Case 40

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 40

Bill has cystic fibrosis and received a double-lung transplant approximately 8 months ago. When you see him in your follow-up clinic today he looks far more short of breath than on his last appearance. Your nurse measures his oxygen saturation at rest on room air (normal, nonsmoker: 97%-100%), and you are disturbed to find his level only 88%. He becomes quite cyanotic (low oxygen supply to peripheral tissues) with minimal exertion in your office. He has diffuse wheezes throughout the lung fields and is afebrile. There has been no recent change in immunosuppressive therapy. You admit him to a hospital for further investigation.

QUESTIONS FOR GROUP DISCUSSION

1. What is the genetic defect in cystic fibrosis? To what types of infections are these patients particularly prone?
2. Explain why patients with cystic fibrosis are prone to infection with Staphylococcus aureus and Pseudomonas aeruginosa.
3. One of the first considerations in a patient with a relatively recent transplant is acute rejection. However, evidence of acute rejection typically occurs in the first 2 months, and so one would have expected some earlier indication that this was occurring. What is the accepted therapy for a patient who is undergoing acute rejection of the transplanted tissue? (See Introduction to Transplantation and Case 42.)
4. This patient had received a double-lung transplant (instead of a single lung). This is a generally accepted procedure for patients with cystic fibrosis. Explain.
5. What is your primary concern in a patient who is immunosuppressed? Explain why immunosuppressive therapy would predispose an individual to viral and fungal infections, in particular.
6. To which viral infections are immunosuppressed patients particularly prone? Describe the immunoevasive strategies that are protective for these viruses and explain why they hinder destruction of the virally infected cells.
7. The wheezing probably reflects generalized airway irritation/hyperreactivity and not a type I hypersensitivity reaction in that no change in medication is reported. Type I hypersensitivity reactions are associated with the production of IgE, mast cell degranulation, histamine and leukotriene release, and eosinophilia. As a review, discuss the mechanisms by which each of these occurs with emphasis on the role of interleukin (IL)-4 and IL-5.
8. A bronchoscopy sample of this patient’s lung revealed a chronic inflammatory/fibrosing picture referred to as bronchiolitis obliterans (loss of small airways and chronic graft loss). Explain why increasing immunosuppressants would not help this patient yet would help a patient experiencing acute rejection. (Bronchoscopy is a diagnostic technique in which a tiny camera, within a tube, is inserted into the lungs via the nose or mouth. In addition to generating a “picture” of the airways, it is possible to obtain samples of the lung tissue and secretions.) (See Introduction to Transplantation and Case 42.)
9. Treatment measures are still in their infancy, among which is the administration of IL-10 in aerosolized fashion. Explain the rationale for this approach. Include in your discussion each of the following: antigen-presenting cells; natural killer (NK) cells; Thp, Th0, and Th1 cells; and type 1 cytokines.
10. Explain the rationale for considering anti-integrin antibodies as therapeutic agents for chronic rejection. (Hint: inflammation is a component of chronic rejection.) What is the “down side” to this type of approach?

RECOMMENDED APPROACH

Implications/Analysis of Family History

Cystic fibrosis is an autosomal recessive disorder resulting from mutations in a gene that encodes the cystic fibrosis transmembrane regulator (CFTR), an epithelial chloride channel expressed in a number of tissues, including airways, testis, and pancreas. Depending on the mutation, CFTR may function abnormally or not be expressed at all. Although we are not given a family history, Bill’s parents would both have been carriers (heterozygotes) for the mutated CFTR. In the general population the frequency of heterozygosity is 1:40, with the incidence of CF about 1:2000.

Implications/Analysis of Clinical History

Patients with cystic fibrosis represent the highest group receiving double-lung transplants for end-stage lung disease. These patients generally receive a double-lung transplant instead of a single lung because Staphylococcus aureus and Pseudomonas aeruginosa infections are common in this patient population. Given that Bill had a double-lung transplant, a bacterial infection as a result of cross-contamination from the donor lung is unlikely, particularly since he is afebrile.

The fact that Bill is short of breath with minimal exertion suggests that his peripheral tissues are not receiving sufficient oxygen. In addition, the wheezes throughout the lung fields probably reflect generalized airway irritation/hyperreactivity and should be treated with bronchodilators and/or corticosteroids (which is temporizing therapy until we find the cause). There is no change in medications reported. Thus, it is (in general) unlikely to be a new hypersensitivity reaction to a medication. Such a reaction would likely be associated with predominant IL-4/IL-5 and leukotriene mediator release, along with hypereosinophilia.

The fact that Bill is receiving immunosuppressive therapy, a viral infection, particularly with cytomegalovirus (human herpesvirus 5) or Epstein-Barr virus (human herpesvirus 4) as a causative agent for pneumonitis is plausible.

