A)INTRODUCTION

• States of dysregulated humoral immunity are characterized by ineficiency of antibody activity or production. In this scenario, the human organism becomes more succeptible to diverse complications, specially infectious ones. However, non-infectious complications may also occur and can be extreamelly harmfull.
•  Various diseases can compromise humoral immunity and lead to those complications, affecting multiple systems and parts of the human body. The thoracic involvement is very common and related to big morbidity and mortality.
  

  Fig 1: Example of pathologies that compromise humoral immunity and affect the chest.

B)GENERAL CONCEPTS

• The immune system is a network of cells and organs that work together to defend the body against different threats, like deffective cells and outside agents (eg. neoplasic cells, bacteria, viruses). It’s composed by two main parts: innate and adaptive immunity.
  

  Fig 2: Differences between innate and adaptive immunity.
• Adaptive immunity is also divided in two parts with different characteristics however fundamental for our deffense: humoral and cellular immunity.
  

  Fig 3: Differences between humoral and celullar immunity.
• There're many conditions and mechanisms related to chest manifestations: infections, neoplasias, lymphatic disorders, interstitial diseases, bronchial abnormalities, inflamatory conditions and others.

*Chronic changes and recurrent infections of the respiratory tract are the most common causes of morbidity and mortality of patients with dysregulated humoral immunity.

C)IMAGING

• Imaging plays a fundamental role in patients with dysregulated humoral immunity by allowing early identification of thoracic changes and monitorization of therapy’s response. Computed tomography (CT) is the main imaging modality in this context.
  

  Fig 5: CT findings related to states of dysregulated humoral immunity.
• Chest manifestations are frequent in patients with dysregulated humoral immunity, especially involving the respiratory tract. Nonetheless, non-respiratory manifestations may also occur.
  

  Fig 4: Thoracic findings related to states of dysregulated humoral immunity.

*CT plays an important role in diagnosis, management and evaluation of treatment’s response. 

D)PATHOLOGIES AND MANIFESTATIONS

1) Common Variable Immunodeficiency (CVID)

Fig 6: Male, 25y/o, with CVID and recurrent respiratory infections, presenting...

• Most common cause of symptomatic primary immunodeficiency in adults
• Characterized by a loss of B-Cell function usually expressed by a defect in circulating memory cells and differentiation in plasma cells
• Bronchiectasis, infections by encapsuled bacteria, limphadenopathy and interstitial lung diseases (ILD) are often found, however, thoracic manifestations are diverse
  

  Fig 10: Male, 33 y/o, with CVID and bronchiectasis, presenting cough and dyspnea. At...
• ILD’s incidence is 240x higher in patients with CVID and recurrent respiratory infecitons then in the general population
• Lymphoid Intestitial Pneumonia (LIP) and Organized Pneumonia (OP) are the most common pathologies in this context
  

  Fig 7: Male, 58y/o, with CVID and recurrent respiratory infections, presenting...
• LIP’s manifestations usually are diffuse bilateral ground glass opacities or with lower lobes predominance. Perivascular cysts may also appear
  

  Fig 8: Male, 23y/o with CVID  presenting ground glass opacities predominating at the...
• OP’s usually presents ground glass opacities or consolidations with peripheral or peribronchial destribution
• Low levels of IgG and a defective antibody response are related to recurrent respiratory infections.
  

  Fig 11: Male, 48y/o, with CVID and recurrent respiratory infections, presenting...
• Diagnosis is based on low IgG serum levels and exclusion of other hypogammaglobulinemia causes
• IgG replecement is essential to prevent infections and structural changes in the chest, like bronchiectasis
  

  Fig 9: Male, 23y/o, with CVID and recurrent respiratory infections, presenting...
• Malignant neoplasms (solid tumors; lymphoma; thymoma) occur more frequently in patients with CVID
• The association of immunodeficiency and Thymoma is called Good Syndrome and it’s associated with a poor prognosis
• CT has a fundamental role in early diagnosis of thoracic manifestations and monitorazation of therapy’s response
• Lung MRI with difusion may be usefull for detecting bronchial and parenchimal abnormalitties for long-term follow up
• 18FDG PET-CT might be helpull to evaluate therapeutic response

  • GLILD

    • Among the various chest manifestations, there’s a specific one recently identified and potentially harmfull: Granulomatous Lymphocitic interstitial lung disease (GLILD). It’s a thoracic complication related to dysregulated humoral immunity, initally related to CVID, defined as a distinct clinico-radio-pathological ILD

    • Granulomatous Lymphocitic Intestitial Lung Disease (GLILD) is a recently defined entity characterized by granulomatous and lymphoid infiltration. CT findings usually include multiple nodules and lymphadenopathy. Although first described in CVID, it might happen in other pathologies.  

      

      Fig 12: Female, 22y/o, with CVID and GLILD, presenting diffuse multiple ...

