Pulmonary Nocardiosis and Empyema in a Patient with Metastatic Neuroendocrine Tumor

Nimesh K. Patel, DO

Linda Snyder, MD

University of Arizona, Department of Medicine. Tucson, Arizona

Reference as: Patel NK, Snyder L. Pulmonary nocardiosis and empyema in a patient with metastatic neuroendocrine tumor. Southwest J Pulm Crit Care 2011;3:28-33. (Click here for a PDF version)

Abstract

Nocardia is a ubiquitous aerobic gram-positive bacterium that can cause local or disseminated infection. Nocardiosis involves the lung in the majority of cases. Nocardiosis is often an opportunistic infection, but can also affect non-immunocompromised hosts. This case report highlights the presence of empyema due to Nocardia cyriacigeorgica infection, an unusual feature of Nocardia pulmonary involvement. 

Case Presentation

History of Present Illness: A 65 year-old male with a history of metastatic neuroendocrine tumor of the pancreas, was admitted to the hospital with a one-week history of hemoptysis, cough, and dyspnea. He was treated for presumed community acquired pneumonia with moxifloxacin two weeks prior to admission. He was receiving monthly octreotide injections for treatment of the neuroendocrine tumor. The patient had no history of corticosteroid use.  

Physical examination:

Vital signs: Temperature 99.9F, Respirations18, Blood Pressure 104/69, Pulse 96, SaO2 91% on oxygen at 2 liters per minute by nasal cannula

General: The patient was in no acute distress. He was alert and oriented to person, place and time.

HEENT: No significant abnormalities.

Chest: Dullness to percussion, mid-lower right thoracic cavity, with scattered crackles. 

Cardiovascular: regular rate, normal S1 and S2, no murmurs appreciated.  Abdomen: positive bowel sounds, soft, non-tender, non-distended, positive hepatosplenomegaly. 

Extremities: +2 pitting edema bilaterally extending to mid-thigh level

Laboratory and radiographic findings: The peripheral white blood cell count was 8, 000 cell/mm³ with a differential as follows 91% neutrophils/bands, 7% lymphocytes, 1% myelocyte, 1% reactive lymphocyte, hemoglobin was 11 g/dL and the platelet count was normal. The basic metabolic panel revealed blood urea nitrogen of 30 mg/dl and creatinine of 1.5 mg/dl. The hepatic panel was normal except for an elevated alkaline phosphatase of 530 IU/L. Coccidioides IgM and IgG serology performed by immunodiffusion were negative.

The chest radiographs from two weeks prior to admission (Figure 1), admission (Figure 2) and admission computerized tomography of the chest (Figure 3) are shown.  

Figure 1. Chest radiograph two weeks before admission:  Right middle lobe consolidation with volume loss and small right pleural effusion

 

Figure 2.  Chest radiograph on admission: Increasing patchy opacifications involving the right upper lobe, right middle lobe, and left lower lobe, with cavity formation noted in the left lung. There is right paratracheal lymphadenopathy noted.

Figure 3: Computerized tomography of the chest showing multifocal consolidation with a necrotizing process containing central lucencies. A loculated, moderate sized right anterior pleural effusion with lucencies is compatible with an empyema.

Hospital course:

Our patient was started on broad-spectrum antimicrobial therapy and underwent chest tube drainage of the loculated effusion.  A sputum gram stain revealed 4+ weakly acid-fast branching bacilli, consistent with Nocardia. The gram stain of the pleural fluid showed 3+ polymorphonuclear cells and 3+ gram-positive, branching, weakly acid-fast bacilli, consistent with Nocardia.  The culture from sputum and pleural fluid grew Nocardia cyriacigeorgica. 

Computerized tomography of the brain showed no intracranial abnormalities. The patient was treated with high dose trimethoprim/sulfamethoxazole, two double strength tablets three times a day with monitoring of sulfamethoxazole levels. The patient clinically improved with antimicrobial treatment and drainage of the empyema. The chest tube was successfully removed and the patient’s symptoms of cough and dyspnea resolved. A chest x-ray showed resolution of the right middle lobe and left lower lobe infiltrative process.

Figure 4.  Chest radiograph post-antimicrobial treatment: Interval resolution of right middle lobe and left lower lobe infiltrative process. Post infectious inflammatory changes are noted in the right middle lobe.

Discussion

Nocardiosis is an important opportunistic infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia asteroides has been considered the most common species to cause human disease, however classification has become more complex with the use of molecular techniques. Species formerly included in the Nocardia asteroides complex are now considered distinct species.  Nocardia cyriacigeorgica is one of the more common isolates and has been noted to cause pleural disease and empyema.  Nocardia species are found in soil and can become airborne; the most common route of entry for infection is inhalation. Effective cell-mediated immunity of the host is crucial to combating infection with Nocardia species.  Two recent reviews of nocardiosis highlight important clinical features of this disease (1,2). The most common symptoms are fever, cough, pleuritic chest pain and headache. Specific risk factors for Nocardia infection are present in the majority of patients and include corticosteroid treatment and immunosuppression. Additional risk factors include malignancy and chronic lung disease. Of interest to pulmonologists, chronic obstructive pulmonary disease (COPD) was a common underlying condition, representing over 20% of patients with nocardiosis in these reports. Common chest radiographic presentations of pulmonary nocardiosis include consolidation, nodules and cavities. The diagnosis of pulmonary nocardiosis is made from sputum and bronchoalveolar lavage specimens in the majority of patients. In addition, recent reviews document that pleural effusions are present in up to 35% of patients with pulmonary nocardiosis.  In one report, when pleural fluid was sampled, Nocardia was isolated in the majority of patients. Nocardia cyriacigeorgica can cause invasive pulmonary disease and was found to be the predominant species in pulmonary nocardiosis in one review.

