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Pulmonary and Critical Care Pearls |

Fever and Progressive Respiratory Failure in Three Elderly Family Members* FREE TO VIEW

F. Eun-Hyung Lee, MD; Christopher C. Daigle, MD, FCCP; Marguerite A. Urban, MD; Leon A. Metlay, MD; John J. Treanor, MD; David R. Trawick, MD, PhD, FCCP
Author and Funding Information

Affiliations: *From the Divisions of Pulmonary and Critical Care Medicine (Drs. Lee, Daigle, and Trawick) and Infectious Disease (Drs. Urban and Treanor), and Department of Pathology (Dr. Metlay), University of Rochester, Rochester, NY.,  Currently at Southern New Hampshire Medical Center, Nashua, NH.

Correspondence to: F. Eun-Hyung Lee, MD, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester Medical Center, 601 Elmwood Ave, Box 692, Rochester, NY 14642; e-mail: eunhyung_lee@urmc.rochester.edu



Chest. 2005;128(3):1863-1867. doi:10.1378/chest.128.3.1863
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A 65-year-old white woman with a history of COPD presents with a chief complaint of nonproductive cough and dyspnea for 3 days in February 2002. She complains of fevers, chills, dizziness, and profound weakness leading to a “fall” where she could not “get herself off the floor.” She has lost 20 lb in the past 3 months. Her medical history is notable for COPD, recurrent upper respiratory infections since the age of 14, chronic fatigue syndrome, and essential tremor. She has a family history of hereditary hemorraghic telangectasia. She lives with her mother and sister. Her medications are albuterol inhaler and theophylline. Two days prior to hospital admission, the patient’s sister (age 64 years) was admitted with acute onset of dyspnea, fever, and chills; and 1 day prior to hospital admission, her mother (age 86 years) was admitted with cough, lethargy, fever (39°C), and wheezing.

An examination reveals a cachectic woman in moderate respiratory distress with a BP of 110/60 mm Hg, pulse rate of 98 beats/min, and respiratory rate of 18 breaths/min. She is afebrile with a pulse oxygen saturation of 96% on room air. Diffuse bilateral wheezes with scattered rhonchi are audible in the lungs. Her cardiac examination reveals a regular rate and rhythm with no murmurs, rubs, or gallops. The abdomen and lower extremities are unremarkable.

WBC count is 8,600 cells/μL with 500 lymphocytes/μL, hematocrit of 31%, and platelet count of 231,000/μL. Findings from a comprehensive electrolyte panel, alanine aminotransferase, and coagulation factors are normal. Her aspartate aminotransferase level is 117 IU/L, and creatine kinase is 1,578 IU/L. Her chest radiograph reveals a right lobar infiltrate and diffuse bilateral interstitial infiltrates. A CT of the head reveals atrophy, bifrontal subdural hygromas, and nonspecific white matter changes consistent with small-vessel disease.

The patient is treated with predinisone, 40mg/d, azithromycin, ceftriaxone, and oseltamivir for presumed influenza infection. On hospital day 3, her symptoms of wheezing worsen, and she receives increased methlyprednisolone, 60 mg q8h. Urine culture reveals yeast. Her respiratory symptoms continue to worsen with wheezing, increased sputum production, and hypoxemia (pulse oxygen saturation of 85% on 40% fraction of inspired oxygen). Her WBC count initially was 4,600 cells/μL but continues to increase as high as 23,300 cell/μL with persistent lymphopenia < 1,500/μL. Hospital day 11 reveals thick, yellow-green sputum, and cultures grew mold. The patient requires intubation by hospital day 17. Chest radiography reveals worsening interstitial and alveolar infiltrates (Fig 1 ). She is febrile to 38.8°C. Her pulmonary infiltrates continue to worsen, and a new heart murmur develops. By hospital day 20, she is hypotensive, with a WBC count of 2,100 cells/μL and worsening mental status. By the evening, she no longer has evidence of pupillary, corneal, or gag reflexes. A CT of her head reveals multiple (n = 25) hypodense lesions in the supratentorial and infratentorial brain parenchyma (Fig 2 ). The family wishes to withdraw care, and the patient dies on hospital day 25. An autopsy is performed.

