), 489–502 (2008).
N. Common variable immunodeficiency: with common variable immunodeficiency.
a heterogeneous group needs further 49 Oksenhendler E, Gérard L, Fieschi C et al.;
J. Allergy Clin. Immunol. 109(6),
subclassification. Expert Rev. Clin. DEFI Study Group. Infections in 252
1001–1004 (2002).
Immunol. 5(6), 629–631 (2009). patients with common variable immuno
39 Björkander J, Wadsworth C, Hanson LA. deficiency. Clin. Infect. Dis. 46(10),
29 Aghamohammadi A, Kanegane H, Moein 1040 prophylactic infusions with an 1547–1554 (2008).
M et al. Identification of an SH2D1A unmodified intravenous immunoglobulin
mutation in a hypogammaglobulinemic 50 Aghamohammadi A, Moazzami K, Rezaei
product causing few side-effects in patients
male patient with a diagnosis of common N et al. ENT manifestations in Iranian
with antibody deficiency syndromes.
variable immunodeficiency. Int. J. Hematol. patients with primary antibody deficien-
Infection 13(3), 102–110 (1985).
78(1), 45–47 (2003). cies. J. Laryngol. Otol. 122(4), 409–413
40 de Gracia J, Vendrell M, Alvarez A et al. (2008).
30 Oraei M, Aghamohammadi A, Rezaei N Immunoglobulin therapy to control lung
et al. Naive CD4 + T cells and recent thymic 51 Hampson FA, Chandra A, Screaton NJ
damage in patients with common variable
emigrants in common variable immunode- et al. Respiratory disease in common
immunodeficiency. Int. Immunopharmacol.
ficiency. J. Investig. Allergol. Clin. Immunol. variable immunodeficiency and other
4(6), 745–753 (2004).
22(3), 160–167 (2012). primary immunodeficiency disorders. Clin.
41 Pourpak Z, Aghamohammadi A, Radiol. 67(6), 587–595 (2012).
31 Rezaei N, Aghamohammadi A, Sedighipour L et al. Effect of regular
Nourizadeh M et al. Cytokine production 52 Martínez García MA, de Rojas MD,
intravenous immunoglobulin therapy on
by activated T cells in common variable Nauffal Manzur MD et al. Respiratory
prevention of pneumonia in patients with
immunodeficiency. J. Investig. Allergol. disorders in common variable
common variable immunodeficiency.
Clin. Immunol. 20(3), 244–251 (2010). immunodeficiency. Respir. Med. 95(3),
J. Microbiol. Immunol. Infect. 39(2),
191–195 (2001).
32 Salzer U, Maul-Pavicic A, 114–120 (2006).
Cunningham‑Rundles C et al. ICOS 53 Cunningham-Rundles C. Common
42 Warnatz K, Denz A, Dräger R et al. Severe
deficiency in patients with common variable immunodeficiency. Curr. Allergy
deficiency of switched memory B cells
variable immunodeficiency. Clin. Immunol. Asthma Rep. 1(5), 421–429 (2001).
(CD27(+)IgM(-)IgD(-)) in subgroups of
113(3), 234–240 (2004). patients with common variable immunode- 54 Onbasi K, Günsar F, Sin AZ, Ardeniz O,
ficiency: a new approach to classify a Kokuludag A, Sebik F. Common variable