Summary

Nocardiosis is an important opportunistic pulmonary disease. The diagnosis should be included in the differential diagnosis of pulmonary infiltrates in immunosuppressed populations, including patients after organ transplantation, with advanced HIV infection and those receiving chronic corticosteroid therapy or chemotherapy. Radiographic findings of lung involvement are variable and include single or multiple nodules or cavities, alveolar or interstitial infiltrates, and pleural effusions. This case report highlights the unusual presentation of Nocardia cyriacigeorgica pulmonary infection with extensive cavitary parenchymal disease and concomitant empyema. 

References

1. Minero MV, et al. Nocardiosis at the Turn of the Century.  Medicine 2009;88:250-61.
2. Tomas RM, et al. Pulmonary Nocardiosis: Risk factors and outcomes. Respirology 2007;12:394-400 .
3. Latef SM, et al. Nocardia cyriacigeorgica empyema in 45-yr-old male with dual granulomatous lung disease. Chest 2008 134:c12001.
4. Schlaberg R. Nocardia cyriacigeorgica: an emerging pathogen in the United States.  Journal of Clinical Microbiology 2008;46:265-73.
5. Maraki S. Nocardia cyriacigeorgica pleural empyema in an immunocompromised patient.  Diagnostic Microbiology and Infectious Disease 2006;56:333-5.

SANDSTORM IN THE CHEST?

Manmadha Rao Talluri, M.D.

Department of General Medicine, Nizam’s Institute of Medical Sciences, Hyderabad, INDIA

Reference as: Talluri MR. Sandstorm in the chest? Southwest J Pulm Crit Care 2011;3:1-4. Click here for a PDF version

Corresponding Author:

Dr.Manmadha Rao Talluri

Associate professor

Department of General Medicine

Senior Pulmonologist

Nizams institute of Medical Sciences,

Panjagutta, Hyderabad, India

Phone – 914023489240

Mobile-919490295029

Email: manmadh2277@rediffmail.com

Abstract 

A 32 year old female presented with dry cough and progressive breathlessness of one year duration. There was no history suggestive of collagen vascular disease, lung parenchymal infection or allergic airway disease. Clinical evaluation showed basal fine inspiratory crepitations. Radiographic examination of the chest revealed a black pleura line and lung parenchymal calcification. CT scan of the chest demonstrated nodular calcification of lung parenchyma with a “crazy pavement” pattern, which is suggestive of alveolar calcification. Pulmonary function test showed a severe restrictive defect. On transbronchial lung biopsy calcific spherules suggestive of the alveolar microlithiasis were seen. Diagnosis of pulmonary alveolar microlithiasis was made and symptomatic treatment was given, as there is no specific therapy available. The case illustrates an unusual cause of shortness of breath in a young female with striking radiographic features. 

Case Summary

History and Physical Examination: A 32 year old woman presented with dry cough and progressive exertional shortness of breath of one year duration. There was no history of bronchial asthma, varicella, rheumatic heart disease, recurrent respiratory tract infections, tuberculosis, occupational dust exposure or connective tissue disease. Furthermore there was no family history of similar complaints but family members were unavailable for screening. Clinical examination showed normal vital signs, facial puffiness with acne and no clubbing. Upper respiratory tract examination was normal. Fine end inspiratory crepitations were heard on lung auscultation. No rhonchi or wheezing was heard. The remainder of the physical examination was normal.

Laboratory Evaluation: Complete blood count, urine examination and renal function tests were within normal limits. Calcium and phosphate were normal. A parathyroid hormone level was not performed. Immunological evaluation showed an antinuclear antibody (ANA) of 1:1 and a rheumatoid factor 42 IU/ml (normal < 30 IU/ml). DsDNA, Anti SS-a, SS-b and U1 RNP were all negative.

Radiography: Radiograph of the chest shown multiple high-density pulmonary nodules in both the lung fields involving all zones with increased density noted in the bases, with a sand storm appearance and a black pleura line (Figure 1).

Figure 1 Radiograph of the chest shows multiple high density pulmonary nodules in both lungs involving all zones with increased density in base as compared to apex, with sand storm appearance and bilateral black pleural lines indicated by the white arrows.

CT scan of the chest is shown in Figure 2.

Figure 2. CT scan cross-sectional imaging showing multiple calcific densities in both lungs with thickening and increased density along the fissure and along the mediastinal margin. A black pleural line is noted.