Eventually, her mother and sister die on their hospital days 14 and 21, respectively. Both have a history of COPD and were treated with corticosteroids for diffuse wheezing. Lymphopenia developed in both (lymphocyte count < 1,500/μL), and sputum samples from the sister grew mold during her hospitalization. The three family members had not been placed in the same hospital wards.

Influenza A infection is the most common respiratory pathogen with increased mortality and morbidity, especially in the elderly, and complications of aspergillus infections in immunocompetent hosts have been described more frequently since 1979. Invasive aspergillus infection is uniformly fatal without treatment; however, distinguishing aspergillus in the sputum culture as a true pathogen has been difficult without lung biopsies. This patient had evidence of mold in the sputum on day 11 and was started on liposomal amphotericin B on day 21 when her symptoms were deteriorating. A report of early aggressive intervention with liposomal amphotericin, inhaled amphotericin-B, interferon (IFN)-γ and granulocyte macrophage-colony stimulating factor in a patient with postinfluenza pseudomembranous necrotizing bronchial aspergillosis resulted in successful treatment and survival with fixed airway obstruction. Perhaps, early treatment of the aspergillus in the sputum after influenza infection should be considered.

Why would three family members living in the same household die of influenza A with overwhelming invasive Aspergillus infection? Host (genetic) susceptible factors, influenza A viral pathogenesis, comorbid conditions, and common environmental factors may have played important roles.

Chest radiographs of invasive pulmonary aspergillus pneumonia in 11 immunocompetent hosts revealed diffuse alveolar or interstitial infiltrates and showed 5 patients with nodular infiltrates or cavitation. Pneumonias caused by aspergillus were often nonspecific and difficult to distinguish from bacterial and viral processes. These three patients had worsening diffuse alveolar and interstitial infiltrates without development of nodules or cavitation.

The diagnosis of influenza A (H3N2) that was isolated from the three family members was confirmed by the Centers for Disease Control and Prevention. There were no reported cases of increased virulence with this strain of influenza A that year.

Widely recognized immune-mediated risk factors for invasive aspergillus infection include intrinsic defects in phagocyte function, corticosteroid-induced suppression of phagocyte function, and prolonged neutropenia. Aspergillus spores inhaled into the bronchial tree are usually killed by alveolar macrophages before they can convert into the tissue invasive hyphal form. Germinating spores and hyphal forms, which are too large to be phagocytized, are killed by neutrophils via oxidative mechanisms.

Host defense against tissue invasion in pulmonary aspergillosis is contingent on the response of alveolar macrophages and neutrophils to the fungus. Reports of influenza virus-immune complexes have been shown to suppress alveolar macrophage phagocytosis in mice. Defects in macrophage phagocytosis from these patients were not tested but may have played an important role in the pathogenesis. Although neutropenia did not occur in these patients, host defects of neutrophil function by the lack of H2O2 and superoxide production (chronic granulomatous disease) have been shown to increase the risk of invasive aspergillus. Neutrophils from all three family members reduced nitro blue tetrazolium, making chronic granulomatous disease unlikely. A retrospective analysis suggests that chronic granulomatous disease can present in adults, and a diagnosis is possible only by a quantitative measurement of superoxide production in the granulocytes. Unfortunately, the quantitative measurements were not performed in these patients.

Data show that lymphocytes, especially CD4 T-cell immunity and cytokine responses, play an important role in the pathogenesis of invasive aspergillus infection by the cytokine-induced dysfunction of phagocytic function. Lymphopenia, in addition to other well-known factors such as neutropenia, graft-vs-host disease, receipt of corticosteroids, and cytomegalovirus disease increased risk of invasive aspergillus after allogeneic stem-cell transplant. CD4 T-cell responses result in a balance between T-helper type 1 (Th1) and T-helper type 2 (Th2) responses. IFN-γ and interleukin (IL)-12 are signature cytokines for Th1 responses, and Th2 responses include IL-4, IL-5, and IL-10. Mouse models have shown IL-10 and IL-4, which are important Th2 cytokines, increasing susceptibility to invasive pulmonary aspergillosis through suppression of Th1 responses.

