A Previously Healthy 37-Year-Old Man With Acute Hypoxic Respiratory Failure and Fevers

Case Presentation

A previously healthy 37-year-old man initially presented to a hospital near his home with persistent cough after failing outpatient azithromycin for empiric treatment of pneumonia. He was newly employed as a bulldozer operator burying trash in a landfill in Virginia, which he continued throughout his illness. He owned two healthy dogs, had never traveled outside the state, and denied a history of cigarette smoking, alcohol, and substance use. His WBC count was 13.4 × 10⁹/L (11% eosinophils). CT scan of the chest showed ground glass opacities. Subsequent bronchoscopy with BAL of the right middle lobe showed eosinophilic predominance (46%); transbronchial biopsy of right lower lobe was performed. Infectious and autoimmune work up that was negative included blood, urine, and BAL cultures, BAL Pneumocystis pneumonia direct immunofluorescence assay, urine legionella antigen, serum HIV antibody, antinuclear antibodies, anti-neutrophil cytoplasmic antibodies, and angiotensin converting enzyme. After improvement in hypoxia with inpatient corticosteroid therapy, he was discharged home with a two week course of prednisone for a presumptive diagnosis of acute eosinophilic pneumonia. He subsequently experienced worsening fever and difficulty breathing; six weeks after his symptoms began, he was admitted to our hospital.

Physical Examination Findings

On admission, the patient appeared acutely ill due to respiratory distress. He was febrile to 38.4°C, normotensive, tachycardic with pulse 118 beats/min, tachypneic with respiratory rate 38 breaths/min, and had an oxygen saturation of 70% on room air with an increase to 95% with oxygen supplementation of 12 L/min by nasal cannula. Physical examination revealed diffuse inspiratory and expiratory crackles with increased work of breathing. The rest of his physical examination was normal.

Diagnostic Studies

His WBC count was 8.6 × 10⁹/L (83% neutrophils, 0% eosinophils). Hemoglobin and platelets were normal. Complete metabolic panel demonstrated sodium 127 mEq/L, BUN 30 mg/dL, and albumin 2.8 g/dL but was otherwise normal. Lactic acid was 3.1 mmol/L. HIV 1/2 antibodies and p24 antigen were negative. Testing for anti-neutrophil cytoplasmic antibodies to myeloperoxidase and proteinase-3, and antinuclear antibodies were negative. Urine Legionella and urine Streptococcus pneumoniae antigen tests were both negative. A nasal swab was negative for methicillin-resistant Staphylococcus aureus by polymerase chain reaction.

Chest radiograph showed diffuse bilateral pulmonary airspace opacities (Fig 1). CT scan of the chest revealed extensive bilateral nodular consolidations and two cavitary lesions in the left lower lobe, as well as mediastinal and hilar lymphadenopathy (Fig 2).

Figure 1.

Chest radiograph on admission.

Figure 2.

Chest CT scan on admission shows bilateral consolidations (A, B, C) with cavitary lesions in the left lower lobe (B, C).

Right middle lobe BAL demonstrated fungal septate hyphae with dichotomous branching (Fig 3) and intracellular bacteria. Serum and BAL β-D-glucan were >500 pg/mL (negative, <80 pg/mL); serum and BAL galactomannan were >1.250 (negative, <0.5). BAL cultures subsequently grew Aspergillus fumigatus and Nocardia cyriacigeorgica. All other test results were negative, including blood cultures, urine Blastomyces antigen, urine Histoplasma antigen, serum cryptococcal antigen, TB interferon-gamma release assay and Strongyloides IgG. On hospital day five, the lung histopathology from his prior hospitalization was received and reviewed; it showed non-caseating granulomas (Fig 4).

Figure 3.

BAL direct microscopy stained with Gömöri methenamine silver demonstrated fungal septate hyphae with dichotomous branching.

Figure 4.

Lung tissue from transbronchial biopsy demonstrated non-caseating granulomas (hematoxylin-eosin stain, 100X).

What is the diagnosis? What test will confirm the underlying cause of disease?

Diagnosis: Fulminant mulch pneumonitis in chronic granulomatous disease. The dihydrorhodamine test can be done to confirm the dysfunctional oxidative burst of neutrophils leading to the disease.

Discussion

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency characterized by recurrent and, classically, severe infections. It is caused by one of five different defects of the NADPH oxidase complex, which result in impaired reactive oxygen intermediate (ROI) production by phagocytes during the inflammatory response to infection. The different defects confer varied degrees of impairment of ROI production, with p47^phox deficiency having higher residual ROI production and milder disease. The preferred diagnostic test for CGD is the dihydrorhodamine test, which uses flow cytometry to detect the reduction of dihydrorhodamine to its fluorescent form in the presence of ROIs produced by the patient’s phagocytes. The dihydrorhodamine test’s sensitive detection of small quantities of ROIs can assess for the different forms of CGD.

The characteristic histopathologic manifestation of CGD is granulomatous inflammation (Fig 3), which can be seen in multiple organ systems but most commonly the GI, genitourinary, or respiratory tract. Granulomas in CGD are hypothesized to be both sequelae of the chronic inflammatory response to infection and secondary to inherent inflammatory dysregulation, even in the absence of infection.