Additional Studies: Pulmonary function test demonstrated a severe restrictive defect. Ultrasound abdomen was normal with no evidence of nephrocalcinosis. Two dimensional echocardiography was normal. Transbronchial biopsy of the lung showed calciphic spherules, which is the hall mark of the pulmonary alveolar microlithiasis (Figure 3).

Figure 3. Transbronchial biopsy showing intra-alveolar calcific spherules (H & E, X 200). Insert shows higher magnification of calcific spherules (H&E, X400).

Genetic studies and level of surfactant A and D were not measured.

Clinical Course: The patient was continued on corticosteroids and theophyllines empirically added for dyspnea. Bisphosphonates or chelating agents were not used. She was advised to undergo lung transplantation; which could not be done due to financial constraints. The patient gradually worsened over 2 years and succumbed due to respiratory failure. Permission for an autopsy was not granted.

Discussion

Pulmonary alveolar microlithiasis is a rare disease of unknown etiology, characterized by wide spread laminated clacipherites in alveolar spaces. Other causes of diffuse lung calcification include following tuberculosis, varicella, silicosis, and the metastatic calcification seen with hypercalcemia or renal disease (1).

Pulmonary alveolar microlithiasis is usually sporadic, but an autosomal recessive form has been described in Mediterranean countries (1). The disease is characterized by paucity of symptoms despite wide spread involvement of the lung. Usually presenting in the third or fourth decade of life with cough and dyspnea, pulmonary alveolar microlithiasis usually is a progressive disease with an insidious clinical course resulting in respiratory failure (1,2).

Calcium metabolism has been reported as normal in pulmonary alveolar microlithiasis. Changes in the alveolar membrane secretions resulting in greater alkalinity have been hypothesized to play a major role in the pathogenesis of the disease. The change in alkalinity promotes the intra alveolar precipitation of calcium phosphates. Mutations in the SLC34A2 gene in type II pneumocytes that encodes type IIb sodium phosphate co-transporter have been reported (3). Serum surfactant protein A&D are markedly elevated, which can be useful to monitor the disease activity and progression (4).

Radiograph of the chest is characterized by the presence of a “sand storm” appearance and a black line along the pleura. CT scan usually shows bilateral lung parenchymal nodular calcifications and a “crazy paving” pattern, which is not specific for the diagnosis of pulmonary alveolar microlithiasis (5). Crazy paving has a variety of other causes some of which follow: infectious (Pneumocystis), neoplastic (mucinous bronchoalveolar carcinoma), idiopathic (pulmonary alveolar proteinosis, nonspecific interstitial pneumonitis), inhalational (lipoid pneumonia), and sanguineous disorders (pulmonary hemorrhage syndromes). 

Unfortunately, no established treatment is available.  Management with corticosteroids, chelating agents, bisphopshonates and bronchoalveolar lavage have all been disappointing. The only viable option for these patients is the bilateral lung transplantation (1).

Conclusion

Pulmonary alveolar microlithiasis is a rare disorder, which should always be considered in the differential diagnosis of calcific micronodular pulmonary lesions.

References

1. Tachibana T, Hagiwara K, Johkoh T. Pulmonary alveolar microlithiasis: review and management. Curr Opin Pulm Med 2009;15:486-490.

2. Castellana G, Gentile M, Castellana R, Fiorente P, Lamorgese V. Pulmonary alveolar microlithiasis: clinical features, evolution of the phenotype, and review of the literature. Am J Med Genet 2002;111:220-224.

3. Huqun, Izumi S, Miyazawa H, Ishii K, Uchiyama B, Ishida T, et al. Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis. Am. J. Respir. Crit. Care Med  2007;175:263-268.

4. Takahashi H, Chiba H, Shiratori M, Tachibana T, Abe S. Elevated serum surfactant protein A and D in pulmonary alveolar microlithiasis. Respirology 2006;11:330-333.

5. Gasparetto EL, Tazoniero P, Escuissato DL, Marchiori E, Frare E Silva RL, Sakamoto D. Pulmonary alveolar microlithiasis presenting with crazy-paving pattern on high resolution CT. Br J Radiol 2004;77:974-976.

This case was presented at the Great Cases session during the American Thoracic Society meeting in Denver, CO on May 15, 2011. A PowerPoint slide presentation was prepared for than session and a link to the slides is below.

Click here for a PowerPoint slide presentation

A MIDDLE-AGED MAN WITH A HISTORY OF RENAL CELL CARCINOMA

Roxanne Garciaorr

Richard A. Robbins

Phoenix VA Medical Center, Phoenix, AZ

Reference as: Garciaorr R, Robbins RA. A middle-aged man with a history of renal cell carcinoma. Southwest J Pulm Crit Care 2011;2:79-84. (Click here for PDF version)

Presented at the Arizona Thoracic Society April, 2009 in Scottsdale, AZ and the Great Cases Session at the American Thoracic Society International Conference, May, 2011 in San Diego, CA. 