Similarly, a predominate Th1 and not Th2 (CD4 T-cell) responses confer better clinical outcomes in humans. Elevated serum concentrations of IL-10 in nonneutropenic patients have been demonstrated in patients with invasive aspergillosis. Favorable responses to invasive aspergillus infection correlated with higher IFN-γ/IL-10 ratios (median ratio, IFN-γ/IL-10 = 1.0) compared with patients with progressive or stable disease (median ratio, IFN-γ/IL-10 = 0.1). Healthy individuals demonstrate predominate Th1 (IFN-γ) and not Th2 (IL-4) responses with Aspergillus fumigatus stimulation and a positive lymphoproliferative response. In addition, IL-10–pretreated monocytes from healthy adults suppress superoxide production increasing susceptibility to invasive aspergillosis in vitro, suggesting a mechanism for a poor outcome with Th2-predominant genetic responses.

Although these three patients had no history of immune diseases, persistent or transient lymphopenia with influenza A infection may have caused a transient “immunocompromised state.” Influenza infection has been known to cause lymphopenia with the greatest decrease occurring in T cells with unclear mechanisms. On hospital admission, the patient and her sister had a normal WBC count with notable lymphopenia, and it did not improve during their hospitalizations. The mother suffered a transient lymphopenia for 3 days. Furthermore, corticosteroids may have exacerbated the lymphopenia, and enhanced phagocyte dysfunction with underlying influenza infection led to increased susceptibility of aspergillus infection.

Aspergillus colonization in the lungs plays a role in invasive aspergillus infection. Prior colonization with aspergillus in immunocompromised organ transplant patients is a risk factor for invasive aspergillosis. The Monroe County Health Department, New York, investigated this outbreak by visiting this family’s home. Samples of dust taken from the furnace filter grew pure Aspergillus niger in high colony counts.

The cause of death in this cluster of three family members was multifactorial. They included postinfluenza genetic immune susceptibilities, corticosteroid treatment, and prior heavy colonization with aspergillus. Viral-associated lymphopenia may be one important unrecognized mechanism in the pathogenesis of postinfluenza aspergillosis that leads to phagocytic dysfunction and a transient immunocompromised state with an altered Th1 and Th2 balance. This relative immune dysregulation may be exacerbated by corticosteroid therapy and result in increased susceptibility to opportunistic pathogens such as aspergillus. This report recommends that invasive aspergillosis should be added to the differential diagnosis of postinfluenza respiratory complications.

The patient, sister, and mother had positive influenza A (H3N2) nasal swab cultures. The sputum cultures of the patient grew A fumigatus, and sputum from the sister had A niger and A fumigatus. Although the mother had increasing pulmonary infiltrates on chest radiography when she died, sputum cultures from the mother were not sent. The autopsy of the patient showed multiple studding lesions of aspergillus in the tracheobronchial tree with necrotizing pneumonia and abscesses (Fig 3 ). The heart revealed aspergillus endocarditis (Fig 4 ); the kidneys had subcapsular microabscesses due to aspergillus, and the brain revealed multiple brain aspergillus abscesses. The patient died from influenza A infection with complications of fulminant invasive A fumigatus in the lungs, heart, kidneys, and brain. The most probable cause of death for the mother and sister was also influenza A infection with complications of invasive aspergillus infection, although autopsies were not performed. The patient and family members refused the influenza A vaccine during the fall/winter of 2001. There were no increases in the number of cases of aspergillosis nor any other clusters of cases within the hospital from 2001 to 2002.

1. Invasive aspergillus infection should be considered as an important respiratory complication of postinfluenza infection.

2. Viral-associated lymphopenia may be one important unrecognized mechanism that leads to phagocytic dysfunction.

3. Corticosteroids may exacerbate post-viral immune dysregulation resulting in increased susceptibility to opportunistic pathogens.

