Uncommon presentations of common variable immunodeficiency

Abstract

Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder that causes decreased immunity and increased susceptibility to infections. It affects B lymphocyte differentiation, resulting in predominantly bacterial and less frequently viral, fungal, and protozoal infections. The respiratory and gastrointestinal tracts where antibody defences are essential are usually affected. Individuals with CVID are also predisposed to developing lymphoid and gastrointestinal malignancies. We present two cases with rare infectious and oncological complications of CVID, including a patient with Mycobacterium avium complex-intracellular infection and ovarian cancer, and another patient with group B Streptococcus empyema of the lung with acute myeloid leukaemia. The main objective of this study is to highlight how CVID-induced hypogammaglobulinaemia can lead to rare infections and malignancies. The management of these complications can vary according to severity, but an awareness of their existence is crucial to diagnose them promptly in an already immunocompromised CVID patient.

Background

Common variable immunodeficiency (CVID) is the most common primary immunodeficiency disorder in adults and children. The term ‘variable’ depicts the diversity of clinical presentations of this disease. It is characterised by decreased levels of immunoglobulin G (IgG), IgA, and IgM due to the failure of B lymphocytes to differentiate and produce immunoglobulins. In this series, we present two cases of CVID with rare infectious and malignant associations that resulted primarily because of CVID-induced hypogammaglobulinaemia. Although CVID is associated with several infections and malignancies, our cases are unique as they further broaden the spectrum of such known and reported associations. This will help in spreading awareness about the consequences of CVID-induced hypogammaglobulinaemia and facilitate immediate recognition and treatment of the same.

CASE PRESENTATION

Case 1

A female patient in her early 60s, with intravenous immunoglobulin (IVIG) dependent CVID, presented with cough and haemoptysis. The patient also complained of shortness of breath, night sweats, significant weight loss and intermittent fever. She had a history of bronchiectasis and stage 3 ovarian cancer treated with surgery and chemotherapy. On examination, the vital signs were a blood pressure (BP) of 131/84 mm Hg, heart rate (HR) of 88/min, respiratory rate (RR) of 22/min, and a normal temperature and oxygen saturation. The physical examination was overall unremarkable except for mild expiratory wheezing more on the left side than on the right. Preliminary tests including blood cultures were negative. CT scan of the chest showed a 2.1 cm left hilar nodular mass encasing the lingular bronchus, associated with mucus plugging and bilateral hilar lymphadenopathy (figure 1). The patient underwent bronchoalveolar lavage that grew Mycobacterium avium complex-intracellulare on Lowenstein-Jensen media that was susceptible to clarithromycin, moxifloxacin, rifampin, ethambutol, linezolid, and amikacin. Her symptoms were well-controlled during the hospital stay. She was monitored with serial CT scans and responded well to symptomatic management.

Figure 1.

CT scan of patient 1 showing Mycobacterium avium complex-intracellulare infection.

The patient is alive today and getting treatment for ovarian cancer with maintenance bevacizumab, and there is no evidence of progression by radiological findings. She is also receiving IVIG for CVID, and azithromycin, ethambutol, and amikacin, Monday, Wednesday, and Friday, for Mycobacterium avium complex-intracellulare pneumonia and bronchiectasis, with stable CT chest findings.

Case 2

A female patient in her late 30s, with CVID and acute myeloid leukaemia (AML), status-post allogeneic stem cell transplant and associated graft-versus-host disease, presented with fever, cough, and pleuritic chest pain. She had multiple infections in the past with methicillin-sensitive and resistant Staphylococcus aureus, Pseudomonas aeruginosa, coagulase-negative Staphylococcus, Clostridium difficile, vancomycin-resistant Enterococcus, Escherichia coli, parainfluenza-3, influenza, herpes simplex, and Aspergillus species. These occurred in the form of cellulitis, sinusitis, panniculitis, colitis, meningitis, bronchitis, urinary tract infections, pneumonia, mucositis, and simple colonisation, over several years. More recently, she developed empyema of the right lower lobe for which she underwent a video-assisted thoracoscopic decortication of the pleura and drainage of the pleural effusion which demonstrated purulent material that grew group B Streptococcus (GBS) on agar culture. She was treated with a prolonged course of intravenous antibiotics. The patient also reported multiple drug allergies and a significant past surgical history of tonsillectomy along with a family history of hypogammaglobulinaemia.

On examination, her vital signs were a BP of 100/70 mm Hg, HR of 90/min, RR of 18/min, and normal oxygen saturation on room air. A temperature of 101°F (38.3°C) was found on admission, but remained normal thereafter. A review of systems was unremarkable. Respiratory viral panels and blood cultures were negative. A CT scan of the chest revealed a decreased fluid collection in the lower thorax and diminished parenchymal consolidation compared with previous scans, consistent with improving empyema status (figure 2). Hence, due to lack of any active infections, the patient did not require antibiotic therapy and was discharged home in stable condition with orders of regular follow-up.