    • GLILD is a severe non-infectious complication related to states of dysregulated humoral immunity, with a pathogenesis not yet understood. Besides, studies have shown to be related to poor prognosis
      

      Fig 13: Female, 15y/o, with CVID and  GLILD, presenting multiple perilymphatic...
    • If GLILD is suspected, chest CT, lung function tests, bronchoscopy and surgical lung biopsy should be done

2) Hypogammaglobulinemia

• A laboratory diagnosis defined by low serum IgG levels that might present diverse CT findings
  

  Fig 14: Female, 64y/o, with hypogammaglobulinemia and GLILD, presenting diffuse...
• Can be of either primary of secondary origin:
  • Primary: Due to genetic disorders or chromossomal annormalities

                   eg: Common variable immunodeficiency; X-  linked agammaglobulinemia; Transient   immunoglobulinemia of infancy

• • Secondary: Induced by external or acquired factors

                   eg: Drugs; nutritional disorders; infections; malignancy; nephrotic syndrome; metabolic diseases; severe burns

3) IgG4-Related Respiratory Disease (IgG4-RD)

• IgG4-related disease (IgG4-RD) is a systemic pathology characterized by fibroinflammatory infiltration with abundant IgG4 plasma cells
  

  Fig 16: Female, 53y/o, with IgG4-RRD presenting scattered nodules throughout the lungs,...
• Thoracic manifestations represent about 13-35% of IgG4-RD cases with often extrapulmonary localization
• Diverse chest manifestations and imaging patterns can be found like mass, nodules, septal thickening, honeycombing, bronchiectasis, and often lymphadenopathy
  

  Fig 15: Female, 43y/o, with IgG4-RD presenting Usual Interstitial Pneumonial (UIP)...
• Consolidations, bronchiolitis, pleural thickening and fibrosing mediastinitis are also describe in literature, although not so frequent
  

  Fig 17: Male 43 y/o, with IgG4-RRD presenting pleural thickening ai the lung bases...
• Despite it can affect multiple organs, thoracic involvement can be isolated
• Symptoms include cough, hemoptysis, dyspnea and chest pain, however, many patients are asymptomatic
• Diagnosis depends on serum IgG4 levels and incresed IgG4/IgG plasma cells ratio in biopsy
• 18FDG PET-CT might be helpul to guide biopsy and monitor treatment
• Patients with specific risks require treatment to prevent irreversible sequelae in the mediastinum, biliar tree, kidneys, aorta and mesentery
  

  Fig 18: Male, 68y/o, with IgG4-RD confirmed by pancreatic biopsy presenting a right...
• Corticosteroids are the first treatment option for remission
• Maintence therapy options are corticoidsteroids and immunosupressive agents (cyclosphoamide, azathioprine, methothrexate)

4) Pulmonary Light-Chain Deposition Disease (LCDD)

• It’s characterized by deposition of immunoglobulin light chains fragments, Congo red negative, by a plasma clone within the lungs
• Although more often related to kidneys, heart and digestive-tract, Light-Chain Deposition Disease might affect the lungs 
• Chest manifestations include nodular and difuse interstitial patterns, cysts and bronchiectasis
  

  Fig 20: Male, 70y/o, with Chronic Lymphocitic Leukemia presenting diffuse cysts within...
• It’s often associated to myoloma, Walderström globulinemia and lymphoproliferative diseases
• Pulmonary LCDD is usually an indolent or slowly progressive disease
  

  Fig 19: Female, 68y/o, with Multiple myeloma and Pulmonary LCDD presenting diffuse...
• Treatment usually aims to reduce serum light-chain levels, however may include chemotherapy, immunotherapy, autologus stem cell transplantation and lung transplant

5) Respiratory Amiloidosis

• Characterized by extrecellular deposition of fibrillary protein in the respiratory tract, what leads to organic disfunction
• Raspiratory Amiloidosis can be either localized, presenting tracheobronchial or lung parenchyma involvement, or systemic, usually affecting also the heart and kidneys
  

  Fig 21: Female, 56 y/o, with Respiratory Amiloidosis presenting septal thickening,...
• Different patterns are described: traqueobronchial, parenchymal and diffuse interstitial
• Both symptons and CT manifestations depend on disease’s subtypes and patterns. It may include pulmonary nodules, septal and tracheobronchial thickening, usually presenting calcifications. Cysts and bronchitasis may also occur
  

  Fig 22: Male, 61 y/o, with Respiratory Amiloidosis presenting sparse pulmonary nodules,...

E)FUTURE PERSPECTIVES

• Although CT is the most used imaging method for evaluation of patients with dysregulared humoral immunity, MRI and PET-CT might have more applicability in the future. 
• Precision medicine may enable more effective treatment strategies to individual patients, based on their genetic profile
• Future trials should provide more information about GLILD’s impact and study whether biopsy is really necessary for the diagnosis