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A 60-Year-Old Asymptomatic Woman With Pulmonary Lesions and Cervical LymphadenopathyWoman With Pulmonary Lesions and Lymphadenopathy FREE TO VIEW

Tomoko Yamagishi, MD; Nobuaki Ochi, MD; Hiromichi Yamane, MD, PhD; Futoshi Kuribayashi, MD, PhD; Nagio Takigawa, MD, PhD
Author and Funding Information

From the Department of General Internal Medicine 4 (Drs Yamagishi, Ochi, Yamane, and Takigawa), and the Department of Biochemistry (Dr Kuribayashi), Kawasaki Medical School, Kurashiki, Japan.

CORRESPONDENCE TO: Nagio Takigawa, MD, PhD, Department of General Internal Medicine 4, Kawasaki Medical School, 2-1-80, Nakasange, Kita-ku, Okayama, 700-8505, Japan; e-mail: ntakigaw@gmail.com


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(2):e48-e51. doi:10.1378/chest.14-1215
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Published online

A 60-year-old asymptomatic woman was referred to our hospital because of an abnormal chest roentgenogram during a routine medical checkup. The patient had no history of memorable infectious diseases, except a liver abscess caused by Serratia marcescens at age 46 years. Her son was diagnosed with chronic granulomatous disease at the age of 1 year. She had never smoked cigarettes and drank only occasionally.

Figures in this Article

The patient’s vital signs were as follows: temperature, 36.8°C; BP, 136/72 mm Hg; heart rate, 72 beats/min; respiratory rate, 16 breaths/min; and oxygen saturation, 98% on room air. Lungs were clear to auscultation. Nontender enlargement of the left cervical and submental lymph nodes (10 and 8 mm in diameter, respectively) was observed. The rest of the physical examination was unremarkable.

Laboratory data revealed a normal WBC count (6,300/μL) and a slight increase in the C-reactive protein level (0.32 mg/dL; normal range, < 0.30 mg/dL). The interferon-γ release assay and 1,3-β-glucan content were negative. Consolidations were observed in the bilateral lung field on chest roentgenography. Chest CT scan revealed multiple consolidations with surrounding ground-glass opacities (Fig 1). Transbronchial biopsy and bronchial washing showed no evidence of malignancy with negative bacterial and fungal culture results.

Figure Jump LinkFigure 1 –  CT scan of the chest showing multiple consolidations with surrounding ground-glass opacities in bilateral lung field (arrow). A, Right apical segment. B, Lingular segment.Grahic Jump Location
What is the diagnosis?
Diagnosis: Pulmonary aspergillosis as diagnosed by cervical lymph biopsy samples that contained Aspergillus hyphae in this patient with underlying chronic granulomatous disease

Chronic granulomatous disease (CGD) is a rare, inherited immunodeficiency disorder caused by defects in superoxide-generating nicotinamide adenine dinucleotide phosphate oxidase in phagocytes and leading to recurrent, life-threatening bacterial and invasive fungal infections. CGD has at least five different mutations in genes involved in assembly and activation of the nicotinamide adenine dinucleotide phosphate oxidase. Most of patients in Western countries have an X chromosome-linked mutation in gp91phox (CYBB). Other less frequent mutations are inherited in autosomal recessive forms that involve p22phox, p47phox, p67phox, or p40phox. Approximately two-thirds of CGD cases are X-linked (gp91phox deficient). Consequently, the disorder is much more common in men and boys.

CGD involves multiple organs, including the lung, lymph node, bone, and GI tract. Pneumonia is the most frequent infection. Most common pathogens are catalase-positive organisms including Aspergillus species, Staphylococcus, Burkholderia species, Serratia, and Nocardia. Patients with CGD may not manifest typical signs of infection, despite the presence of significant infection. In a review of aspergillosis in patients with CGD, one-third of patients are asymptomatic at diagnosis, and only about 20% are febrile. Another important manifestation of CGD is abnormally exuberant inflammatory responses leading to granuloma formation, such as granulomatous enteritis resembling Crohn’s disease.