Abstract

A 56 year old man was seen with a lung nodule. He had an extensive past medical history including renal cell carcinoma, congestive heart failure, obstructive sleep apnea and a 135 pack-year history of smoking. His physical examination was consistent with congestive heart failure. Sputum cultures for bacteria, fungi and tuberculosis were all negative. A CT scan revealed a spiculated, noncalcified 2.1 mass in the right lower lobe.  PET scan showed the lesion to have a standard uptake value of 1.5. The lesion was followed and after 3 months had enlarged to 6.4 cm. Biopsy was done and consistent with a lung abscess. Conservative therapy resulted in resolution only to have the lesion recur 22 months later with the patient expiring from massive hemoptysis and respiratory failure. This case illustrates the usefulness of doubling time in separating benign from malignant lung lesions.

Case Presentation

History of Present Illness.

A 56 year old man was seen in pulmonary consultation because of a right lower lobe mass discovered incidentally during a CT scan for pulmonary embolism. He was admitted to the Phoenix VA with complaints compatible with congestive heart failure. He had an extensive PMH with multiple myocardial infarctions with stent placements; resultant congestive heart failure; obesity: type 2 diabetes mellitus; obstructive sleep apnea, a 135 pack-year history of smoking; and right renal cell carcinoma found incidentally in 2006 with subsequent right nephrectomy 2 years previously.

Physical Examination

The patient was a tall, obese man who was afebrile.  Bilateral rales were noted about half way up the lung fields bilaterally and 2+ pretibial edema. The remainder of the physical examination was unremarkable.

Laboratory Findings

Urine analysis, complete blood count, and basic metabolic panel had the following abnormalities and pertinent negatives: hemoglobin 11.0 g/dl; hematocrit 31.9%; WBC 8200 cells/microl; creatinine 1.9 mg/dl; BUN 41 mg/dl; glucose 200 mg/dl. Hemoglobin A1C was 8.9% and a brain naturetic peptide was 887 pg/ml. Arterial blood gases were PaO2 82 mm Hg, PaCO2 25 mm Hg and pH 7.44 while breathing room air. Sputum cultures for bacteria, fungi and tuberculosis were negative. Serology testing for Coccidiomycosis was negative.

Radiography

The admission chest x-ray is shown in Figure 1.

Figure 1. Admission chest X-ray.

A representative slice of the CT scan showing the right lower lobe mass is shown in Figure 2.

Figure 2. Chest CT showing noncalcified, spiculated 2.1 cm nodule in the right lower lobe indicated by the arrow.

A PET scan was performed and the lesion had a standard uptake value of 1.5.

Subsequent Course

Multiple diagnosis including lung cancer, metastatic renal cancer, and infection were considered. The patient was reluctant to undergo biopsy but agreed to an outpatient course of doxycycline and a repeat CT scan 3 months later (Figure 3).

Figure 3. Repeat CT scan done 3 months later showing enlargement of the right lower lobe mass to 6.4 cm indicated by the arrow.

The patient was agreeable to needle biopsy (Figure 4).

Figure 4. Needle aspiration of lung mass showing an absence of malignant cells with acute inflammation compatible with a lung abcess.

Gastroenterology consultation was obtained and esophageal motility and esophogastroduodenoscopy revealed only gastritis.

The patient was followed and a repeat CT scan done 3 months later revealed shrinkage of the lesion (Figure 5).

Figure 5. CT scan done 6 months after biopsy (9 months after original CT scan). The right lower lobe lesion appears smaller at 1.2 cm.

The patient was followed and was asymptomatic until 22 months after initially seen when he presented with hemoptysis and shortness of breath. Repeat CT scan again showed a lesion in the area of the original lesion with cavitation and an air fluid level (figure 6).

Figure 6. CT scan done 22 months after original CT scan showing cavitation and an air fluid level indicated by the arrow.

Bronchoscopy with bronchoalveolar lavage was performed. Cultures for bacteria, fungi and tuberculosis were negative. He subsequently died from massive hemoptysis and respiratory failure.

Discussion

This case demonstrates the usefulness of doubling time in separating malignant from nonmalignant chest lesions. Between his first and second CT scans this patient’s lesion had enlarged from 2.1 to 6.4 cm over 102 days giving a calculated doubling time of 21 days (1). Lung cancers generally have average doubling times of about 100 days but have been reported to vary between 30 and 500 days. Doubling times of < 30 days usually indicate an infectious process. The lesion was aspirated because of its growth but no organism was identified. However, doubling time may occasionally be difficult to determine when nodules are not spherical or the borders are particularly vague such as in ground glass opacities or semi-solid lesions.

Narrowing the initial cause of this lung lesion was difficult because of the multiple potential causes including lung cancer, infection, pseudotumor and metastatic renal cell carcinoma. PET scans are usually positive in lung cancers. Negative PET scans have been reported with renal cell carcinoma although in the minority of instances (2). PET scans may be variably positive in pulmonary infections (3). However, the low uptake on PET scanning suggested the lesion was not malignant. Furthermore, the rapid growth combined with the low metabolic uptake also suggested the lesion is not malignant because growth of malignant stage I lung cancers and metabolic activity on PET scanning usually correlate (4).

