Acute eosinophilic pneumonia (AEP) is a disease of unknown etiology that presents as febrile illness with nonproductive cough, peripheral eosinophilia and elevated serum IgE levels (1). Some investigators have suggested that AEP is an acute hypersensitivity reaction precipitated by an unidentified inhaled antigen (2). Chest imaging reveals diffuse reticular or ground glass opacities. Small bilateral pleural effusions are also common. BAL fluid demonstrates high percentage of eosinophilia (greater than 25%) and may or may not be associated with peripheral eosinophilia. Patients with AEP can present with severe hypoxic respiratory failure requiring mechanical ventilation. It is a diagnosis of exclusion that requires elimination of other causes of eosinophilia. Bronchoscopy is usually necessary to exclude infection prior to starting corticosteroids for the treatment of AEP. This patient's presentation fits the clinical description of acute eosinophilic pneumonia.
Helminthic infections such as Ascaris lumbricoides, Strongyloides stercoralis and hookworms, are acquired by ingesting materials contaminated by feces of infected hosts. Larvae hatch in the intestine and are hematogenously carried to the lung. In the lung the larvae ascend the tracheobronchial tree, are swallowed and returned to the intestine (3). Transpulmonary passage of larvae from helminthic organisms can cause transient pulmonary infiltrates and peripheral eosinophilia, a condition known as Loffler's syndrome (4). Symptomatic patients often complain of nonproductive cough, dyspnea, wheezing and fevers but antecedent gastrointestinal symptoms may also exist. Sputum may contain eosinophil-derived Charcot-Leyden crystals. Helminthic infection is less likely in this case given lack of oral contact with contaminated soil and absence of antecedent gastrointestinal symptoms.
Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is an interstitial lung disease caused by numerous inhaled agents such as agricultural dusts, bioaerosols, and variety of fungal, bacterial and protozoan microorganisms (5). HP is diagnosed in a presence of a positive precipitin test with a clear recent history of antigen exposure, radiographic evidence of reticulo-nodular and ground glass opacities on chest imaging and lymphocytosis on BAL fluid with a low CD4:CD8 ratio (< 1.0) of lymphocyte surface antigens (6). Positive inhalation challenge testing involves re-exposure to suspected antigen and is occasionally performed when diagnosis is unclear. Laboratory panels for measurement of serum precipitins have high false negative rate and skin tests are not helpful in the diagnosis of hypersensitivity pneumonitis (7). In addition up to 40% of farmers and bird fanciers can have detectable serum precipitins to common causes of HP in the absence of clinical disease (8). Thus, presence of serum precipitins along with suggestive clinical and radiographic data can support the diagnosis of HP, but absence of serum precipitins does not exclude it. Treatment of HP involved removal of causative antigen and occasionally steroids for severe forms of disease. BAL eosinophilia is an uncommon finding in HP although it has been reported in cases of drug-induced HP and in advanced stages of HP (9). The latter is often associated with BAL neutrophilia. In this case, marked eosinophilia on peripheral smear and bronchial lavage, coupled with lack of medication exposure prior to onset of patient's symptoms, warrants a search for alternative diagnosis for pulmonary eosinophilia.
Allergic Bronchopulmonary Aspergillosis (ABPA) is a hypersensitivity reaction that occurs when airways become colonized by Aspergillus. Repeated episodes of bronchial obstruction, inflammation, and mucoid impaction can lead to bronchiectasis, fibrosis, and respiratory compromise. Clinically, patients present with asthma, cystic fibrosis, recurrent episodes of bronchial obstruction, expectoration of brown mucus plugs, hemoptysis, peripheral blood eosinophilia and elevated IgE levels (10). Imaging classically reveals central bronchiectasis. Diagnosis of ABPA is less likely given this patient's clinical presentation and results of imaging studies.
CLINICAL COURSE (continued)
Serum ANA, ANCA, rheumatoid factor and the extractable nuclear antigens (ENA) panel were normal. Hypersensitivity panel against Aspergillus species, Thermoactinomyces species, Saccharomonospora viridis, Micropolyspora faeni, Aureo-basidium pullulans and pigeon serum were also negative. Immunoglobulin profile was notable for an elevated IgE level of 2440 IU/ml. A diagnosis of acute eosinophilic pneumonia was made and the patient was started on intravenous corticosteroids. The patient's symptoms, oxygen requirement and chest radiograph dramatically improved before she was discharged on a tapering dose of prednisone (figure 3a). Discharge medications included trimethoprim-sulfamethoxazole for pneumocystis pneumonia prophylaxis.
FIGURE 3a. Chest radiograph on discharge demonstrating improvement in diffuse bilateral reticulonodular infiltrates.
FIGURE 3b. Chest radiograph demonstrating return of diffuse bilateral reticulonodular infiltrates
Despite adherence to the medications, she returned a week later complaining that her fevers and nocturnal sweats had returned. Again, she was hypoxic with an SaO2 of 84% and a chest radiograph demonstrated return of her infiltrates (figure 3b).