immunodeficiency (CVID) presenting 66 Yong PL, Boyle J, Ballow M et al. Use of Iranian patients with primary immunodefi-
with malabsorption due to giardiasis. intravenous immunoglobulin and ciency diseases. J. Investig. Allergol. Clin.
Turk. J. Gastroenterol. 16(2), 111–113 adjunctive therapies in the treatment of Immunol. 19(2), 139–145 (2009).
(2005). primary immunodeficiencies: A working 74 Aghamohammadi A, Farhoudi A, Nikzad
55 Kalha I, Sellin JH. Common variable group report of and study by the Primary M et al. Adverse reactions of prophylactic
immunodeficiency and the gastrointestinal Immunodeficiency Committee of the intravenous immunoglobulin infusions in
tract. Curr. Gastroenterol. Rep. 6(5), American Academy of Allergy Asthma and Iranian patients with primary immunodefi-
377–383 (2004). Immunology. Clin. Immunol. 135(2), ciency. Ann. Allergy Asthma Immunol.
255–263 (2010). 92(1), 60–64 (2004).
56 Zullo A, Romiti A, Rinaldi V et al. Gastric
pathology in patients with common 67 Orange JS, Hossny EM, Weiler CR et al.; 75 Khan S, Abuzakouk M, Doré PC, Sewell
variable immunodeficiency. Gut 45(1), Primary Immunodeficiency Committee of WA. Administering intravenous immuno-
77–81 (1999). the American Academy of Allergy, Asthma globulin during infection is associated with
and Immunology. Use of intravenous infusion reactions in selected patients. Ir. J.
57 Aghamohammadi A, Abolhassani H,
immunoglobulin in human disease: Med. Sci. 180(1), 125–128 (2011).
Hirbod-Mobarakeh A et al. The uncom-
a review of evidence by members of the
mon combination of common variable 76 Maarschalk-Ellerbroek LJ, Hoepelman IM,
Primary Immunodeficiency Committee of
immunodeficiency, macrophage activation Ellerbroek PM. Immunoglobulin treatment
the American Academy of Allergy, Asthma
syndrome, and cytomegalovirus retinitis. in primary antibody deficiency. Int. J.
and Immunology. J. Allergy Clin. Immunol.
Viral Immunol. 25(2), 161–165 (2012). Antimicrob. Agents 37(5), 396–404 (2011).
117(Suppl. 4), S525–S553 (2006).
58 Rezaei N, Abolhassani H, 77 Brinker KA, Silk HJ. Common variable
68 Eijkhout HW, van Der Meer JW,
Aghamohammadi A, Ochs HD. Indications immune deficiency and treatment with
Kallenberg CG et al.; Inter-University
and safety of intravenous and subcutaneous intravenous immunoglobulin during
Working Party for the Study of Immune
immunoglobulin therapy. Expert Rev. Clin. pregnancy. Ann. Allergy Asthma Immunol.
Deficiencies. The effect of two different
Immunol. 7(3), 301–316 (2011). 108(6), 464–465 (2012).
dosages of intravenous immunoglobulin on
59 Marashi SM, Raeiszadeh M, Enright V the incidence of recurrent infections in 78 Stein MR, Nelson RP, Church JA et al.;
et al. Influence of cytomegalovirus patients with primary hypogammaglobu- IgPro10 in PID study group. Safety and
infection on immune cell phenotypes in linemia. A randomized, double-blind, efficacy of Privigen, a novel 10% liquid
patients with common variable immunode- multicenter crossover trial. Ann. Intern. immunoglobulin preparation for intrave-
ficiency. J. Allergy Clin. Immunol. 129(5), Med. 135(3), 165–174 (2001). nous use, in patients with primary
1349–1356.e3 (2012). immunodeficiencies. J. Clin. Immunol.
69 Moore ML, Quinn JM. Subcutaneous
60 Rotbart HA, Webster AD; Pleconaril 29(1), 137–144 (2009).
immunoglobulin replacement therapy for
Treatment Registry Group. Treatment of primary antibody deficiency: advancements 79 Brennan VM, Salomé-Bentley NJ, Chapel
potentially life-threatening enterovirus into the 21st century. Ann. Allergy Asthma HM; Immunology Nurses Study.
infections with pleconaril. Clin. Infect. Dis. Immunol. 101(2), 114–121; quiz 122 (2008). Prospective audit of adverse reactions
32(2), 228–235 (2001). occurring in 459 primary antibody-defi-
70 Chapel HM, Spickett GP, Ericson D, Engl
61 Halliday E, Winkelstein J, Webster AD. cient patients receiving intravenous
W, Eibl MM, Bjorkander J. The compari-
Enteroviral infections in primary immunoglobulin. Clin. Exp. Immunol.
son of the efficacy and safety of intravenous
immunodeficiency (PID): a survey of 133(2), 247–251 (2003).
versus subcutaneous immunoglobulin
morbidity and mortality. J. Infect. 46(1), replacement therapy. J. Clin. Immunol. 80 de Albuquerque Campos R, Sato MN,
1–8 (2003). 20(2), 94–100 (2000). da Silva Duarte AJ. IgG anti-IgA subclasses