Patients suspected of having CGD should initially undergo neutrophil function test. The most common diagnostic assays are the nitroblue tetrazolium reduction test and dihydrorhodamine 123 (DHR) test. Genetic testing, such as immunoblotting and direct gene sequencing, can be used to confirm the diagnosis of CGD.

Long-term antibacterial and antifungal prophylaxis with trimethoprim-sulfamethoxazole and itraconazole has been shown to reduce the rate of infection among patients with CGD. Treatment of acute infection must be performed by early and aggressive therapies. Patients should be treated empirically for gram-negative bacteria, gram-positive bacteria, and fungal infections until the pathogen is identified.

The prognosis of CGD has been improved dramatically during the last decade by prophylaxis. Delayed diagnosis of CGD may lead to fatal outcome due to infectious and noninfectious complications. Most patients with CGD are diagnosed during childhood, but the presentation of adult-onset CGD has been reported in a few cases; this is considered to be due to age-related skewing of lyonization. Thus, the appropriate testing for CGD might be considered at any age if the patient has a suspicious history.

Meanwhile, the CT scan halo sign of ground-glass opacity surrounding a pulmonary nodule was first described in the patient with invasive pulmonary aspergillosis (IPA). Patients with such lesions on CT scan may have other invasive fungal infection (eg, candidiasis, cryptococcosis, and mucormycosis). Aspergillus galactomannan antigen and capsular antigen of Cryptococcus neoformans in serum are also useful as indirect diagnostic test. The main host factors for IPA development are neutropenia, receipt of an allogeneic stem cell transplant, and immunosuppressive agents (for example, corticosteroids and cyclosporine). Other immunocompromised patients, such as patients with CGD, have high risk for developing IPA.

Clinical Course

The patient’s serum Aspergillus galactomannan antigen level was elevated at 4.5 (normal range, < 0.5), and polysaccharide antigens of the capsule of Cryptococcus neoformans were negative. Based upon the clinical presentation of CT scan halo sign and elevated Aspergillus galactomannan antigen level, she was considered to have pulmonary aspergillosis. Thus, we performed cervical lymph node biopsy, which detected Aspergillus fungal elements (Fig 2) and suggested the presence of underlying immunocompromise. The history of a liver abscess and the son’s history of CGD prompted neutrophil function testing, which demonstrated that the patient had CGD. Direct sequencing of the gp91phox gene revealed a missense mutation (Gly408Arg) in exon 10. The patient was treated with IV voriconazole 4 mg/kg q12h after two loading doses of 6 mg/kg. Three months after initiation of voriconazole, chest roentgenogram and CT scan images showed improvement of consolidations, and the Aspergillus galactomannan antigen level was normalized. She was switched to oral antimicrobial prophylaxis with itraconazole (200 mg/d) and trimethoprim-sulfamethoxazole after approximately 6 months of voriconazole therapy. The patient has no clinical signs of infection and currently remains stable.

Figure Jump LinkFigure 2 –  A, Histopathologic analysis of cervical lymph node biopsy specimen showing suppurative granuloma containing necrosis and neutrophils (magnification × 100). B, Grocott stain demonstrating the presence of fungal filament (arrow) (magnification × 400).Grahic Jump Location

  • 1. Appropriate testing for CGD might be considered at any age if the patient has a suspicious history.

  • 2. Neutrophil function test should be initially performed for patients suspected of having CGD.

  • 3. CGD is a genetically heterogeneous disorder characterized by recurrent life-threatening bacterial and fungal infections and granuloma formation.

  • 4. One-third of Aspergillus infections in patients with CGD were asymptomatic at diagnosis, despite the presence of significant infection.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Segal BH, DeCarlo ES, Kwon-Chung KJ, Malech HL, Gallin JI, Holland SM. Aspergillus nidulansinfection in chronic granulomatous disease. Medicine (Baltimore). 1998;77(5):345-354. [CrossRef] [PubMed]
 
Rösen-Wolff A, Soldan W, Heyne K, Bickhardt J, Gahr M, Roesler J. Increased susceptibility of a carrier of X-linked chronic granulomatous disease (CGD) toAspergillus fumigatusinfection associated with age-related skewing of lyonization. Ann Hematol. 2001;80(2):113-115. [CrossRef] [PubMed]
 