Laboratory data were significant for a white blood cell count of 23,000/µL with a 77% neutrophils, 10% bands, and no eosinophils. Repeat BAL demonstrated a white blood cell count of 440/µL with 5% eosinophils. Random transbronchial biopsies revealed granulomatous inflammation with rare fungal hyphae branching at 45 degrees but an underlying necrotizing vasculitis could not be excluded. Fungal cultures from the BAL specimen grew Aspergillus fumigatus. Despite antifungal treatment, the patient's respiratory status deteriorated and she required supportive mechanical ventilation. Given the importance of distinguishing between fungal invasion and fungal colonization, as well as the need to exclude vasculitis, patient underwent open lung biopsy. Pathology revealed numerous necrotic granulomas with fungal hyphae consistent with invasive aspergillosis and no evidence of vasculitis. (figure 4)
FIGURE 4: Silver stain, high power magnification. Numerous intraparencymal hyphae with acute angle branching consistent with invasive aspergillosis.
Intravenous voriconazole 6mg/kg loading dose followed by 4mg/kg every 12 hours and micafungin 100mg every 24 hours were started but despite antifungal therapy her sputum cultures continued to grow aspergillus.
When a seemingly otherwise healthy patient is found to have an infection from an unusal or opportunistic organism, such as invasive aspergillosis, an underlying immune deficiency should be suspected and investigated. Most causes of immunodeficiency in adults result from underlying diseases such as diabetes, HIV, malignancy, autoimmune diseases, as well as medications such as steroids and anti-TNF antibody inhibitors. Once the common secondary causes of immunosuppression are excluded, patients should be evaluated for primary defects in immune system. Patterns with recurrent infection may provide clues regarding which limb of the immune system is affected (11). Defects in immunoglobulins and complement proteins cause recurrent sinopulmonary infections, bacteremia and meningitis due to failure to clear encapsulated organisms such as
Streptococcus pneumoniae,
Haemophilus influenzae b and
Neisseria meningitides. Patients with defects in granulocyte function, caused either by inability of neutrophils to generate oxidative burst or by defects in chemotaxis and phagocytosis, present with recurrent cutaneous infections, typically caused by
Staphylococcus aureus. More severe invasive infection with gram-negative bacteria and aspergillus may also be seen. Finally defects in cell mediated immunity can cause infections with viruses, opportunistic intracellular pathogens and fungi. Clinical evaluation of an adult with suspected congenital immune disorder also involves a thorough review of family history for recurrent infections which may uncover a genetic mode of inheritance. Given the unusual nature of this patient's infection she requires an evaluation for congenital causes of immunodeficiency.
The use of itraconazole to treat invasive aspergillosis is inappropriate in a patient who is not responding to voriconazole. Response rate with itraconazole, when studied in 76 patients with mild immunosuppression and non-life-threatening aspergillus infection, was only 39% (12). Voriconazole has greater intrinsic activity against Aspergillus fumigatus, and is better tolerated compared to itraconazole. Other drawbacks of itraconazole are poor bioavailability and numerous drug-drug interactions.
Fluconazole is a widely used antifungal agent in treatment of infections due to candida species (except Candida krusei and some Candida glabrata species), Coccidiomycosis, Cryptococcosis, Histoplasmosis and Blastomycosis. However fluconazole has no activity against Aspergillus species and therefore should not be used to treat invasive aspergillosis (13,14).
Due to its limited activity and unfavorable side effect profile compared to fluconazole and itraconazole, ketoconazole is used as an alternative second-line drug for treatment of infections due to Candida species, Cryptococcus neoformans and dimorphic fungi such as Histoplasma capsulatum, Blastomyces dermatitidis and Coccidiodes immitis (15). Ketoconazole is also not recommended for treatment against meningeal infections due to fungal organisms due to its limited penetration to cerebrospinal fluid (16). Akin to fluconazole, ketoconazole has no activity against Aspergillus species (16).
CLINICAL COURSE (continued)
The patient was evaluated for immunodeficiency. She had a negative HIV test and a normal T cell subset profile as determined by flow cytometry. Due to lack of readily identifiable cause for failure to respond to antifungal therapy a congenital etiology of immunodeficiency was suspected. An abnormal evaluation of patient's neutrophil function raised suspicion for chronic granulomatous disease (CGD), a diagnosis which was subsequently confirmed via flow cytometry, and a defect was localized to p47 phagocyte oxidase (phox) subunit.
The majority of patients with CGD are diagnosed as toddlers and children, with the median age of diagnosis being 3 years of age according to several large studies (17-19).