62 van de Ven AA, Douma JW, Rademaker C in common variable immunodeficiency and
71 Abolhassani H, Sadaghiani MS,
et al. Pleconaril-resistant chronic parecho- association with severe adverse reactions to
Aghamohammadi A, Ochs HD, Rezaei N.
virus-associated enteropathy in agamma- intravenous immunoglobulin therapy.
Home-based subcutaneous immunoglobu-
globulinaemia. Antivir. Ther. 16(4), J. Clin. Immunol. 20(1), 77–82 (2000).
lin versus hospital-based intravenous
611–614 (2011). immunoglobulin in treatment of primary 81 Burks AW, Sampson HA, Buckley RH.
63 Weiler CR. Immunoglobulin therapy: antibody deficiencies: systematic review Anaphylactic reactions after gamma
history, indications, and routes of and meta analysis. J. Clin. Immunol. 32(6), globulin administration in patients with
administration. Int. J. Dermatol. 43(3), 1180–1192 (2012). hypogammaglobulinemia. Detection of
163–166 (2004). IgE antibodies to IgA. N. Engl. J. Med.
72 Berger M; Flebogamma 5% DIF Investiga-
314(9), 560–564 (1986).
64 Salehzadeh M, Aghamohammadi A, Rezaei tors. A multicenter, prospective, open label,
N. Evaluation of immunoglobulin levels historically controlled clinical trial to 82 Sati HI, Ahya R, Watson HG. Incidence
and infection rate in patients with common evaluate efficacy and safety in primary and associations of acute renal failure
variable immunodeficiency after immuno- immunodeficiency diseases (PID) patients complicating high-dose intravenous
globulin replacement therapy. J. Microbiol. of Flebogamma 5% DIF, the next immunoglobulin therapy. Br. J. Haematol.
Immunol. Infect. 43(1), 11–17 (2010). generation of Flebogamma. J. Clin. 113(2), 556–557 (2001).
Immunol. 27(6), 628–633 (2007). 83 Saroukhani S, Aghamohammadi A,
65 Koleba T, Ensom MH. Pharmacokinetics
of intravenous immunoglobulin: a system- 73 Dashti-Khavidaki S, Aghamohammadi A, Mahmoudi-Gharaei J et al. Behavior
atic review. Pharmacotherapy 26(6), Farshadi F et al. Adverse reactions of abnormality following intravenous
813–827 (2006). prophylactic intravenous immunoglobulin; immunoglobulin treatment in patients with
a 13-year experience with 3004 infusions in primary antibody deficiencies. Hum.
Psychopharmacol. 25(5), 419–422 (2010).
84 Lindberg K, Gustafson R, Samuelson A, defects. J. Allergy Clin. Immunol. 128(1), parameters and clinical conditions in
Rynnel-Dagöö B. Impact of IgG replace- 223–225.e2 (2011). children with bronchiectasis. J. Clin.
ment therapy and antibiotic treatment on 95 Medlicott SA, Coderre S, Horne G, Pharm. Ther. 31(1), 49–55 (2006).
the colonization of non-encapsulated Panaccione R. Multimodal immuno 107 Koh YY, Lee MH, Sun YH, Sung KW,
Haemophilus influenzae in the nasopharynx suppressant therapy in steroid-refractory Chae JH. Effect of roxithromycin on
in patients with hypogammaglobulinaemia. common variable immunodeficiency sprue: airway responsiveness in children with
Scand. J. Infect. Dis. 33(12), 904–908 a case report complicating cytomegalovirus bronchiectasis: a double-blind, placebo-
(2001). infection. Int. J. Surg. Pathol. 14(1), controlled study. Eur. Respir. J. 10(5),
85 Stirling RG. Primary immunodeficiency: 101–106 (2006). 994–999 (1997).
a call for multidisciplinary care. Lancet 96 Sicherer SH, Winkelstein JA. Primary 108 Cymbala AA, Edmonds LC, Bauer MA
372(9653), 1877–1878; author reply 1878 immunodeficiency diseases in adults. et al. The disease-modifying effects of
(2008). JAMA 279(1), 58–61 (1998). twice-weekly oral azithromycin in patients
86 Sewell WA, Buckland M, Jolles SR. 97 Tanaka N, Kim JS, Bates CA et al. Lung with bronchiectasis. Treat. Respir. Med.
Therapeutic strategies in common variable diseases in patients with common variable 4(2), 117–122 (2005).
immunodeficiency. Drugs 63(13), immunodeficiency: chest radiographic, and 109 Lin HC, Cheng HF, Wang CH, Liu CY,
1359–1371 (2003). computed tomographic findings. Yu CT, Kuo HP. Inhaled gentamicin
87 López-Boado YS, Rubin BK. Macrolides as J. Comput. Assist. Tomogr. 30(5), 828–838 reduces airway neutrophil activity and
immunomodulatory medications for the (2006). mucus secretion in bronchiectasis. Am. J.
therapy of chronic lung diseases. Curr. 98 Roifman CM, Levison H, Gelfand EW. Respir. Crit. Care Med. 155(6), 2024–2029