Figure Jump LinkFigure 1. Chest radiographs obtained at hospital admission (left) and hospital day 6 (right).Grahic Jump Location
Figure Jump LinkFigure 2. CT of the head showing multiple hypodense lesions on hospital day 22.Grahic Jump Location
Figure Jump LinkFigure 3. Studding in the tracheobronchial tree, gross specimen (left); aspergillus in the tracheobronchial tree (center) [Gormoni methenamine silver, original × 2]; aspergillus hyphal forms in the lung (right) [periodic acid Schiff, original × 40].Grahic Jump Location
Figure Jump LinkFigure 4. Studding in the left ventricle, formulin-fixed gross specimen (left); aspergillus in the left ventricle (center) [hematoxylin-eosin, original × 2]; aspergillus hyphal forms in the cardiac tissue (right) [Gormoni methenamine silver, original × 20].Grahic Jump Location
Allam, MF, Del Castillo, AS, Diaz-Molina, C, et al (2002) Invasive pulmonary aspergillosis: identification of risk factors.Scand J Infect Dis34,819-822. [CrossRef] [PubMed]
 
Astry, CL, Jakab, GJ Influenza virus-induced immune complexes suppress alveolar macrophage phagocytosis.J Virol1984;50,287-292. [PubMed]
 
Barker, WH, Mullooly, JP Influenza vaccination of elderly persons: reduction in pneumonia and influenza hospitalizations and deaths.JAMA1980;244,2547-2549. [CrossRef] [PubMed]
 
Boots, RJ, Paterson, DL, Allworth, AM, et al Successful treatment of post-influenza pseudomembranous necrotising bronchial aspergillosis with liposomal amphotericin, inhaled amphotericin B, gamma interferon and GM-CSF.Thorax1999;54,1047-1049. [CrossRef] [PubMed]
 
Cenci, E, Mencacci, A, Del Sero, G, et al Interleukin-4 causes susceptibility to invasive pulmonary aspergillosis through suppression of protective type I responses.J Infect Dis1999;180,1957-1968. [CrossRef] [PubMed]
 
Cenci, E, Perito, S, Enssle, KH, et al Th1 and Th2 cytokines in mice with invasive aspergillosis.Infect Immun1997;65,564-570. [PubMed]
 
Clancy, CJ, Nguyen, MH Acute community-acquired pneumonia due to Aspergillus in presumably immunocompetent hosts: clues for recognition of a rare but fatal disease.Chest1998;114,629-634. [CrossRef] [PubMed]
 
Criswell, BS, Couch, RB, Greenberg, SB, et al The lymphocyte response to influenza in humans.Am Rev Respir Dis1979;120,700-704. [PubMed]
 
Denning, DW Therapeutic outcome in invasive aspergillosis.Clin Infect Dis1996;23,608-615. [CrossRef] [PubMed]
 
Finkelman, FD, Shea-Donohue, T, Goldhill, J, et al Cytokine regulation of host defense against parasitic gastrointestinal nematodes: lessons from studies with rodent models.Ann Rev Immunol1997;15,505-533. [CrossRef]
 
Fischer, JJ, Walker, DH Invasive pulmonary aspergillosis associated with influenza.JAMA1979;241,1493-1494. [CrossRef] [PubMed]
 
Gerson, SL, Talbot, GH, Hurwitz, S, et al Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia.Ann Intern Med1984;100,345-351. [PubMed]
 
Hebart, H, Bollinger, C, Fisch, C, et al Analysis of T-cell responses toAspergillus fumigatusantigens in healthy individuals and patients with hematologic malignancies.Blood2002;100,4521-4528. [CrossRef] [PubMed]
 
Jariwalla, AG, Smith, AP, Melville-Jones, G Necrotising aspergillosis complicating fulminating viral pneumonia.Thorax1980;35,215-216. [CrossRef] [PubMed]
 
Lewis, DE, Gilbert, BE, Knight, V Influenza virus infection induces functional alterations in peripheral blood lymphocytes.J Immunol1986;137,3777-3781. [PubMed]
 
Lewis, M, Kallenbach, J, Ruff, P, et al Invasive pulmonary aspergillosis complicating influenza A pneumonia in a previously healthy patient.Chest1985;87,691-693. [CrossRef] [PubMed]
 
