His hospitalization was remarkable for ventilatory, radiographic, and pulmonary artery parameters consistent with acute respiratory distress syndrome. He required aggressive ventilatory support to include pressure control ventilation with lung-protective strategies , pronation, and high levels of oxygen. Empiric broad-spectrum antimicrobials were initiated. Blood cultures drawn in the emergency room at the community hospital grewS. aureus(pan-sensitive except for resistance to penicillin and ampicillin). Secondary to the aggressive ventilatory management, the patient was heavily sedated and, at times, paralytics were necessary. As the patient’s respiratory status improved, allowing decreases in ventilatory support, sedation was removed. Neurological examination was concerning for hypoxic injury. Computerized tomography of the head without contrast was performed; it showed diffuse cerebral edema with a loss of the gray-white differentiation and nearly complete sulcal effacement. The patient’s family was presented with the grave prognosis, and it was thought that the patient would not want to live unless he could be returned to his preadmission level of independence. Life supportive measures were withdrawn, and the patient expired.
Autopsy results were significant for hepatomegaly with extensive iron deposition and parenchymal fibrosis, which was confirmed with Prussian Blue and Masson’s Trichrome staining (seeFig. 3). Coarse pigmentation consistent with iron deposition was also found in the pancreas. Iron studies, which had been drawn the day of his death, revealed an iron of 52 μg/dL and total iron binding capacity of 118 μg/L, giving a transferrin saturation of 44%. Ferritin was 2385 ng/mL. Genetic testing was performed, which revealed the patient was homozygous for the C282Y mutation of the HFE gene, supporting the diagnosis of hemochromatosis .
The role of iron in infection can be broken down into two general categories: iron utilization by bacteria for growth and proliferation, and iron’s effects on human immune function [2,8]. Although iron is ubiquitous in biochemistry, its most critical role for bacterial growth and proliferation is in intracellular respiration (especially related to the function of the electron transport chain) and DNA synthesis. Reactions along the electron transport chain ultimately yield adenosine triphosphate (ATP), used as the energy source for numerous cellular processes from maintenance of membrane potentials to protein synthesis. Within the electron transport chain, iron-sulfur complexes and heme iron are essential to the structure of enzymes such as NADH-Q and succinate-Q reductase, as well as several cytochromes .
The role of iron in DNA synthesis is in the production of deoxyribonucleotides, the precursors of DNA, from ribonucleotides. The final stage of this transformation is catalyzed by ribonucleotide reductase. This enzyme contains a B1 and a B2 subunit. The B1 subunit is involved in binding, while the B2 subunit, an iron-sulfur complex, acts as a catalyst . Without the high-energy phosphate bonds of ATP and the ability to create new DNA, bacteria would be ineffective pathogens.
Humans have developed mechanisms to prevent bacteria from acquiring free iron. The majority of total body iron is stored in the form of hemoglobin, myoglobin, and cytochromes. The remainder of iron is kept bound primarily by the proteins—transferrin, lactoferrin, and ferritin. Transferrin is the major form of transport iron in the blood. It loses its affinity for iron in areas of low pH (e.g., sites of infection with elevated local production of lactic acid), which could free more iron to be used by bacteria. Lactoferrin is found in milk, other body secretions, and in the secondary granules of neutrophils. Converse to transferrin, lactoferrin has an increased affinity for iron in low pH settings. Activated macrophages increase lactoferrin binding, which allows the iron to be internalized, harboring it from microorganisms. Once inside the macrophages, the iron is transferred to ferritin, which has a very high iron-binding capacity. Infection is a stimulus for the release of pro-inflammatory cytokines such as interleukin-1 beta and tumor necrosis factor alpha. In this inflammatory milieu, the liver suspends normal protein production and produces acute phase reactants including ferritin. The cumulative effect of these iron sequestering mechanisms is decreased levels of free iron available to bacteria (and other cells including developing erythrocytes). This process is manifested clinically by a resultant anemia, often referred to as anemia of inflammation [8,10].
Bacteria attempt to overcome these protective mechanisms. Methods used by bacteria include: use of siderophores, enzymatic breakdown of iron-binding proteins, reduction of iron to facilitate release from the iron binding protein, and utilization of surface receptors to bind with the iron-glycoprotein complex . The most documented of these is the siderophore system.
