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Hemochromatosis as a Risk Factor for Fulminant Staphylococcus aureus Pneumonia*

Baranko, Darrell J.; Flynn, Joseph M.; Blanchard, Jeremy R.

Infectious Diseases in Clinical Practice: January 2001 - Volume 10 - Issue 1 - p 44-49
Instructive Cases

From the Department of Medicine (DJB); Hematology/Oncology Service (JMF); Critical Care Medicine Service (JRB), Walter Reed Army Medical Center, Washington, DC.

Address for correspondence: Jeremy R. Blanchard, M.D., Critical Care Medicine Service, Department of Medicine, Walter Reed Army Medical Center, 6825 16th Street NW, Washington, D.C. 20307–5001. Fax: 202–782-5043. Telephone: 202–782-3891.

*The views expressed in this article are those of the authors, and should not be interpreted as representing the opinion of the Walter Reed Army Medical Center or the United States Army.

Hemochromatosis is a disease of systemic iron overload characterized by iron deposition in various organs, including the liver, heart, and pancreas, which ultimately leads to end-organ dysfunction and failure if not adequately treated. A less commonly recognized consequence of systemic iron overload is its effect on limiting the ability to fight bacterial infection through its support of bacterial growth and its inhibition of normal immune function. We present a case of a 36-year-old white male who developed Staphylococcus aureus pneumonia, which subsequently lead to his death. At autopsy, he was found to have hemochromatosis. This case demonstrates the clinical effect of iron overload on infection. It illustrates the need for early identification of hemochromatosis patients, because their immunocompromised state warrants a more aggressive approach to infection. Also, an understanding of the underlying pathophysiology of iron overload points to new antimicrobial strategies including new antibiotic design and new transfusion strategies.

Hemochromatosis is a disease of systemic iron overload characterized by iron deposition in multiple organs. In genetic hemochromatosis, there is an excessive absorption of dietary iron in the small bowel. The mechanism for this physiologic iron hoarding is unknown. The excess iron is then stored in parenchymal cells throughout the body. The accumulation of these iron stores causes organ damage over time reflected in the more common clinical presentations. The classic clinical triad is diabetes, bronze skin coloration, and cirrhosis. Other common clinical effects of the excessive body iron overload are arthritis, cardiomyopathy, and pituitary-related hypogonadism. Clinically, this disease is more commonly expressed in men, and is initially diagnosed most often in the 40-to 60-year-old patient [1].

Beyond these commonly recognized abnormalities associated with iron overload states, including hemochromatosis, is the effect on limiting the ability to fight bacterial infection. It is known that bacteria require iron for growth and survival, and iron overload states have been shown to negatively affect the immune system at various levels [2,3,4,5]. This could be the reason behind the increased susceptibility to infection with Vibrio vulnificus, Listeria monocytogenes, Yersinia enterocolitica, Salmonella enteritidis serotype typhimurium, Klebsiella pneumoniae, Escherichia coli, Rhizopus arrhizus, and mucor species that is found in patients with hemochromatosis [1]. We present a case of a 36-year-old white male who developed Staphylococcus aureus (S. aureus) pneumonia, which subsequently lead to his death. At autopsy, he was found to have hemochromatosis. Our review of the literature has revealed several specific mechanisms by which this patient’s underlying state of iron overload contributed to the severity of his infection and, ultimately, to his death. Early identification of hemochromatosis patients is critical not only for prevention of chronic sequelae of the disease, but also for prevention of acute infectious complications that may be lessened in severity by a more aggressive surveillance. Recognition of the underlying mechanisms of increased susceptibility to infection opens the door for novel therapeutic strategies.

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Case Report.

A 36-year-old white male presented to a community hospital with a 2-day history of a dry cough, chills and pleuritic chest pain. His past medical history was unremarkable except for a 20 pack-year smoking history and an antecedent, self-limited viral infection 10 days before admission. On initial evaluation, he was febrile to 101.5°F, heart rate 110 bpm, respiratory rate 20 bpm, and oxygen saturation of 90% on room air. He had rales at the right lung base. Initial white blood cell count was 19,300/mm3 with a differential of 57% segmented neutrophils, 23% band forms, 12% lymphocytes, and 8% monocytes. Initial liver-associated enzymes revealed an alkaline phosphatase 61 U/L, aspartate aminotransferase 41U/L, alanine aminotransferase 91U/L, and total bilirubin 1.3mg/dL. A chest radiograph revealed a right middle lobe and right lower lobe infiltrate (seeFig. 1). Shortly after arrival to the emergency department, the patient’s condition deteriorated and he developed cardiorespiratory arrest, requiring intubation and electric defibrillation. After his intubation, a repeat chest radiograph showed diffuse bilateral airspace disease (seeFig. 2). He received vigorous resuscitation in the form of intravenous crystalloid solution and vasopressors, and was transferred to our medical center for further care.





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 [6], 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 [7].



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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 [9].

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 [9]. 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 [8]. 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 [11]. Siderophore production is increased in low iron states [8].

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% [12]. 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 [4]. Similar immunologic defects were noted by Verbrugh and colleagues in patients with recurrent S. aureus infections [5]. 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 [3].

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 [1]. Uncontrolled studies have shown increased exacerbations of latent infections in patients given iron therapy [13]. Hemodialysis patients with the highest serum ferritins also have the highest infection rate [2]. Yang and colleagues published data on hemochromatosisassociated mortality, which showed an increased proportionate mortality ratio for patients with hemochromatosis and bacteremia [14]. 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 [15].

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 [23]. 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) [24]. 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.

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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.

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