Marr, KA, Carter, RA, Boeckh, M, et al Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors.Blood2002;100,4358-4366. [CrossRef] [PubMed]
 
Morgenstern, DE, Gifford, MA, Li, LL, et al Absence of respiratory burst in X-linked chronic granulomatous disease mice leads to abnormalities in both host defense and inflammatory response toAspergillus fumigatus.J Exp Med1997;185,207-218. [CrossRef] [PubMed]
 
Roilides, E, Dimitriadou, A, Kadiltsoglou, I, et al IL-10 exerts suppressive and enhancing effects on antifungal activity of mononuclear phagocytes againstAspergillus fumigatus.J Immunol1997;158,322-329. [PubMed]
 
Roilides, E, Katsifa, H, Tsaparidou, S, et al Interleukin 10 suppresses phagocytic and antihyphal activities of human neutrophils.Cytokine2000;12,379-387. [CrossRef] [PubMed]
 
Roilides, E, Sein, T, Roden, M, et al Elevated serum concentrations of interleukin-10 in nonneutropenic patients with invasive aspergillosis.J Infect Dis2001;183,518-520. [CrossRef] [PubMed]
 
Schaffner, A, Douglas, H, Braude, A, et al Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus: observations on these two lines of defensein vivoandin vitrowith human and mouse phagocytes.J Clin Invest1982;69,617-631. [CrossRef] [PubMed]
 
Schapiro, BL, Newburger, PE, Klempner, MS, et al Chronic granulomatous disease presenting in a 69-year-old man.N Engl J Med1991;325,1786-1790. [CrossRef] [PubMed]
 
Seder, RA, Mosmann, TR Differentiation of effector phenotypes of CD4+ and CD8+ T cells. Paul, WE eds.Fundamental immunology1999,879 Raven Press. New York, NY:
 
Waldorf, AR Pulmonary defense mechanisms against opportunistic fungal pathogens.Immunol Ser1989;47,243-271. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Chest radiographs obtained at hospital admission (left) and hospital day 6 (right).Grahic Jump Location
Figure Jump LinkFigure 2. CT of the head showing multiple hypodense lesions on hospital day 22.Grahic Jump Location
Figure Jump LinkFigure 3. Studding in the tracheobronchial tree, gross specimen (left); aspergillus in the tracheobronchial tree (center) [Gormoni methenamine silver, original × 2]; aspergillus hyphal forms in the lung (right) [periodic acid Schiff, original × 40].Grahic Jump Location
Figure Jump LinkFigure 4. Studding in the left ventricle, formulin-fixed gross specimen (left); aspergillus in the left ventricle (center) [hematoxylin-eosin, original × 2]; aspergillus hyphal forms in the cardiac tissue (right) [Gormoni methenamine silver, original × 20].Grahic Jump Location

Tables

Suggested Readings

Allam, MF, Del Castillo, AS, Diaz-Molina, C, et al (2002) Invasive pulmonary aspergillosis: identification of risk factors.Scand J Infect Dis34,819-822. [CrossRef] [PubMed]
 
Astry, CL, Jakab, GJ Influenza virus-induced immune complexes suppress alveolar macrophage phagocytosis.J Virol1984;50,287-292. [PubMed]
 
Barker, WH, Mullooly, JP Influenza vaccination of elderly persons: reduction in pneumonia and influenza hospitalizations and deaths.JAMA1980;244,2547-2549. [CrossRef] [PubMed]
 
Boots, RJ, Paterson, DL, Allworth, AM, et al Successful treatment of post-influenza pseudomembranous necrotising bronchial aspergillosis with liposomal amphotericin, inhaled amphotericin B, gamma interferon and GM-CSF.Thorax1999;54,1047-1049. [CrossRef] [PubMed]
 
Cenci, E, Mencacci, A, Del Sero, G, et al Interleukin-4 causes susceptibility to invasive pulmonary aspergillosis through suppression of protective type I responses.J Infect Dis1999;180,1957-1968. [CrossRef] [PubMed]
 