The infectious cause of this patient’s right lower lobe abscess was never identified despite repeated sputum cultures, bronchoscopies and even a needle aspiration biopsy. Despite the negative evaluation for esophageal dysmotility, it seems most likely that aspiration caused with a subsequent anaerobic abscess was the cause of his lesions. Anaerobic organisms can be difficult to culture (5,6). The patient repeatedly denied any difficulty swallowing, water brash, etc.

It is unclear whether the original lesion identified was the same as the subsequent cavity with an air fluid level. Although progressive pneumonia can occur with aspiration, we suspect repeated aspiration as the subsequent cause of his cavity because of the improvement followed by the worsening 22 months after the initial presentation (5). However, prevention of aspiration may be difficult and it is unclear what measures could have been invoked to prevent his eventual demise.

References

1. http://www.chestx-ray.com/spn/DoublingTime.html (accessed 3-29-11).
2. Chang CH, Shiau YC, Shen YY, Kao A, Lin CC, Lee CC. Differentiating solitary pulmonary metastases in patients with renal cell carcinomas by 18F-fluoro-2-deoxyglucose positron emission tomography--a preliminary report. Urol Int 2003;71:306-9.
3. Bomanji J, Almuhaideb A, Zumla A. Combined PET and X-ray computed tomography imaging in pulmonary infections and inflammation. Curr Opin Pulm Med. 2011;17:197-205.
4. Tann M, Sandrasegaran K, Winer-Muram HT, Jennings SG, Welling ME, Fletcher JW. Can FDG-PET be used to predict growth of stage I lung cancer? Clin Radiol 2008;63, 856-863.
5. Dines DE, Titus JL, Sessler AD. Aspiration pneumonitis.  Mayo Clinic Proc 1970;45:347-60.
6. Bynum LJ, Pierce AK. Pulmonary aspiration of gastric contents. Am Rev Respir Dis 1976;114:1129-36.

This case was presented at the Great Cases session during the American Thoracic Society meeting in San Diego, CA on May 17, 2009. A link to the slides used for that presentation is below.

Click here for a PowerPoint slide presentation

A YOUNG LADY WITH VANISHING LUNG SHADOWS

Johnson Samuel MD, FRCP

Balamugesh Thangakunam, MD, DM 

Basildon University Hospital, United Kingdom 

Presented at the Great Cases Session at the American Thoracic Society International Conference, May 16, 2010 in New Orleans, LA.

Reference as: Samuel J, Thangakunam B. A young lady with vanishing lung shadows. Southwest J Pulm Crit Care 2011;2:40-4. (Click here for PDF version)

Abstract

   A previously well 20-year-old young lady who presented with nonspecific right-sided chest pain was found to have a rounded shadow on chest X-ray. Investigations to rule out malignancy revealed multiple lung masses. Initial blood tests and percutaneous image guided biopsy were inconclusive. Surgical lung biopsy revealed features suggestive of Bronchocentric Granulomatosis. Her lung shadows spontaneously resolved and there was no evidence of symptomatic or radiological recurrence on follow up for five years. Bronchocentric Granulomatosis is a rare condition particularly in non-asthmatic individuals and should be considered in the lesser-known differential diagnosis of benign lung shadows. 

Case Presentation 

History and Examination

   A 20-year-old lady presented to the Emergency department with right-sided pleuritic chest pain after watching a football match in the local pub.  A Chest radiograph showed a 1cm oval opacity in the periphery of the left upper zone. She was treated with a course of antibiotics and a repeat chest radiograph two weeks later showed an increase in the size of the opacity (Fig 1).

 

Figure 1.  Chest radiograph showing a rounded opacity in left upper zone.

   She was then referred to the respiratory clinic for evaluation. She was a non-smoker with no previous medical history of note. There was no history of recent respiratory infections. Clinical examination including breast examination was entirely normal.

Investigations

    Haemoglobin was 11.2 gm/dl, white cell count 7.0 x10⁹/L, platelet count 255x10⁹/L and erythrocyte sedimentation rate 22mm/hr. Differential white cell count was normal with absolute eosinophil count 0.1x10⁹/L.  Serum angiotensin converting enzyme was 36 IU/L. Serum compliment levels were normal and tumour markers were negative. Human chorionic gonadotrophin level was not elevated. Rheumatoid factor was 38 IU/ml, autoantibodies and Human Immunodeficiency Virus tests were negative. Mantoux test was non-reactive

   Computed Tomography (CT) showed three opacities, two of which were on the right side (Fig 2).

 Figure 2.  Computerised Tomography scan of chest showing bilateral lung opacities

   A CT guided biopsy showed necrotizing chronic granulomatous inflammation with no evidence of malignancy. There were many eosinophils seen in the biopsy sample (Fig 3).

 

Figure 3.  Computerised Tomography guided biopsy of the lesion showing necrotizing granulomatous inflammation. The arrowheads indicate necrosis centre of the picture with many eosinophils. The area circled shows a granuloma including a multi-nucleated giant cell indicated by the short arrow. (High power view- formalin fixed, haemotoxylin and eosin staining).