These viruses sabotage the expression of the peptide/class I MHC complexes on the cell surface. This effectively protects the virus and the infected cells can serve as veritable “factories and reservoirs” for viruses.

Implications/Analysis of Laboratory Tests

Your nurse measures Bill’s oxygen saturation at rest on room air (normal, nonsmoker: 97%-100%), and you are disturbed to find his level only 88%. Oxygen saturation is a measure of the amount of oxygen bound to hemoglobin and hence carried by circulating red blood cells. This can be measured using a pulse oximeter, which is a noninvasive technique in which a probe is attached to a patient’s finger. The probe is linked to a computerized unit that displays the value as a percentage. An oxygen saturation value of less than 90% puts the patient at risk for chronic hypoxic damage to end organs (e.g., brain, heart, lungs, kidney). Alternatively, the amount of oxygen in a sample of arterial blood can be measured directly.

Additional Laboratory Tests

It is most likely that you will want a sputum sample; however, a bronchoscopy sample will be more diagnostic. This sample is obtained using a thin, flexible instrument called a bronchoscope, through which air passages in the lung can be examined directly. The advantage of a bronchoscopy sample is that it enables you to make more informed judgment about the pathology, based on the histologic and cytologic examination of the sample. Moreover, it allows for concomitant biopsy of the lung tissue with the same investigation. In Bill’s case, no microbial pathology was seen, but pathologic reports of the biopsy suggest the diagnosis.

DIAGNOSIS

In the absence of a defined etiology, the clinical picture described already suggested a diagnosis of bronchiolitis obliterans, a syndrome in which small airways and alveolar sacs become partially or completely blocked by scar tissue formed when healing processes are activated to repair the damage caused by nonspecific inflammatory processes. Bronchiolitis obliterans (besides acute rejection graft loss) is the most common cause of chronic rejection and failure of lung transplants today. In Bill’s case there is no other etiology and all evidence points toward a chronic inflammatory/fibrosing picture, a fact confirmed by biopsy.

THERAPY

Treatment measures are still in their infancy, but an experimental approach generating a great deal of interest involves gene transfer of IL-10 as a potent anti-inflammatory cytokine (to the transplanted organ and/or to the recipient post transplantation in aerosolized fashion). Additional regimens include measures directed toward prevention of infiltration of the graft bed with host leukocytes capable of causing damage (e.g., anti-integrins), although recognizing that this may increase susceptibility to airway microbial pathogens.

ETIOLOGY: CYSTIC FIBROSIS

Cystic fibrosis is an autosomal recessive disorder resulting from mutations in a gene that encodes the cystic fibrosis transmembrane regulator (CFTR), an epithelial chloride channel expressed in a number of tissues, including airways, testis, and pancreas. A mutation in this protein disrupts the normal homeostasis (ion exchange) across the lung epithelium, and a thick, sticky mucus accumulates in the airways, resulting in airway obstruction and an inability to clear inhaled pathogens. In the normal state, a thin, moist mucus layer overlies the epithelial cells such that pathogen binding is hindered while cilia that line the airways expel microbes that enter the airways.

For most patients, a diagnosis of cystic fibrosis is made after two elevated sweat chloride measures on separate days or by identification of a mutation using molecular techniques.

Chronic airway infections with S. aureus and P. aeruginosa are common in patients with cystic fibrosis and lead to vigorous inflammatory responses characterized by the migration of neutrophils to this region. In fact, most deaths from cystic fibrosis result from complications associated with infections. One of the factors contributing to infection with these pathogens is the increased numbers of asialolated glycolipids (e.g., asialoGM1) present on epithelial cells that express a mutated CFTR (or that are regenerating). AsialoGM1 functions as a receptor for pili present on both S. aureus and P. aeruginosa. This receptor/ligand interaction leads to the activation of NFκB, a transcription factor for IL-8, which is a chemokine specific for neutrophils. The activated epithelial cells secrete IL-8, which recruits more neutrophils to the site; however, they are unable to clear these infections. Neutrophils in patients with cystic fibrosis have been shown to spontaneously secrete IL-8, with airway neutrophils secreting more than blood neutrophils in the same patient. Additionally, neutrophils release a number of inflammatory products that can cause damage to the lung tissue.

The chronic inflammatory state that characterizes cystic fibrosis may, in fact, represent a defect in immunoregulation in that cystic fibrosis airways are deficient in IL-10, a cytokine that is known to downregulate inflammatory responses. In vitro studies have shown that T cells expressing a mutated form of CFTR secrete less of the anti-inflammatory cytokine IL-10 than controls. (Note: IL-10 inhibits secretion of IL-12 by antigen-presenting cells. In the absence of IL-10, IL-12 activates NK cells to secrete interferon gamma (IFNγ), which plays a role in the differentiation of CD4+ T cells to Th1 cells secreting inflammatory cytokines (e.g., IFNγ, tumor necrosis factor).

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