Case 46

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 18/02/2015

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CASE 46

Anne is 20 months of age and has been hospitalized with a fever, irritability, and moderate dehydration. Blood work suggests a bacterial infection, with elevated neutrophils (see Appendix for reference value), although chest radiograph and urinalysis are normal. A lumbar puncture taken yesterday showed an elevated white blood cell count, and preliminary culture results today suggest growth of Neisseria meningitidis. She has been receiving intravenous antibiotics for 30 hours, and there is some improvement in her condition. Physical examination indicated that Anne was below the 50th percentile for weight, had recurrent diarrhea, and had seborrheic dermatitis, more commonly referred to as “cradle cap.” Detailed question of Anne’s clinical history revealed that she had had recurrent infections, but none had ever been this bad. Detailed family history reveals that a distant male cousin and an aunt both died at an early age (<2 years) of meningitis. What further tests might you order? What is the significance of the history and findings?

QUESTIONS FOR GROUP DISCUSSION

1. Bacterial infections characterize defects in B cells, complement, or phagocytes. Explain why a major B cell defect (e.g., agammaglobulinemia) is unlikely in this case. Discuss how you would test for defects in phagocytes. To test for complement defects you would measure overall complement activity using the CH50 test. Assuming that the results of this test show a complement defect, how would you proceed? What single test would allow you to determine if the defect is in the terminal pathway or the classical pathway?
2. Because preliminary culture results suggested growth of Neisseria meningitidis, Anne was diagnosed with systemic inflammatory response syndrome (SIRS), formerly referred to simply as “sepsis” during infection. Review the processes that are activated during inflammation (see Case 23), with emphasis on the role of interleukin (IL)-1 and tumor necrosis factor (TNF). Note that the current dogma states that SIRS leads to the excessive release of cytokines that produce fever, shock, and often death.
3. Infections with Gram-negative bacteria lead to their lysis, release of lipopolysaccharide (LPS/endotoxin) from the cell wall outer membrane, and subsequent secretion of TNF by monocytes and macrophages. Describe how these events are connected. Include in your discussion each of the following terms: lipopolysaccharide binding protein (LBP), soluble CD14, MD-2, and TLR-4. How would you explain the fact that in animal models of endotoxin-induced peritonitis and in human SIRS trials blocking both TNF and TNF antagonists increased mortality?
4. With respect to question 4, how would you explain the following: (a) in humans, mortality associated with meningococcemia correlates with high TNF levels; (b) in SIRS patients (infected with Gram-negative bacteria), antagonists of IL-1 receptor, TNF, and endotoxin do not improve outcome; and (c) mice that have mutations in the TLR-4 gene have increased mortality to SIRS induced by infection with Gram-negative bacteria.
5. Review the differentiation of Thp cells to Th1 or Th2 cells secreting type 1 and type 2 cytokines, respectively. List these cytokines. What factors influence the polarization of a response to either a Th1 or a Th2 cell? An increased level of IL-10 in SIRS patients is a predictor of mortality. What is the role of IL-10 in the regulation of Thp cell activation? What is the consequence of increased IL-10 on the production of type 1 cytokines by Th1 cells?
6. Antigen presentation by macrophages after phagocytosis of necrotic cells polarizes the Thp differentiation to that of a Th1 phenotype, whereas phagocytosis of apoptosed cells polarizes the response to that of a Th2 phenotype. Patients who died of SIRS have evidence for apoptosis-induced loss of immune cells. What cytokines would you expect to be increased in these patients? What effect would this have on the production of type 1 cytokines? Based on this information, why would apoptosis-induced death of immune cells be a predictor of mortality?
7. Explain why neutrophils are regarded as “double-edged swords” in SIRS. What is the rationale for the administration of the cytokine granulocyte colony-stimulating factor (G-CSF)? Explain the role of activated protein C in the extrinsic coagulation system. How do you reconcile the use of recombinant protein C with studies in which G-CSF increased survival rates in patients with SIRS? How would you rationalize the use of this therapeutic agent with studies that showed that antigen presentation by macrophages that have ingested apoptosed cells leads to the induction of Th2 cells secreting type II cytokines (e.g., interleukin [IL]-10) and the fact that increased IL-10 is an independent predictor of mortality?
8. Intensive insulin therapy has been shown to result in lower morbidity and mortality in patients with SIRS. Although the mechanism of action is unknown, insulin prevents apoptotic death of cells. What effect would this have on IL-10 levels? Discuss the studies that could be used to rationalize the use of insulin therapy.
9. Newer therapies for SIRS that are under consideration include interferon gamma (IFNγ), IL-12, and C5a. Provide a rationale for each of these as potential therapeutic agents.
10. Ischemic preconditioning is a term used to describe a phenomenon in which a transient episode of myocardial ischemia subsequently protects the individual from severe myocardial ischemia. Extrapolate this concept to SIRS patients who survive SIRS sepsis.

RECOMMENDED APPROACH

Implications/Analysis of Family History

Detailed family history revealed that a distant male cousin and an aunt both died at an early age (<2 years) of meningitis. The fact that this disease susceptibility is so rare in the family suggests that we should be considering disorders with an autosomal recessive mode of inheritance.

Implications/Analysis of Clinical History

Anne’s immediate problem is the Neisseria meningitidis infection, which is the cause of the overwhelming sepsis, now referred to as systemic inflammatory response syndrome (SIRS). Although deficiencies in B cells, phagocytes, and complement are considerations in patients with severe bacterial infections, the fact that this is a Neisseria infection suggests that we should be focusing our attention on possible deficiencies in the terminal pathway of complement. Patients with deficiencies in the proteins that compose the membrane attack complex are particularly susceptible to infections with Neisseria species (Fig. 46-1).

image

FIGURE 46-1 Neisseria gonorrhoeae. Gram stain of urethral pus from a patient with gonorrhea. Note that the diplococci occur mostly intracellularly. (×1000.)

(From Hart CA, Shears P: Color Atlas of Medical Microbiology, 2nd ed. St. Louis, Mosby, 2004.)

Note, however, that in addition to Anne’s immediate problem of SIRS, she has a triad of symptoms—recurrent diarrhea, seborrheic dermatitis (which often manifests as cradle cap), and failure to thrive. Therefore, we should be attempting to determine if there is a defect that will account for both SIRS and the symptoms described.

Implications/Analysis of Laboratory Investigation

Results of blood work and culture were consistent with a strong inflammatory response to systemic infection with Neisseria meningitidis

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