Under aerobic conditions, iron is in the ferrous form (Fe3+), which is not accessible to bacteria because of its tendency to form a minimally soluble hydroxide. Aerobic and facultative organisms, including S. aureus, secrete low molecular weight compounds called siderophores, which solubilize the iron by chelation and transport it into the bacterium using cell membrane receptors. Once inside, the iron is released from the siderophore by reduction of the iron to the ferric form (Fe2+) or by hydrolysis . Siderophore production is increased in low iron states .
The second mechanism of iron’s impact on infection involves its effect on the immune response. Iron overload states have been associated with a variety of defects in cellular immunity including: decreased phagocytosis by polymorphonuclear leukocytes (PMNs) and mononuclear leukocytes (MNs), decreased chemotaxis by PMNs, decreased bactericidal activity of MNs, decreased proliferation of helper and cytotoxic T cells, and enhanced suppresser T-cell function [2,4].
Our patient’s underlying problem was S. aureus pneumonia, which lead to bacteremia. The mortality of S. aureus bacteremia in the general population is 11–43% . Van Asbeck and colleagues showed that patients with iron overload, including patients with hemochromatosis, have decreased phagocytosis of S. aureus by PMNs and MNs, decreased chemotaxis to S. aureus by MNs, and decreased bactericidal activity of MNs on S. aureus . Similar immunologic defects were noted by Verbrugh and colleagues in patients with recurrent S. aureus infections . Moura and associates also demonstrated decreased ability to phagocytize S. aureus in patients with hemochromatosis. However, in their study, this difference diminished as phagocytosis time increased .
Although the effect of iron overload on bacterial growth and immune competence is well documented, clinical data are sparser. It is known that patients with hemochromatosis have an increased susceptibility to infection with certain organisms, as was described earlier . Uncontrolled studies have shown increased exacerbations of latent infections in patients given iron therapy . Hemodialysis patients with the highest serum ferritins also have the highest infection rate . Yang and colleagues published data on hemochromatosisassociated mortality, which showed an increased proportionate mortality ratio for patients with hemochromatosis and bacteremia . Although these data are provocative, formal studies comparing hemochromatosis patients to normal controls need to be done.
Our patient presented to us after resuscitation from full cardiopulmonary arrest secondary to septic shock. We suggest that his underlying iron overload state contributed to the severity of his infection and subsequently to his death.
Perhaps earlier antibiotic therapy could have prevented his deterioration, although his initial presentation would have classified him as a low-risk community-acquired pneumonia by Fine’s criteria .
This case illustrates two important points. First, in addition to the hepatic and cardiac complications, the infectious complications of hemochromatosis can be life threatening. Given that the prevalence of hemochromatosis is approximately 4.5/1000, screening tests are effective, and treatment (phlebotomy) has documented survival benefit, high priority must be given to investigating the feasibility of a routine screening program for this disease [16,17]. To date, the studies to evaluate this issue have been greatly hampered by the lack of a firm case definition [18,19,20,21,22]. A working case definition needs to be established, and further prospective studies must be undertaken to develop an effective population-based screening program. Presently, there are inadequate data available to make a definitive recommendation. Identification would only be the first step. Most clinicians are vigilant regarding infection surveillance in other higher risk groups such as diabetics. Hemochromatosis patients deserve that same level of vigilance.
Second, the pathophysiology underlying the increased infection risk in hemochromatosis patients provides several potential new avenues for infection therapy. For example, antimicrobials that utilize the siderophore system to gain entry into the bacterial cell are already under investigation . Additional information on packed red blood cell transfusion in the setting of severe infection would be useful. Hebert and colleagues from the Canadian Critical Care Trial Group looked at transfusion requirements in critically ill patients. In a subgroup analysis, they showed no difference in 30-day mortality in patients with severe infection or sepsis who were randomized to a restrictive transfusion strategy (goal hemoglobin >7) versus those who were randomized to a liberal transfusion strategy (goal hemoglobin > 10) . However, they did not include the subgroup data on the actual numbers of units transfused. The number of units transfused gives a better index of free iron exposure, which would have a greater impact on the severity of infection. This, too, requires further investigation in a prospective manner to establish an effective transfusion strategy in this patient population. As more basic science and clinical data become available, the potential role of iron chelation therapy could be explored. In vitro studies have shown a synergistic effect of the iron chelator deferoxamine and numerous antibiotics [25,26]. In this era of burgeoning antibiotic resistance, novel strategies will be needed to provide reinforcement to the physician’s armament against infection.
The authors would like to thank Dr. Keith Kaplan of the Walter Reed Army Medical Center Department of Pathology for providing the liver section used in the illustration.