Figure 2.

CT scan of patient 2 showing improving group B Streptococcus empyema status.

The patient died from central nervous system (CNS) AML refractory to treatment.

Discussion

CVID is frequently associated with diverse infections caused by numerous microbes. Table 1 highlights the various respiratory infections and their aetiologies that have been reported with CVID, the most common being with encapsulated organisms like Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis along with Enterovirus.^1–17

Table 1.

A literature review of various respiratory infections reported with common variable immunodeficiency^1–17

Study	Infection	Aetiology
Janeway et al	Sinusitis, pneumonia	Haemophilus influenzae
Cunningham-Rundles	Recurrent bacterial infections including tonsillitis, bronchiectasis, pneumonia, empyema	Streptococcus pneumoniae, metapneumovirus
Kokron et al	Lung infection	Mycobacterium tuberculosis
Arora et al	Lung infection	Mycobacterium simiae
Antachopoulos et al	Colonisation and infestation	Aspergillus species, Histoplasma capsulatum
Oksenhendler et al	Bronchitis	Multiple
Berbers et al	Structural airway disease, interstitial lung disease	Prevotella, Alloprevotella, Selenomonas, Streptococcus
Cohen et al	Pneumonia	COVID-19
Rushchel et al	Pneumonia	Moraxella catarrhalis, Staphylococcus aureus, Pneumocystis jirovecii, Mycoplasma pneumoniae
Więsik-Szewczyk et al		Chlamydia pneumoniae
Kralickova et al	Pneumonia	Cytomegalovirus, atypical Mycobacteria
Kellner et al	Lung infection	Candida albicans, Cryptococcus neoformans, herpes simplex virus, varicella zoster virus, Epstein-Barr virus, Pseudomonas aeruginosa
Tam et al	Pneumonia	Ureaplasma urealyticum
Yazdani et al	Pneumonia, otitis media, rhinosinusitis, pharyngitis, laryngitis, epiglottis	Bordetella pertussis, Neisseria meningitidis, Mycobacterium hominis, adenovirus, enterovirus, human herpes virus 8
Aydogan et al	Bronchiectasis	Proteus mirabilis, Serratia marcescens
Urschel et al	Pneumonia	Measles
Baumann et al	Upper respiratory tract Infection	Rhinovirus

Hypogammaglobinaemia leads to decreased antibody formation that is required to fight infections. IgA is essential to maintain mucosal immunity and its scarcity in CVID patients leads to mucosal inflammation throughout the body, leading to decreased function of mucosal surfaces and increased susceptibility to infections.¹ Lower IgM memory B-cells can result in development of infections due to encapsulated microorganisms.¹⁸ Alteration of gut microbiota and decreased absorption capacity can also play a role in gastrointestinal infections. Viral and fungal infections can occur due to decreased B- and T-cell interaction and reduced T-cell signalling.¹⁹ In spite of various mechanisms by which infections can occur in CVID patients, the main objective of this study is to highlight how primarily hypogammaglobulinaemia can lead to respiratory infections with microbes that are lesser known in the background of CVID with the help of a two-case series.

In the first case we reported a patient with Mycobacterium avium complex-intracellulare (MAC-I) infection which is relatively rare with CVID. This could be because of hypogammaglobulinaemia, decreased B- and T-cell interaction, and reduced T-cell signalling caused by CVID. Although Mycobacterium tuberculosis, Mycobacterium simiae and Mycobacterium hominis lung infections and Mycobacterium bovis systemic infections have been reported before, MAC-I is relatively rare in CVID.²⁰ The presentation of MAC-I is often similar to our patient. A CT scan can show the ‘feeding bronchus’ sign which pertains to the peribronchial nodules evolving into focal cystic bronchiectasis manifesting as cavitary lesions. Bronchoalveolar lavage with biopsy and culture confirms the diagnosis. For mild disease, supportive management with regular follow-up including sputum culture every 3 months and radiological evaluation every 6 months is sufficient. A two-drug and a three-drug regimen is recommended in moderate and severe disease, respectively. The antibiotics of choice for MAC-I include macrolides, clofazimine, rifampin, ethambutol, rifabutin, fluoroquinolones, linezolid, and aminoglycosides.²¹ This patient was also found to have bronchiectasis, which consistently occurs in CVID patients along with other chronic lung disorders, and itself predisposes the lungs to infections.²²