Opin. Pharmacol. 8(3), 286–291 (2008). High-dose versus low-dose intravenous (1997).
88 Luisi F, Gandolfi TD, Daudt AD, Sanvitto immunoglobulin in hypogammaglobuli- 110 Tsang KW, Tan KC, Ho PL et al. Inhaled
JP, Pitrez PM, Pinto LA. Anti-inflammato- naemia and chronic lung disease. Lancet fluticasone in bronchiectasis: a 12 month
ry effects of macrolides in childhood lung 1(8541), 1075–1077 (1987). study. Thorax 60(3), 239–243 (2005).
diseases. J. Bras. Pneumol. 38(6), 786–796 99 Quartier P, Debré M, De Blic J et al. Early 111 Jensen T, Pedersen SS, Garne S, Heilmann
(2012). and prolonged intravenous immunoglobu- C, Høiby N, Koch C. Colistin inhalation
89 Langelot M, Cellerin L, Germaud P. lin replacement therapy in childhood therapy in cystic fibrosis patients with
Anti-inflammatory effects of macrolides: agammaglobulinemia: a retrospective chronic Pseudomonas aeruginosa lung
applications in lung disease. Rev. Pneumol. survey of 31 patients. J. Pediatr. 134(5), infection. J. Antimicrob. Chemother. 19(6),
Clin. 62(4), 215–222 (2006). 589–596 (1999). 831–838 (1987).
90 Resnick E, Cunningham-Rundles C. 100 Aghamohammadi A, Moin M, Kouhi A 112 Chuchalin A, Csiszér E, Gyurkovics K
Treatment of common variable immune et al. Chromosomal radiosensitivity in et al. A formulation of aerosolized
deficiency. Exp. Opin. Orphan Drugs 1(2), patients with common variable immunode- tobramycin (Bramitob) in the treatment
157–166 (2013). ficiency. Immunobiology 213(5), 447–454 of patients with cystic fibrosis and
91 Kroger AT, Atkinson WL, Marcuse EK, (2008). Pseudomonas aeruginosa infection:
Pickering LK; Advisory Committee on 101 Palanduz S, Palanduz A, Yalcin I et al. a double-blind, placebo-controlled,
Immunization Practices (ACIP) Centers for In vitro chromosomal radiosensitivity in multicenter study. Paediatr. Drugs
Disease Control and Prevention (CDC). common variable immune deficiency. Clin. 9(Suppl. 1), 21–31 (2007).
General recommendations on immuniza- Immunol. Immunopathol. 86(2), 180–182 113 Corless JA, Warburton CJ. Surgery vs
tion: recommendations of the Advisory (1998). non-surgical treatment for bronchiectasis.
Committee on Immunization Practices 102 Vorechovský I, Scott D, Haeney MR, Cochrane Database Syst. Rev. 4, CD002180
(ACIP). MMWR. Recomm. Rep. Webster DA. Chromosomal radiosensitivity (2000).
55(RR‑15), 1–48 (2006). in common variable immune deficiency. 114 O’Donnell AE, Barker AF, Ilowite JS,
92 Atkinson WL, Pickering LK, Schwartz B, Mutat. Res. 290(2), 255–264 (1993). Fick RB. Treatment of idiopathic
Weniger BG, Iskander JK, Watson JC; 103 Bates CA, Ellison MC, Lynch DA, Cool bronchiectasis with aerosolized recombi-
Centers for Disease Control and Preven- CD, Brown KK, Routes JM. Granuloma- nant human DNase I. rhDNase Study
tion. General recommendations on tous-lymphocytic lung disease shortens Group. Chest 113(5), 1329–1334 (1998).
immunization. Recommendations of the survival in common variable immunodefi- 115 Touw CM, van de Ven AA, de Jong PA
Advisory Committee on Immunization ciency. J. Allergy Clin. Immunol. 114(2), et al. Detection of pulmonary complica-
Practices (ACIP) and the American 415–421 (2004). tions in common variable immunodefi-
Academy of Family Physicians (AAFP). ciency. Pediatr. Allergy Immunol. 21(5),
MMWR. Recomm. Rep. 51(RR-2), 1–35 104 Garrod R, Lasserson T. Role of physiother-
apy in the management of chronic lung 793–805 (2010).
(2002).
diseases: an overview of systematic reviews. 116 Busse PJ, Farzan S, Cunningham-Rundles
93 Serana F, Airò P, Chiarini M et al. Thymic Respir. Med. 101(12), 2429–2436 (2007). C. Pulmonary complications of common
and bone marrow output in patients with variable immunodeficiency. Ann. Allergy
common variable immunodeficiency. 105 Bradley J, Moran F, Greenstone M.
Physical training for bronchiectasis. Asthma Immunol. 98(1), 1–8; quiz 8
J. Clin. Immunol. 31(4), 540–549 (2011). (2007).
Cochrane Database Syst. Rev. 3, CD002166
94 Nakagawa N, Imai K, Kanegane H et al. (2002). 117 Foruny JR, Bárcena R, Moreno A et al.
Quantification of k-deleting recombination Benefit of pegylated interferon-alpha-2a/
excision circles in Guthrie cards for the 106 Yalçin E, Kiper N, Ozçelik U et al. Effects
of claritromycin on inflammatory ribavirin in a patient with common variable
identification of early B-cell maturation