1. Andrews NC. Medical progress: disorders of iron metabolism. N Engl J Med 1999; 341:1986–1995.
2. Good MF, Powell LW, Halliday JW. Iron status and cellular immune competence. Blood Rev 1988; 2 (1):43–49.
3. Moura E, Verheul AFM, Marx JJM. A functional deficit in hereditary hemochromatosis monocytes and monocyte-derived macrophages. Eur J Clin Invest 1998; 28:164–173.
4. Van Asbeck BS, Marx JoJM, Struyvenberg A, et al. Functional defects in phagocytic cells from patients with iron overload. J Infect 1984; 8:232–240.
5. Verbrugh HA, van Dijk WC, Hendrickx GFM, et al. Phagocytic and chemotactic function of polymorphonuclear and mononuclear leucocytes in patients with recurrent staphylococcal infections. Scand J Infect Dis 1980; 12:111–116.
6. Amato MBP, Barbas CSV, Medeiros DM, et al. Effect of protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998; 338:347–354.
7. Powell LW, George DK, McDonnell SM, et al. Diagnosis of hemochromatosis. Ann Intern Med 1998; 129:925–931.
8. Jurado RL. Iron, infections, and anemia of inflammation. Clin Infect Dis 1997; 25:888–895.
9. Stryer L. Biochemistry. 2nd ed. New York: WH Freeman and Company; 1981. pp 311–319,524–526.
10. Weinberg ED. Iron, infection, and neoplasia. Clin Physiol Biochem 1986; 4:50–60.
11. Davis BD, Dulbecco R, Eisen HN, et al. Microbiology. 4th ed. Philadelphia: J.B. Lippincott Company; 1990. pp 84–85.
12. Lowy FD. Staphylococcus Aureus
infections. N Engl J Med 1998; 339:520–532.
13. Oppenheimer S J. Iron and infection: the clinical evidence. Acta Paediatr Scand Suppl 1989; 361:53–62.
14. Yang Q, McDonnell SM, Khoury MJ, et al. Hemochromatosis-associated mortality in the United States from 1979 to 1992: an analysis of multiple cause mortality data. Ann Intern Med 1998; 129:946–953.
15. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997; 336:243–250.
16. Phatak PD, Sham RL, Raubertas RF, et al. Prevalence of hereditary hemochromatosis in 16031 primary care patients. Ann Intern Med 1998; 129:954–961.
17. Cogswell ME, McDonnell SM, Khoury MJ, et al. Iron overload, public health, and genetics: evaluating the evidence for hemochromatosis screening. Ann Intern Med 1998; 129:971–979.
18. Balan V, Baldus W, Fairbanks V, et al. Screening for hemochromatosis: a cost-effectiveness study based on 12,258 patients. Gastroenterology 1994; 107:453–459.
19. Phatak PD, Guzman G, Woll JE, et al. Cost-effectiveness of screening for hereditary hemochromatosis. Arch Intern Med 1994; 154:769–776.
20. Baer DM, Simons JL, Staples RL, et al. Hemochromatosis screening in asymptomatic ambulatory men 30 years of age and older. Am J Med 1995; 98:464–468.
21. Adams PC, Kertesz AE, McLaren CE, et al. Population screening for hemochromatosis: a comparison of unbound iron-binding capacity, transferrin saturation, and C282Y genotyping in 5,211 voluntary blood donors. Hepatology 2000; 31 (5):1160–1164.
22. El-Serag HB, Inadomi JM, Kowdley KV. Screening for hereditary hemochromatosis in siblings and children of affected parents: a cost-effectiveness analysis. Ann Intern Med 2000; 132:261–269.
23. Trivier D, Courcol RJ. Iron depletion and virulence in Staphylococcus aureus
. FEMS Microbiol Lett. 1996; 141:117–127.
24. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999; 340:409–417.
25. Van Asbeck BS, Marcelis JH, Marx JJM, et al. Inhibition of bacterial multiplication by the iron chelator deferoxamine: potentiating effect of ascorbic acid. Eur J Clin Microbiol 1983; 2 (5):426–431.
© 2001 Lippincott Williams & Wilkins, Inc.
26. Van Asbeck BS, Marcelis JH, van Kats JH, et al. Synergy between the iron chelator deferoxamine and the antimicrobial agents gentamicin, chloramphenicol, cefalothin, cefotiam, and cefsulodin. Eur J Clin Microbiol 1983; 2 (5):432–438.