   As the diagnosis was still uncertain and as there was the suspicion of metastatic malignancy of uncertain origin, she underwent a video assisted thoracoscopic biopsy (VATS biopsy). Histopathology of the nodule revealed abundant necrosis, surrounded by a rim of chronically inflamed fibrous tissue with focal areas of discontinuous elastic lamina (Fig 4).

Figure 4.  Video assisted thoracoscopic biopsy showing focal necrotizing granulomatous inflammation. Arrowhead indicated the central necrosis. Short arrow indicated the multi-nucleated giant cell (High power view – formalin fixed, haemotoxylin and eosin staining).

   Mycobacterial and fungal cultures were negative. There were no features of vasculitis or malignancy.  Based on the histopathology and the clinical features, a diagnosis of Bronchocentric Granulomatosis was made.

Follow up

   The patient was asymptomatic throughout she did not receive treatment. On follow up, after initial increase in size, the nodules started regressing and serial chest X-ray’s showed complete resolution of the lung lesions in four months. She has since been followed up in the respiratory clinic for five years and there was no radiological evidence of recurrence. Her serial spirometry during follow up was normal. She remains asymptomatic and has joined the police force leading an active lifestyle.

Discussion

   Bronchocentric granulomatosis is a necrotizing granulomatous inflammation of the small to medium sized bronchi and bronchioles (1). Approximately half the patients are asthmatics and among these patients, the disease appears to be a hypersensitivity reaction to inhaled allergens particularly Aspergillus fumigatus. (2,3). In the non-asthmatic group, the causative agent is usually not identified. Similar appearances have been described in patients with Pulmonary Echinococcosis, Wegener’s Granulomatosis and Rheumatoid Arthritis (4). Occasionally, it may show histological features indistinguishable from tuberculosis.

    Asthmatic patients, who are usually in the age group 20-40 years, present with worsening wheeze, dyspnoea, cough, fever and occasionally haemoptysis. Peripheral blood may show eosinophilia and Aspergillus fumigatus is commonly grown in sputum culture. Non-asthmatic patients are often asymptomatic or may present with an acute febrile illness. Radiologically, Bronchocentric Granulomatosis can present as mass lesions, alveolar infiltrates, pneumonic consolidation or reticulo-nodular opacities (5). As this can mimic malignancy as in our case, a surgical lung biopsy may be required to rule out vasculitis or malignancy.  There are no definite diagnostic criteria and diagnosis is based on clinical, radiological and pathological correlation. Some patients may need corticosteroids for rapid clinical and radiological resolution while others recover without treatment. Surgical resections have been done to firmly establish the diagnosis given the concern about malignancy. However, when there are no alarming symptoms or signs, it may be appropriate to monitor progress or consider medical treatment.

    Bronchocentric Granulomatosis though rare is a reassuringly benign and usually self-limiting condition, which can present with alarming radiological signs. It should be considered in the asthmatic and asymptomatic patient when other sinister causes are ruled out by definitive investigations, which may include a surgical biopsy.

Acknowledgement:

   Dr. Nazar Alsanjari, Pathology department, Basildon University Hospital, Basildon. For kindly providing the photomicrographs of the biopsy specimens.

References

1. Liebow AA. Pulmonary angiitis and granulomatosis. American Review of Respiratory Disease 1973;108:1-18.

2.  Sulavik SB. Bronchocentric granulomatosis and allergic bronchopulmonary aspergillosis. Clin Chest Med 1988;9:609-21.

3.  Koss MN, Robinson RG, Hochholzer L. Bronchocentric granulomatosis. Hum  Pathol 1981;12:632-8.

4. Bonafede RP, Benatar SR. Bronchocentric granulomatosis and rheumatoid arthritis. Br J Dis Chest 1987;81:197-201.

5. Ward S, Heyneman LE, Flint JD, Leung AN, Kazerooni EA, Miller NL. Bronchocentric granulomatosis: computed tomographic findings in five patients. Clin Radiol 2000;55:296-300.

Corresponding author:

Balamugesh Thangakunam

Speciality Doctor

Respiratory services

Basildon University Hospital

Basildon, Essex, United Kingdom

SS16 5NL

E mail: drbalamugesh@yahoo.com

This case was presented at the Great Cases session at the American Thoracic society meeting in New Orleans, LA on May 16, 2009. A link to the slides used in that presentation is below.

Slide Presentation

A 61 Year Old Immunosuppressed Man With A Symptomatic Pulmonary Infiltrate

Carmen Luraschi-Monjagatta¹

Amber Noon¹

Neil Ampel¹

Suzette Chavez¹

Mitch Goldman²

Kenneth S  Knox¹

University of Arizona, Department of Medicine. Southern Arizona VA Healthcare System. Tucson, Arizona¹

Indiana University School of Medicine, Indianapolis, IN²

Reference as: Luraschi-Monjagatta C, Noon A, Ampel N, Chavez S, Goldman M, Knox KS. A 61 year old immunosuppressed man with a symptomatic pulmonary infiltrate. Southwest J Pulm Crit Care 2011;2:17-24. (Click here for PDF version)

Abstract

   Coccidioidomycosis is a common cause of community acquired pneumonia in Arizona.  Although self-limited in the majority of patients, immunosuppression often causes a blunting of symptoms and a poor antibody response.  We present a patient with coccidioidomycosis while receiving adalimumab for psoriasis.  The diagnosis was challenging due to negative serology and constellation of symptoms on immunosuppression.