Chronic granulomatous disease is a condition characterized by recurrent life threatening infections from catalase-positive microorganisms and granuloma formations due to a genetic defect in ability of neutrophils and macrophages to destroy microbial organisms via phagocytosis (20). Normally phagocytosis involves generation of reactive oxygen species utilizing the NADPH oxidase system, a process known as oxidative burst, which leads to an intracellular cascade resulting in activation of proteases that are responsible for ingestion of phagocytosed microorganisms (21). NADPH complex is composed of five subunits labeled gp91 phox, p22 phox, p47phox, p67phox and p40 phox (21). In CGD there is a mutation in one of the subunits of the NADPH oxidase complex that leads to inability to produce oxidative burst. NBT reduction test is a nonspecific neutrophil function test that provides a qualitative determination of phagocyte NADPH oxidase activity. Superoxide produced by normal peripheral blood neutrophils reduces yellow NBT to dark blue / black formazan, which forms a precipitate in the cells and indicates the amount of phagocyte oxidase activity detected. NBT is commonly used as a screening test for CGD.
X-linked inheritance is the primary mode of transmission of CGD, with over two thirds of new cases being diagnosed in males (22). X-linked inheritance is caused by mutations in the gene encoding for gp91 phox subunit, which accounts for 65%-70% of known cases of CGD (23). The second most common mutation is in the gene encoding p47 phox subunit. This less common type of mutation accounts for only 25% of CGD cases and are associated with autosomal recessive mode of transmission, as seen in our patient. X-linked carrier state in female patients is not entirely silent since lionization (inactivation of one X chromosome in every cell) leads to dual population of phagocytes and a characteristic mosaic pattern on respiratory burst testing (24). However having as few as 10 percent of cells with normal respiratory burst activity is usually sufficient to prevent severe infections (24). Therefore most female carriers of X-linked CGD mutations do not present with clinically significant disease.
The cornerstone of CGD management is antimicrobial prophylaxis, early recognition of infection and aggressive management of infectious complications. Antimicrobial prophylaxis includes life long administration of trimethoprim-sulfamethoxazole (TMP-SMX) for prevention of bacterial infections, itraconazole for lifelong antifungal prophylaxis and immunomodulatory therapy with interferon-gamma. Interferon -gamma is a cytokine that is secreted by various T cells and plays a crucial role in both innate and cell mediated immunity. Effects of interferon-gamma include stimulation of antigen presentation and activation of lysosomal activity in macrophages, promotion of leukocyte adhesion and migration, and promotion of NK cell activation (25). Earlier trials have shown that prophylaxis with interferon-gamma has led to significant reduction in development of serious infections (26). Major limitation of these trials was that patients in the control group did not receive any antibacterial or antifungal prophylaxis. A recent prospective study comparing addition of interferon-gamma to a standard prophylactic regiment with TMP-SMX and itraconazole failed to demonstrate any difference in the rate of severe infection in the two groups (27). Therefore it is unclear how much additional benefit is provided with interferon-gamma beyond that of TMP-SMX and itraconazole as prophylactic therapy for CGD. Routine use of interferon-gamma in the setting of acute infection is controversial since the addition of interferon-gamma may cause fever and malaise which can obscure the clinical picture (18). Interferon-gamma may be cautiously used in patients with invasive aspergillosis who fail to respond to standard antimicrobial therapy (18). In such cases the decision to use interferon-gamma must be individualized and collaboration with experts in this fields in necessary.
CLINICAL COURSE (continued)
With respiratory failure requiring ventilatory support and tracheostomy, the patient was started on subcutaneous treatment with IFN-gamma at 50 mcg/m2 three times weekly. Voriconazole was dose escalated to 6mg/kg IV every 8 hours and micafungin to 150mg IV daily. She experienced gradual clinical improvement and was discharged from the hospital after spending more than two months in the intensive care unit. The patient was initially maintained on antimicrobial prophylaxis with TMP-SMX, voriconazole and interferon-gamma. TMP-SMX and interferon-gamma have been since been discontinued due to intolerance. She successfully returned to her active lifestyle and resumed her hobby of running marathons. The patient has not experienced any infectious illnesses during her three year follow up period. Genetic testing was offered to the family.
CONCLUSION:
This case describes a previously healthy 32-year old woman who presented with acute eosinophilic pneumonia following a visit to a compost repository. Opportunistic invasive pulmonary aspergillosis led to immunologic workup which ultimately uncovered occult chronic granulomatous disease. The case is unusual in that the initial presentation and response to therapy would suggest a diagnosis of AEP but the subsequent recovery of an invasive opportunistic organism lead to further investigation and the diagnosis of CGD. We suspect that an environmental exposure during her visit to the compost repository (such aerosolized aspergillus) may have lead to AEP initially. However, we further suspect that while appropriate corticosteroid therapy resulted in clinical improvement and resolution of the initial radiograph findings, the therapy coupled with her unknown history of CGD unknowingly predisposed her to opportunistic invasive nature of the aspergillus that had colonized in her airways. Of further interest is the fact that the patient's CGD diagnosis was delayed until adulthood presumable due to the less common autosomal gene mutation. We conclude that underlying immune deficiency should be suspected when a seemingly healthy patient presents with an unusual or opportunistic infection and adult age should not preclude the consideration of CGD in the appropriate clinical situation.
ACKNOWLEDGMENT: Steven M. Holland, MD, Laboratory of Clinical Infectious Diseases at the National Institute of Allergy and Infectious Diseases, Bethesda, MD for neutrophil function and CGD genetic testing.
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