immunodeficiency and hepatitis C virus patients with common variable immunode- 140 Knight AK, Cunningham-Rundles C.
cirrhosis after liver transplantation and ficiency (CVID). J. Clin. Immunol. 33(1), Inflammatory and autoimmune complica-
splenic embolization. Transplantation 30–39 (2013). tions of common variable immune
82(2), 289–290 (2006). 129 Aghamohammadi A, Abolhassani H, Rezaei deficiency. Autoimmun. Rev. 5(2), 156–159
118 Cunningham-Rundles C, Bodian C, Ochs N et al. Cutaneous granulomas in common (2006).
HD, Martin S, Reiter-Wong M, Zhuo Z. variable immunodeficiency: case report and 141 Paramothayan S, Lasserson TJ, Walters
Long-term low-dose IL-2 enhances review of literature. Acta Dermatovenerol. EH. Immunosuppressive and cytotoxic
immune function in common variable Croat. 18(2), 107–113 (2010). therapy for pulmonary sarcoidosis.
immunodeficiency. Clin. Immunol. 100(2), 130 Park JH, Levinson AI. Granulomatous- Cochrane Database Syst. Rev. 3, CD003536
181–190 (2001). lymphocytic interstitial lung disease (2006).
119 Rump JA, Jahreis A, Schlesier M, Stecher (GLILD) in common variable immunode- 142 Smith KJ, Skelton H. Common variable
S, Peter HH. A double-blind, placebo- ficiency (CVID). Clin. Immunol. 134(2), immunodeficiency treated with a recombi-
controlled, crossover therapy study with 97–103 (2010). nant human IgG, tumour necrosis
natural human IL-2 (nhuIL-2) in 131 Bouvry D, Mouthon L, Brillet PY et al.; factor-alpha receptor fusion protein. Br. J.
combination with regular intravenous Groupe Sarcoïdose Francophone. Dermatol. 144(3), 597–600 (2001).
gammaglobulin (IVIG) infusions in 10 Granulomatosis-associated common 143 Fernández-Ruiz M, Guerra-Vales JM,
patients with common variable immunode- variable immunodeficiency disorder: Francisco-Javier CF et al. Fever of
ficiency (CVID). Clin. Exp. Immunol. a case-control study versus sarcoidosis. Eur. unknown origin in a patient with common
110(2), 167–173 (1997). Respir. J. 41(1), 115–122 (2013). variable immunodeficiency associated with
120 Ten RM, Anderson PM, Zein NN, 132 Lin JH, Liebhaber M, Roberts RL, Dyer Z, multisystemic granulomatous disease.
Temesgen Z, Clawson ML, Weiss W. Stiehm ER. Etanercept treatment of Intern. Med. 46(15), 1197–1202 (2007).
Interleukin-2 liposomes for primary cutaneous granulomas in common variable 144 Hatab AZ, Ballas ZK. Caseating granu-
immune deficiency using the aerosol route. immunodeficiency. J. Allergy Clin. lomatous disease in common variable
Int. Immunopharmacol. 2(2–3), 333–344 Immunol. 117(4), 878–882 (2006). immunodeficiency treated with infliximab.
(2002). J. Allergy Clin. Immunol. 116(5),
133 Ardeniz O, Cunningham-Rundles C.
121 Franco F, Sheikh A, Greenstone M. Short Granulomatous disease in common variable 1161–1162 (2005).
acting beta-2 agonists for bronchiectasis. immunodeficiency. Clin. Immunol. 133(2), 145 Baughman RP, Drent M, Kavuru M et al.;
Cochrane Database Syst. Rev. 3, CD003572 198–207 (2009). Sarcoidosis Investigators. Infliximab
(2003). therapy in patients with chronic sarcoidosis
134 North ME, Webster AD, Farrant J. Primary
122 Sheikh A, Nolan D, Greenstone M. defect in CD8 + lymphocytes in the antibody and pulmonary involvement. Am. J. Respir.
Long-acting beta-2-agonists for bronchiec- deficiency disease (common variable Crit. Care Med. 174(7), 795–802 (2006).
tasis. Cochrane Database Syst. Rev. 4, immunodeficiency): abnormalities in 146 Thatayatikom A, Thatayatikom S, White
CD002155 (2001). intracellular production of interferon-gam- AJ. Infliximab treatment for severe
123 Corless JA, Warburton CJ. Surgery vs ma (IFN-gamma) in CD28 + (‘cytotoxic’) granulomatous disease in common variable
non-surgical treatment for bronchiectasis. and CD28- (‘suppressor’) CD8 + subsets. immunodeficiency: a case report and
Cochrane Database Syst. Rev. 4, CD002180 Clin. Exp. Immunol. 111(1), 70–75 (1998). review of the literature. Ann. Allergy
(2000). 135 Davies CW, Juniper MC, Gray W, Gleeson Asthma Immunol. 95(3), 293–300 (2005).
124 Bethune CA, Spickett GP. Common FV, Chapel HM, Davies RJ. Lymphoid 147 Sève P, Bourdillon L, Sarrot-Reynauld F