Marciano BE, Rosenzweig SD, Kleiner DE, et al. Gastrointestinal involvement in chronic granulomatous disease. Pediatrics. 2004;114(2):462-468. [CrossRef] [PubMed]
 
De Pauw B, Walsh TJ, Donnelly JP, et al; European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46(12):1813-1821. [CrossRef] [PubMed]
 
Seger RA. Modern management of chronic granulomatous disease. Br J Haematol. 2008;140(3):255-266. [CrossRef] [PubMed]
 
Matute JD, Arias AA, Wright NA, et al. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity. Blood. 2009;114(15):3309-3315. [CrossRef] [PubMed]
 
Towbin AJ, Chaves I. Chronic granulomatous disease. Pediatr Radiol. 2010;40(5):657-668. [CrossRef] [PubMed]
 
Segal BH, Veys P, Malech H, Cowan MJ. Chronic granulomatous disease: lessons from a rare disorder. Biol Blood Marrow Transplant. 2011;17(suppl 1):S123-S131. [CrossRef] [PubMed]
 
Mahdaviani SA, Mohajerani SA, Rezaei N, Casanova JL, Mansouri SD, Velayati AA. Pulmonary manifestations of chronic granulomatous disease. Expert Rev Clin Immunol. 2013;9(2):153-160. [CrossRef] [PubMed]
 
Roos D, de Boer M. Molecular diagnosis of chronic granulomatous disease. Clin Exp Immunol. 2014;175(2):139-149. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  CT scan of the chest showing multiple consolidations with surrounding ground-glass opacities in bilateral lung field (arrow). A, Right apical segment. B, Lingular segment.Grahic Jump Location
Figure Jump LinkFigure 2 –  A, Histopathologic analysis of cervical lymph node biopsy specimen showing suppurative granuloma containing necrosis and neutrophils (magnification × 100). B, Grocott stain demonstrating the presence of fungal filament (arrow) (magnification × 400).Grahic Jump Location

Tables

Suggested Readings

Segal BH, DeCarlo ES, Kwon-Chung KJ, Malech HL, Gallin JI, Holland SM. Aspergillus nidulansinfection in chronic granulomatous disease. Medicine (Baltimore). 1998;77(5):345-354. [CrossRef] [PubMed]
 
Rösen-Wolff A, Soldan W, Heyne K, Bickhardt J, Gahr M, Roesler J. Increased susceptibility of a carrier of X-linked chronic granulomatous disease (CGD) toAspergillus fumigatusinfection associated with age-related skewing of lyonization. Ann Hematol. 2001;80(2):113-115. [CrossRef] [PubMed]
 
Marciano BE, Rosenzweig SD, Kleiner DE, et al. Gastrointestinal involvement in chronic granulomatous disease. Pediatrics. 2004;114(2):462-468. [CrossRef] [PubMed]
 
De Pauw B, Walsh TJ, Donnelly JP, et al; European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46(12):1813-1821. [CrossRef] [PubMed]
 
Seger RA. Modern management of chronic granulomatous disease. Br J Haematol. 2008;140(3):255-266. [CrossRef] [PubMed]
 
Matute JD, Arias AA, Wright NA, et al. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity. Blood. 2009;114(15):3309-3315. [CrossRef] [PubMed]
 
Towbin AJ, Chaves I. Chronic granulomatous disease. Pediatr Radiol. 2010;40(5):657-668. [CrossRef] [PubMed]
 
Segal BH, Veys P, Malech H, Cowan MJ. Chronic granulomatous disease: lessons from a rare disorder. Biol Blood Marrow Transplant. 2011;17(suppl 1):S123-S131. [CrossRef] [PubMed]
 
Mahdaviani SA, Mohajerani SA, Rezaei N, Casanova JL, Mansouri SD, Velayati AA. Pulmonary manifestations of chronic granulomatous disease. Expert Rev Clin Immunol. 2013;9(2):153-160. [CrossRef] [PubMed]
 
Roos D, de Boer M. Molecular diagnosis of chronic granulomatous disease. Clin Exp Immunol. 2014;175(2):139-149. [CrossRef] [PubMed]
 
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