In our second case, the patient had a history of several infections in alignment with those reported in the literature for adults with CVID. However, she also went on to develop Streptococcus agalactiae empyema that is less frequent. Most cases of GBS have been reported in pregnant women and infants. Infections with other encapsulated organisms have been reported in CVID, but GBS empyema is less frequent and can be due to exhaustion of bacteria-specific CD4 cells and microbial translocation, along with hypogammaglobulinaemia.²³ Such an infection can present in conjunction with a loculated pleural effusion and may require aggressive interventions including decortication, video-assisted thoracotomy and lobectomy along with broad-spectrum antibiotics. Patients complain of non-productive cough, fever, pleuritic chest pain and occasionally a bulging anterior chest wall. The empyema can sometimes extend to the subcutaneous tissue causing chest wall tenderness, crepitus, and fistula formation. Consequently, special precautions need to be taken to diagnose such occult infections and treat them with culture-appropriate antibiotics.²⁴

Our second patient also had a history of vancomycin-resistant Enterococcus (VRE), which is another rare infection in CVID patients. VRE is associated with infections of the urinary tract, abdomen, pelvis, endocardium, and the blood stream. Rare manifestations include skin and soft tissue infections, osteomyelitis, pneumonia, and iatrogenic CNS infections. VRE can be treated with β-lactam antibiotics and aminoglycosides. Linezolid and daptomycin is the treatment of choice in resistant cases. Chloramphenicol can be used for CNS infections and tigecycline for recalcitrant patients. Thus, the existence of VRE in an already immunocompromised patient with CVID can have catastrophic consequences if not managed adequately.²⁵ A family history of hypogammaglobulinaemia in our second patient also suggests the genetic nature of CVID.

The presence of CVID can enhance the incidence of several malignancies in patients, as shown in table 2.^26–29

Table 2.

A system-wise review of various malignancies reported with common variable immunodeficiency^26–29

Haematological malignancies	Gastrointestinal malignancies	Malignancies of the female reproductive system	Other malignancies
Non-Hodgkin's lymphoma including diffuse large B-cell lymphoma	Adenocarcinoma of the stomach	Cervical cancer	Bladder cancer
Hodgkin’s lymphoma	Gastric schwannoma	Vulvar cancer	Lung cancer
Anaplastic large cell lymphoma	Pancreatic cancer	Uterine cancer	Tonsillar cancer
Large granular lymphocytic leukaemia	MALT lymphoma	Breast carcinoma	Thymus cancer
Mycosis fungoides (granulomatous cutaneous T-cell lymphoma)	Hepatocellular carcinoma		Thyroid cancer (papillary)
Myelodysplastic syndrome	Neuroendocrine carcinoma of the pancreas		Melanoma
Natural killer cell leukaemia			Squamous cell carcinoma
Acute lymphocytic leukaemia			Basal cell carcinoma
Chronic myeloid leukaemia			Vocal cord cancer
Monoclonal gammopathy
Multiple myeloma

MALT, mucosa-associated lymphoid tissue.

In our case series we have highlighted relatively rare malignancies that can occur in association with this disease. Our first patient was diagnosed with ovarian cancer in the setting of CVID. Though other cancers of the female reproductive tract have been recognised earlier, this is the first reported case of ovarian cancer in the setting of CVID. Haematological malignancies often exist in CVID patients as depicted in table 2, but acute myeloid leukaemia as reported in our second patient is an uncommon association. The second patient was treated with bone marrow transplant and immunosuppression which itself could have predisposed the patient to develop several infections.

Haematological and gastrointestinal malignancies are most frequently found in association with CVID. The reasons may include hypogammaglobulinaemia,²⁶ immune dysregulation, genetics, radiosensitivity, and chronic infections. Lack of IgA plays a similar role for cancers as in the case of infections in CVID. In such a setting, chronic infections like Epstein-Barr virus, Helicobacter pylori and human herpesvirus 8 can lead to the corresponding cancers. Moreover, reduction in natural killer cell numbers due to CVID has also been credited for increased risk of malignancies in these patients.^{27 30}

Learning points.

• Common variable immunodeficiency (CVID) can have variable clinical presentations including numerous infections and malignancies. We encountered two unique cases of CVID with rare respiratory infectious aetiologies and malignant associations.

• The cases are intended to create an awareness and vigilance regarding CVID induced hypogammaglobulinaemia which can cause respiratory infections with lesser-known pathogens where antibodies may be important.

• Early recognition of infections in the background of CVID is essential. This will prevent grave complications in patients who are already immunocompromised and are at a greater risk of contracting severe forms of these infections.

• We have also highlighted some rare malignancies that can be seen in the background of CVID along with an explanation of the pathophysiology of their occurrence. This will enhance the understanding of uncommon manifestations that can be expected in CVID and will consequently help in managing them promptly and efficiently.

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