variable immunodeficiency: an update on interstitial pneumonitis associated with et al.; DEF-I Study Group. Autoimmune
therapeutic approaches. BioDrugs 13(4), common variable hypogammaglobulinae- hemolytic anemia and common variable
243–253 (2000). mia treated with cyclosporin A. Thorax immunodeficiency: a case-control study of
125 Burton CM, Milman N, Andersen CB, 55(1), 88–90 (2000). 18 patients. Medicine (Baltimore). 87(3),
Marquart H, Iversen M. Common variable 136 Paramothayan S, Lasserson T. Treatments 177–184 (2008).
immune deficiency and lung transplanta- for pulmonary sarcoidosis. Respir. Med. 148 Wong MS, Chan GC, Ha SY, Lau YL.
tion. Scand. J. Infect. Dis. 39(4), 362–367 102(1), 1–9 (2008). Clinical characteristics of chronic
(2007). 137 Boursiquot JN, Gérard L, Malphettes M idiopathic thrombocytopenia in Chinese
126 Hill AT, Thompson RA, Wallwork J, et al.; DEFI study group. Granulomatous children. J. Pediatr. Hematol. Oncol. 24(8),
Stableforth DE. Heart lung transplantation disease in CVID: retrospective analysis of 648–652 (2002).
in a patient with end stage lung disease due clinical characteristics and treatment 149 Tsuiji M, Yurasov S, Velinzon K, Thomas
to common variable immunodeficiency. efficacy in a cohort of 59 patients. J. Clin. S, Nussenzweig MC, Wardemann H.
Thorax 53(7), 622–623 (1998). Immunol. 33(1), 84–95 (2013). A checkpoint for autoreactivity in human
127 Morimoto Y, Routes JM. Granulomatous 138 Fazzi P. Pharmacotherapeutic management IgM + memory B cell development. J. Exp.
disease in common variable immunodefi- of pulmonary sarcoidosis. Am. J. Respir. Med. 203(2), 393–400 (2006).
ciency. Curr. Allergy Asthma Rep. 5(5), Med. 2(4), 311–320 (2003). 150 Brandt D, Gershwin ME. Common
370–375 (2005). 139 Kyburz D, Brentano F, Gay S. Mode of variable immune deficiency and auto
128 Chase NM, Verbsky JW, Hintermeyer MK action of hydroxychloroquine in RA – immunity. Autoimmun. Rev. 5(7), 465–470
et al. Use of combination chemotherapy for evidence of an inhibitory effect on toll-like (2006).
treatment of granulomatous and lympho- receptor signaling. Nat. Clin. Pract. 151 Cunningham-Rundles C. Hematologic
cytic interstitial lung disease (GLILD) in Rheumatol. 2(9), 458–459 (2006). complications of primary immune
deficiencies. Blood Rev. 16(1), 61–64 162 Ebrahimi Daryani N, Aghamohammadi A, 173 Arenillas Rocha L, Soriano Viladomiu A,
(2002). Mousavi Mirkala MR et al. Gastrointesti- Smithson Amat A. Nodular regenerative
152 Ramyar A, Aghamohammadi A, Moazzami nal complications in two patients with hyperplasia and common variable
K et al. Presence of idiopathic thrombocyto- common variable immunodeficiency. Iran. immunodeficiency. Gastroenterol. Hepatol.
penic purpura and autoimmune hemolytic J. Allergy. Asthma. Immunol. 3(3), 149–152 26(8), 524 (2003).
anemia in the patients with common (2004). 174 Agarwal S, Cunningham-Rundles C.
variable immunodeficiency. Iran. J. Allergy. 163 Sneller MC. Common variable immunode- Autoimmunity in common variable
Asthma. Immunol. 7(3), 169–175 (2008). ficiency. Am. J. Med. Sci. 321(1), 42–48 immunodeficiency. Curr. Allergy Asthma
153 Michel M, Chanet V, Galicier L et al. Auto- (2001). Rep. 9(5), 347–352 (2009).
immune thrombocytopenic purpura and 164 Washington K, Stenzel TT, Buckley RH, 175 Raeiszadeh M, Kopycinski J, Paston SJ
common variable immunodeficiency: Gottfried MR. Gastrointestinal pathology et al. The T cell response to persistent
analysis of 21 cases and review of the in patients with common variable herpes virus infections in common variable
literature. Medicine (Baltimore) 83(4), immunodeficiency and X-linked agamma- immunodeficiency. Clin. Exp. Immunol.
254–263 (2004). globulinemia. Am. J. Surg. Pathol. 20(10), 146(2), 234–242 (2006).
154 Horn J, Thon V, Bartonkova D et al. 1240–1252 (1996). 176 Chua I, Quinti I, Grimbacher B. Lym-
Anti-IgA antibodies in common variable 165 Chua I, Standish R, Lear S et al. Anti- phoma in common variable immunodefi-
immunodeficiency (CVID): diagnostic tumour necrosis factor-alpha therapy for ciency: interplay between immune
workup and therapeutic strategy. Clin. severe enteropathy in patients with dysregulation, infection and genetics. Curr.