Case Presentation

History of Present Illness

   A 61 year-old man with a history of psoriatic arthritis was admitted to the hospital after 5 days of fever, night sweats, dry cough, dyspnea, fatigue and inspiratory chest pain. He was treated for a bacterial community-acquired pneumonia and discharged but was readmitted 2 days later because of persistent symptoms. 

   On readmission he noted that the fevers had resolved, but stated his other symptoms remained unchanged. Twelve years previously, he had been diagnosed with psoriatic arthritis and was initially treated with methotrexate and prednisone. Due to poorly controlled disease, adalimumab was initiated 6 weeks prior to his illness. Coccidioides serology and tuberculin skin testing were negative at that time.

Physical examination

   On re-admission vital signs were within normal limits. Oxygen saturation was 95% on ambient air. He was a well developed man in no acute distress. There was a faint maculopapular rash on his trunk and erythematous plaques with dry silver scale on his limbs. Inspiratory crackles were auscultated over the left lung field anteriorly. Cardiac, abdominal and neurological examinations were normal.

Laboratory findings

   The peripheral blood white cell count was 12,200 cell/mm³ with 12.2 % eosinophils. Other laboratory tests, including hematocrit and hemoglobin, platelets, basic metabolic panel and hepatic panel, were normal. Coccidioides IgM and IgG serology performed by immunodiffusion were negative. The re-admission chest radiography (Figure 1) and computed tomography of the chest (figure 2) are shown.

 

Figure 1: A:  Pulmonary radiograph two months before admission. B: Pulmonary radiograph at admission.

Figure 2: Computerized tomography of the chest showing left lower lobe lesions, left hilar adenopathy, and a right pulmonary nodule (arrow).

   A left-sided pulmonary parenchymal infiltrate, already observed during the first admission, with left hilar adenopathy, were the predominant findings. Indistinct right sided densities were newly appreciated. Bronchoscopy with bronchoalveolar lavage (BAL) was performed which showed a normal airway and a cell differential of 18% macrophages, 14% neutrophils, 15% lymphocytes and 53% eosinophils. A Papanicolau stain was negative for fungal elements. Culture of the BAL fluid was obtained.

Hospital course

   Our patient remained stable with persistent symptoms during his brief hospital stay. Antibacterial treatment for community acquired pneumonia was discontinued and the patient was sent home. Three days later cultures grew Coccidioides. The patient was referred to the Valley Fever Center and started on fluconazole with near complete resolution of his symptoms. Therapy for psoriasis was not restarted.  After 4 weeks, the immunodiffusion (IDTP) turned positive at a titer of 1:4. 

Discussion

   Coccidioidomycosis is a soil-borne fungal infection encountered predominantly in the southwestern United Stated and northern Mexico. In the United States, 60% of symptomatic cases are currently reported from Arizona. Two species, Coccidioides immitis and C. posadasii, are the causative agents. Three important points are illustrated by this case. First, coccidioidomycosis can often be mistaken for a bacterial community acquired pneumonia. Second, the diagnosis of coccidioidomycosis can be challenging, with serology sometimes negative in patients with underlying immunosuppression. Third, therapy with inhibitors of TNF-α may increase the risk of symptomatic coccidioidomycosis.

   Among populations living in the endemic coccidioidal region, approximately 25% of patients presenting to urgent care clinics with community-acquired pneumonia have coccidioidomycosis.(1) The diagnosis can be difficult, but the presence of erythema nodosum, hilar or mediastinal lymphadenopathy on chest radiograph, and peripheral blood eosinophilia are suggestive of coccidioidomycosis.

   Serologic tests for coccidioidomycosis may take up to six weeks in immunocompetent individuals to become positive. Several different assays for coccidioidal antibodies are currently available (2). Acute IgM reactions can be detected using the tube precipitin (TP) assay, immunodiffusion (IDTP), or enzyme immunoassay (EIA). For detection of IgG, complement fixation (CF), immunodiffusion (IDCF), or EIA can be employed. The CF and IDCF can be titrated and elevated titers are an indication of more severe disease.

   Serologic assays for coccidioidomycosis are very specific. Serology testing for coccidioidomycosis is routinely and repeatedly performed during an acute infection but can take up to six weeks in immunocompetent individuals to produce reliably detectable antibodies. In acute disease, IgM can be detected with serologic tests in up to 53% of patients in the first week, which increases to 75% in the presence of erythema nodosum and further increases to 91% at 3-4 weeks of infection (3). However, in the immunosuppressed patient these tests are less likely to be positive than among immunocompetent patients.  Coccidioides antigen testing may be useful in patients with large fungal burden (4).   In our patient, serology was initially negative, but eventually became positive.