Cenci, E, Perito, S, Enssle, KH, et al Th1 and Th2 cytokines in mice with invasive aspergillosis.Infect Immun1997;65,564-570. [PubMed]
 
Clancy, CJ, Nguyen, MH Acute community-acquired pneumonia due to Aspergillus in presumably immunocompetent hosts: clues for recognition of a rare but fatal disease.Chest1998;114,629-634. [CrossRef] [PubMed]
 
Criswell, BS, Couch, RB, Greenberg, SB, et al The lymphocyte response to influenza in humans.Am Rev Respir Dis1979;120,700-704. [PubMed]
 
Denning, DW Therapeutic outcome in invasive aspergillosis.Clin Infect Dis1996;23,608-615. [CrossRef] [PubMed]
 
Finkelman, FD, Shea-Donohue, T, Goldhill, J, et al Cytokine regulation of host defense against parasitic gastrointestinal nematodes: lessons from studies with rodent models.Ann Rev Immunol1997;15,505-533. [CrossRef]
 
Fischer, JJ, Walker, DH Invasive pulmonary aspergillosis associated with influenza.JAMA1979;241,1493-1494. [CrossRef] [PubMed]
 
Gerson, SL, Talbot, GH, Hurwitz, S, et al Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia.Ann Intern Med1984;100,345-351. [PubMed]
 
Hebart, H, Bollinger, C, Fisch, C, et al Analysis of T-cell responses toAspergillus fumigatusantigens in healthy individuals and patients with hematologic malignancies.Blood2002;100,4521-4528. [CrossRef] [PubMed]
 
Jariwalla, AG, Smith, AP, Melville-Jones, G Necrotising aspergillosis complicating fulminating viral pneumonia.Thorax1980;35,215-216. [CrossRef] [PubMed]
 
Lewis, DE, Gilbert, BE, Knight, V Influenza virus infection induces functional alterations in peripheral blood lymphocytes.J Immunol1986;137,3777-3781. [PubMed]
 
Lewis, M, Kallenbach, J, Ruff, P, et al Invasive pulmonary aspergillosis complicating influenza A pneumonia in a previously healthy patient.Chest1985;87,691-693. [CrossRef] [PubMed]
 
Marr, KA, Carter, RA, Boeckh, M, et al Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors.Blood2002;100,4358-4366. [CrossRef] [PubMed]
 
Morgenstern, DE, Gifford, MA, Li, LL, et al Absence of respiratory burst in X-linked chronic granulomatous disease mice leads to abnormalities in both host defense and inflammatory response toAspergillus fumigatus.J Exp Med1997;185,207-218. [CrossRef] [PubMed]
 
Roilides, E, Dimitriadou, A, Kadiltsoglou, I, et al IL-10 exerts suppressive and enhancing effects on antifungal activity of mononuclear phagocytes againstAspergillus fumigatus.J Immunol1997;158,322-329. [PubMed]
 
Roilides, E, Katsifa, H, Tsaparidou, S, et al Interleukin 10 suppresses phagocytic and antihyphal activities of human neutrophils.Cytokine2000;12,379-387. [CrossRef] [PubMed]
 
Roilides, E, Sein, T, Roden, M, et al Elevated serum concentrations of interleukin-10 in nonneutropenic patients with invasive aspergillosis.J Infect Dis2001;183,518-520. [CrossRef] [PubMed]
 
Schaffner, A, Douglas, H, Braude, A, et al Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus: observations on these two lines of defensein vivoandin vitrowith human and mouse phagocytes.J Clin Invest1982;69,617-631. [CrossRef] [PubMed]
 
Schapiro, BL, Newburger, PE, Klempner, MS, et al Chronic granulomatous disease presenting in a 69-year-old man.N Engl J Med1991;325,1786-1790. [CrossRef] [PubMed]
 
Seder, RA, Mosmann, TR Differentiation of effector phenotypes of CD4+ and CD8+ T cells. Paul, WE eds.Fundamental immunology1999,879 Raven Press. New York, NY:
 
Waldorf, AR Pulmonary defense mechanisms against opportunistic fungal pathogens.Immunol Ser1989;47,243-271. [PubMed]
 
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