Immunol. 122(2), 156–162 (2007). common variable immunodeficiency Opin. Hematol. 15(4), 368–374 (2008).
155 Aukrust P, Lien E, Kristoffersen AK et al. (CVID). Clin. Exp. Immunol. 150(2), 177 Abolhassani H, Aghamohammadi A,
Persistent activation of the tumor necrosis 306–311 (2007). Imanzadeh A, Mohammadinejad P,
factor system in a subgroup of patients with 166 Conlong P, Rees W, Shaffer JL et al. Sadeghi B, Rezaei N. Malignancy
common variable immunodeficiency – Primary antibody deficiency and Crohn’s phenotype in common variable immunode-
possible immunologic and clinical disease. Postgrad. Med. J. 75(881), 161–164 ficiency. J. Investig. Allergol. Clin. Immunol.
consequences. Blood 87(2), 674–681 (1999). 22(2), 133–134 (2012).
(1996). 167 Ravindran J, Gillis D, Rowland R, Heddle 178 Kinlen LJ, Webster AD, Bird AG et al.
156 Cunningham-Rundles C, Lieberman P, R. Common variable immunodeficiency Prospective study of cancer in patients with
Hellman G, Chaganti RS. Non-Hodgkin associated with nodular regenerative hypogammaglobulinaemia. Lancet
lymphoma in common variable immunodefi- hyperplasia of the liver. Aust. N. Z. J. Med. 1(8423), 263–266 (1985).
ciency. Am. J. Hematol. 37(2), 69–74 (1991). 25(6), 741 (1995). 179 Iglesias Alzueta J, Matamoros Florí N.
157 Cunningham-Rundles C. Autoimmune 168 Malamut G, Ziol M, Suarez F et al. Common variable immunodeficiency.
manifestations in common variable Nodular regenerative hyperplasia: the main Review. Allergol. Immunopathol. (Madr.)
immunodeficiency. J. Clin. Immunol. liver disease in patients with primary 29(3), 113–118 (2001).
28(Suppl. 1), S42–S45 (2008). hypogammaglobulinemia and hepatic 180 Dhalla F, da Silva SP, Lucas M, Travis S,
158 Wakim M, Shah A, Arndt PA et al. abnormalities. J. Hepatol. 48(1), 74–82 Chapel H. Review of gastric cancer risk
Successful anti-CD20 monoclonal (2008). factors in patients with common variable
antibody treatment of severe autoimmune 169 Smith MS, Webster AD, Dhillon AP et al. immunodeficiency disorders, resulting in a
hemolytic anemia due to warm reactive Orthotopic liver transplantation for chronic proposal for a surveillance programme.
IgM autoantibody in a child with common hepatitis in two patients with common Clin. Exp. Immunol. 165(1), 1–7 (2011).
variable immunodeficiency. Am. J. variable immunodeficiency. 181 Gompels MM, Hodges E, Lock RJ et al.;
Hematol. 76(2), 152–155 (2004). Gastroenterology 108(3), 879–884 (1995). Associated Study Group. Lymphoprolifera-
159 Nos P, Bastida G, Beltran B, Aguas M, 170 Fuss IJ, Friend J, Yang Z et al. Nodular tive disease in antibody deficiency:
Ponce J. Crohn’s disease in common regenerative hyperplasia in common a multi-centre study. Clin. Exp. Immunol.
variable immunodeficiency: treatment with variable immunodeficiency. J. Clin. 134(2), 314–320 (2003).
antitumor necrosis factor alpha. Am. J. Immunol. 33(4), 348–758 (2013). 182 Ochtrop ML, Goldacker S, May AM et al.
Gastroenterol. 101(9), 2165–2166 (2006). 171 Ward C, Lucas M, Piris J, Collier J, Chapel T and B lymphocyte abnormalities in bone
160 Daniels JA, Lederman HM, Maitra A, H. Abnormal liver function in common marrow biopsies of common variable
Montgomery EA. Gastrointestinal tract variable immunodeficiency disorders due to immunodeficiency. Blood 118(2), 309–318
pathology in patients with common nodular regenerative hyperplasia. Clin. Exp. (2011).
variable immunodeficiency (CVID): Immunol. 153(3), 331–337 (2008). 183 Rizzi M, Neumann C, Fielding AK et al.
a clinicopathologic study and review. Am. J. 172 Mañas MD, Marchán E, Gijón J, Martín F. Outcome of allogeneic stem cell trans-
Surg. Pathol. 31(12), 1800–1812 (2007). Nodular regenerative hyperplasia of the plantation in adults with common
161 Khodadad A, Aghamohammadi A, liver in a patient with common variable variable immunodeficiency. J. Allergy
Parvaneh N et al. Gastrointestinal immunodeficiency. An. Med. Interna 23(8), Clin. Immunol. 128(6), 1371–1374.e2
manifestations in patients with common 395–397 (2006). (2011).
variable immunodeficiency. Dig. Dis. Sci.
52(11), 2977–2983 (2007).