   When suspecting pulmonary coccidioidomycosis, a bronchoscopy with bronchoalveolar lavage (BAL) is often performed. Cell differentials frequently show a high percentage of eosinophils. Blood and BAL eosinophilia is common in Coccidioidomycosis. In several recent cases, we have seen intense eosinophilic pneumonia (>50% eosinophils in BAL) due to Coccidioides infection. Although it is tempting to diagnose acute eosinophilic pneumonia in these instances, it is important to keep Coccidioides infection in the differential diagnosis, especially in endemic areas. Cytology examination of BAL secretions can give a rapid diagnosis, but the sensitivity is low, even in severely immunocompromised patients. The Papanicolaou stain is superior to other stains in identifying Coccidioides spherules when compared with 10% potassium hydroxide and to calcofluor white staining. Culture of bronchial specimens increases the yield. The gold standard for the diagnosis of coccidiodomycosis is culture or visualization of spherules in tissue.   Coccidioides grows on routine bacterial or fungal media in three to seven days at 35°C. Growth of Coccidioides on solid culture media is a major hazard for infection and microbiology laboratories should always be alerted when coccidioidomycosis is suspected. In our case, Coccidioides grew from BAL fluid, confirming the diagnosis.

   In humans, an effective response to coccidioidal infection depends on an intact cellular immune response. In this regard, an increased risk of symptomatic coccidioidomycosis (both reactivation and newly acquired infection) in patients with inflammatory arthritis receiving TNF-α antagonists has been documented (5,6). Primary anti-fungal prophylaxis for patients in the endemic area starting anti-TNF therapy is not recommended, but adequate data regarding this subject is lacking. In our practice we check coccidioidomycosis serology and a CXR prior to initiation of anti-TNF therapy and then annually. Although the timing of discontinuing adalimumab in our patient might raise suspicion for immune reconstitution inflammatory syndrome (IRIS), to date Coccidioides related IRIS has not been definitively reported upon withdrawal of anti-TNF therapy.

Summary

   Coccidioidomycosis is a common cause of community acquired pneumonia in the endemic area.  The diagnosis should be included in the differential diagnosis of pulmonary infiltrates with eosinophilia. Immunosuppression with anti TNF- α therapy increases the risk for a negative serologic response in coccidioidomycosis.

References

1. Valdivia L, Nix D, Wright M, Lindberg E, Fagan T, Lieberman D, Stoffer T, Ampel NM, Galgiani JN. Coccidioidomycosis as a common cause of community-acquired pneumonia. Emerg Infect Dis 2006;12:958-62.
2. Blair JE, Coakley B, Santelli AC, Hentz JG, Wengenack NL. Serologic testing for symptomatic coccidioidomycosis in immunocompetent and immunosuppressed hosts. Mycopathologia 2006; 162:317-24.
3. Smith CE, Saito MT, Simons SA. Pattern of 39,500 serologic tests in coccidioidomycosis. JAMA. 1956;160:546-52
4. Durkin M, Estok L, Hospenthal D, Crum-Cianflone N, Swartzentruber S, Hackett E, Wheat LJ. Detection of Coccidioides antigenemia following dissociation of immune complexes. Clin Vaccine Immunol. 2009;16(10):1453-6.
5. Bergstrom L, Yocum DE, Ampel NM, Villanueva I, Lisse J, Gluck O, Tesser J, Posever J, Miller M, Araujo J, Kageyama DM, Berry M, Karl L, Yung CM. Increased risk of coccidioidomycosis in patients treated with tumor necrosis factor alpha antagonists. Arthritis Rheum 2004; 50:1959-66.
6. Ampel NM. New perspectives in coccidioidomycosis. Proc Am Thorac Soc 2010: 7: 181-5.

Corresponding author:

Kenneth S Knox, M.D.

Associate Professor of Medicine, University of Arizona

Southern Arizona VA Health Care System

3601 S 6^th Ave (1-11C)

Tucson, AZ 85723

Tel: 520-629-1848 Fax: (520) 629-4976

Acknowledgment:

We would like to thank the Valley Fever Center for Excellence http://www.vfce.arizona.edu/  for its support

Author Contributions:

- Drs. Luraschi-Monjagatta and Knox had full access to data in the report and take full   responsibility for the integrity and the accuracy of the report.

- Report concept and design: Drs. Luraschi-Monjagatta and Knox.

- Acquisition of data: Drs. Luraschi-Monjagatta, Noon, Knox and Ms Chavez.

- Drafting of the manuscript: Dr. Luraschi-Monjagatta, Ampel and Knox.

- Critical revision of the manuscript for important intellectual content: Drs. Goldman, Ampel, and Knox.

Abbreviations:

tube precipitin (TP), immunodiffusion tube precipitin (IDTP),  enzyme immunoassay (EIA), complement fixation (CF), immunodiffusion compliment fixation (IDCF), Bronchoalveolar lavage (BAL), Immune reconstitution inflammatory syndrome (IRIS)