Due to the variability in severity seen with different defects, CGD can present at any age. The majority of severe infections in CGD are due to five organisms: Aspergillus species, Nocardia species, Staphylococcus aureus, Burkholderia cepacia, and Serratia marcescens. The lung is the most common site of infection. Patients diagnosed with CGD take lifelong antibacterial and antifungal prophylaxis.

Acute presentation of hypoxic respiratory failure, diffuse pulmonary infiltrates, and fever in patients with CGD is consistent with a condition known as mulch pneumonitis, a hypersensitivity reaction to aerosolized fungi. The condition is so named for associated exposure to fungi from gardening, lawn care, or other mulching activities. Waste dumps/landfills previously have not been reported as a risk factor for mulch pneumonitis in patients with CGD but are known to be sites of aerosolized fungi, including Aspergillus spp.

Mulch pneumonitis appears unique to CGD and is the primary presentation of CGD in approximately one-third of cases. The mortality rate for mulch pneumonitis is as high as 73% in a recent review of published cases. Interferon-γ and corticosteroids have both been used to treat mulch pneumonitis; however, the evidence supporting these treatments is limited. Case series of patients with CGD with mulch pneumonitis that have been treated with corticosteroids suggest a clinical benefit, but there are no prospective trials studying the efficacy. For this patient, treatment with a short course of corticosteroids during his initial hospitalization likely attenuated the inflammatory process that was driven by his mulch pneumonitis and CGD. In addition, this initial steroid course reduced his pulmonary eosinophilia, which we subsequently attributed to his polymicrobial infection.

Infection with Aspergillus occurs most frequently in the setting of immunocompromise. CGD has the highest prevalence of invasive aspergillosis among primary immunodeficiencies. Invasive pulmonary aspergillosis is the most common cause of infectious death in CGD. In addition to the fulminant presentation of mulch pneumonitis, Aspergillus infection in CGD can present as an indolent progressive pneumonia. Cavitary lesions, such as occur in aspergilloma and chronic necrotizing pulmonary aspergillosis, have not been described.

Nocardia most commonly infects immunocompromised people. Fungal coinfection with Nocardia is common in CGD (30%). In the largest case series of Nocardia in CGD, all patients had pulmonary origin of infection. CT scan chest findings of pulmonary nocardiosis can include infiltrates, nodules, and cavities. In CGD, disseminated Nocardia occurs in 25% to 50% of patients, with tropism to the CNS. Sulfonamides remain the backbone of therapy.

Clinical Course

After empiric initiation of vancomycin, meropenem, trimethoprim-sulfamethoxazole, and amphotericin and admission to the medical ICU, he experienced rapid worsening of his hypoxemia and septic shock. He was intubated and placed on mechanical ventilation. Within 12 hours of admission, he was started on venoarterial-extracorporeal membrane oxygenation.

Voriconazole and micafungin were initiated to treat Aspergillus, and trimethoprim-sulfamethoxazole and imipenem were given to treat Nocardia. An evaluation for underlying immunodeficiency was conducted due to infection with unusual organisms. Although he had a history of pneumonia as an infant, he did not have other severe or recurrent infections. Immunodeficiency work up was negative, other than dihydrorhodamine testing with a low neutrophil oxidative burst index, which is consistent with CGD. Immunophenotype plot of dihydrorhodamine testing indicated autosomal-recessive CGD (Fig 5). He was started on IV steroids and interferon-γ. On day ten of admission, his neurologic status deteriorated and CT scan of the head demonstrated multiple hypodensities consistent with abscesses, concerning for Nocardia (Fig 6). The patient’s family opted to pursue palliative measures, and he died shortly thereafter.

Figure 5.

Flow cytometric histograms of oxidation of DHR 123 to the green fluorescent rhodamine 123. Neutrophils are exposed to PMA, which induces oxidative burst and the production of reactive oxygen intermediates (ROI). DHR is then introduced, which is converted to rhodamine only in the presence of ROI. Rhodamine has a similar spectral profile to FITC. An absence of fluorescence indicates an absence of ROI, and thus deficiency of NADPH oxidase. The y-axis is cell count and the x-axis is fluorescence intensity of rhodamine (FITC channel). A, Patient's unstimulated neutrophils. B, Patient's PMA-stimulated neutrophils show a broad and dim fluorescence consistent with residual reactive oxygen intermediate production. C, Normal control PMA-stimulated neutrophils show intense fluorescence. DHR = dihydrorhodamine; FITC = fluorescein isothiocyanate; PMA = phorbol myristate acetate.

Figure 6.

CT scan of the head with multiple parenchymal hypodensities.

Clinical Pearls

• 1.Patients diagnosed with pulmonary aspergillosis and/or nocardiosis should be investigated for underlying immunocompromising conditions if none is known, particularly CGD.
• 2.Patients with CGD have a wide spectrum of history and clinical presentation, and testing should not be deferred because of minimal history of severe or recurrent infections.
• 3.Mulch pneumonitis, a hypersensitivity reaction to aerosolized fungi, may be the initial presentation of CGD.
• 4.Antifungals and corticosteroids are recommended treatment for mulch pneumonitis, but mortality rates are high.
• 5.A thorough environmental and occupational history can be key to making the diagnosis of rare conditions such as mulch pneumonitis.