A review on guidelines for management and treatment of common

variable immunodeficiency
To obtain credit, you should first read the journal article. After that physicians not licensed in the US who participate in this
reading the article, you should be able to answer the following, CME activity are eligible for AMA PRA Category 1 Credits™.
related, multiple-choice questions. To complete the questions Through agreements that the AMA has made with agencies in
(with a minimum 70% passing score) and earn continuing medi- some countries, AMA PRA credit may be acceptable as evidence
cal education (CME) credit, please go to www.medscape.org/ of participation in CME activities. If you are not licensed in the
journal/expertimmunology. Credit cannot be obtained for tests US, please complete the questions online, print the AMA PRA
completed on paper, although you may use the worksheet below CME credit certificate and present it to your national medical
to keep a record of your answers. You must be a registered user on association for review.
Medscape.org. If you are not registered on Medscape.org, please
click on the New Users: Free Registration link on the left hand Activity Evaluation
side of the website to register. Only one answer is correct for each Where 1 is strongly disagree and 5 is strongly agree
question. Once you successfully answer all post-test questions 1 2 3 4 5
you will be able to view and/or print your certificate. For ques- 1. The activity supported the learning objectives.
tions regarding the content of this activity, contact the accredited
2. The material was organized clearly for
provider, CME@medscape.net. For technical assistance, contact learning to occur.
CME@webmd.net. American Medical Association’s Physician’s
3. The content learned from this activity will
Recognition Award (AMA PRA) credits are accepted in the
impact my practice.
US as evidence of participation in CME activities. For further
information on this award, please refer to http://www.ama-assn. 4. The activity was presented objectively and
free of commercial bias.
org/ama/pub/category/2922.html. The AMA has determined
1. You are seeing an 18-year-old young woman with recurrent upper respiratory and gastrointestinal infections. She
was just diagnosed with common variable immunodeficiency (CVID). What can you tell her about this diagnosis?
£ A It may be diagnosed among children as young as 2 years of age
£ B The principal clinical presentation of CVID is recurrent infections
£ C Non-encapsulated bacteria promote most bacterial infections among patients with CVID
£ D Campylobacter species promote most gastrointestinal infections among patients with CVID
2. You decide to initiate immunoglobulin G (IgG) replacement therapy for this patient. What should you consider
regarding this therapy?
£ A Only intravenous therapy provides consistently sufficient doses of IgG
£ B Subcutaneous doses of IgG should not exceed 100 mg/kg per week
£ C Subcutaneous administration of IgG provides a more stable serum level of IgG compared with intravenous
administration
£ D Side effects are more common among adolescents vs adults over age 65
3. The patient continues to have a cough after 2 courses of antibiotic therapy. What should you consider regarding pulmonary
complications of CVID?
£ A Younger age is associated with more severe pulmonary complications
£ B Her dosage of IgG may need to be increased
£ C Plain radiography remains the best means to evaluate chronic pulmonary symptoms among patients with CVID
£ D Corticosteroids are to be avoided in the management of pulmonary disease among patients with CVID
4. What else should you consider regarding the potential complications of CVID?
£ A Autoimmune thrombocytopenic purpura and autoimmune haemolytic anemia are the most common autoimmune
complications of CVID
£ B CVID-related enteropathy usually improves after gluten is eliminated from the diet
£ C CVID is associated with a higher risk of hematological but not solid malignancy
£ D The most common malignancy associated with CVID is chronic leukocytic leukemia

A Review On Guidelines For Management and Treatment of Common Variable Immunodeficiency

Uploaded by

Copyright:

Available Formats

A Review On Guidelines For Management and Treatment of Common Variable Immunodeficiency

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

A Review On Guidelines For Management and Treatment of Common Variable Immunodeficiency

Uploaded by

Copyright:

Available Formats

Expert Review of Clinical Immunology

ISSN: 1744-666X (Print) 1744-8409 (Online) Journal homepage: https://www.tandfonline.com/loi/ierm20

A review on guidelines for management and

Hassan Abolhassani, Babak Torabi Sagvand, Tahaamin Shokuhfar, Babak

To link to this article: https://doi.org/10.1586/eci.13.30

Published online: 10 Jan 2014.

Submit your article to this journal

Article views: 15191

View related articles

Citing articles: 8 View citing articles

Full Terms & Conditions of access and use can be found at

A review on guidelines for

Release date: 30 May 2013; Expiration date: 30 May 2014

www.expert-reviews.com 10.1586/ECI.13.30 © 2013 Expert Reviews Ltd ISSN 1744-666X 561

Financial & competing interests disclosure

562 Expert Rev. Clin. Immunol. 9(6), (2013)

Management of infectious complications

564 Expert Rev. Clin. Immunol. 9(6), (2013)

Management of pulmonary complications fluticasone or nebulized gentamicin for reduction of sputum

566 Expert Rev. Clin. Immunol. 9(6), (2013)

Follow-up include the presence of anti-IgA antibodies [154] , autoimmune

568 Expert Rev. Clin. Immunol. 9(6), (2013)

570 Expert Rev. Clin. Immunol. 9(6), (2013)

572 Expert Rev. Clin. Immunol. 9(6), (2013)

574 Expert Rev. Clin. Immunol. 9(6), (2013)

A review on guidelines for management and treatment of common

You might also like

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.