March 2015 Pulmonary Case of the Month: Sticks and Stones May Break My Bronchi

Syed Amer MBBS

Kenneth Sakata MD

Karen Swanson DO

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 67-year-old woman presented to the emergency department with a chief complaint of persistent cough of 2 months duration, productive of yellow sputum. Her symptoms progressed to include dyspnea despite an outpatient course of antibiotics, bronchodilators, and corticosteroids. She denied fevers, chills, hemoptysis, or chest pain. 

PMH, FH, SH

She was on chronic immunosuppression secondary to a history of liver transplant due to non-alcoholic steatohepatitis and kidney transplant due to calcineurin toxicity. She denied any history of smoking, alcoholism or recreational drug use.  

Medications

• Tacrolimus 3.5 mg bid
• Mycophenolate mofetil 720 mg bid
• Fluconazole 100 mg daily

Physical Examination

Vitals: Temperature 37.1°C, respiratory rate 18 breaths/min, heart rate 88 beats/min, blood pressure 130/76 mm Hg, SpO2 95% on room air.

General: Elderly female in no apparent distress.

Lungs: Scattered inspiratory and expiratory squeaks and pops bilaterally, louder in the left lower lobe

The rest of her exam was within normal limits

Laboratory

WBC 4.8 x 10³ cells/µL, Hemoglobin 8.0 g/dL, Hematocrit 23.5, Platelets 122 x 10³ cells/µL.

Creatinine 1.3, electrolytes, blood urea nitrogen, glucose were within normal limits.

Radiography

Her admission chest x-ray is presented in Figure 1.

Figure 1. Admission chest radiograph.

Which of the following is (are) appropriate at this time? (Click on the correct answer to proceed to the second of 4 panels)

1. Cocci serology
2. Empirically begin antibiotics
3. Thoracic CT scan
4. Sputum culture
5. All of the above

Reference as: Amer S, Sakata K, Swanson K. March 2015 pulmonary case of the month: sticks and stones may break my bronchi. Southwest J Pulm Crit Care. 2015:10(3):99-104. doi: http://dx.doi.org/10.13175/swjpcc026-15 PDF 

Systemic Lupus Erythematosus Presenting As Cryptogenic Organizing Pneumonia: Case Report

Anthony Jedd, MD

Sashank Kolli, MD 

Thomas Liao, MD

Isabel Oliva, MD

Loyola University Of Chicago

Stritch School Of Medicine

Maywood, IL

and

University of Arizona

Tucson, AZ

Introduction

Systemic Lupus Erythematosus (SLE) is a systemic disease with multiorgan involvement. In the respiratory system, SLE can involve the lung parenchyma and pleura with intrathoracic manifestations of pleuritis, alveolar hemorrhage and pulmonary fibrosis. Cryptogenic organizing pneumonia (COP) is a rare complication of SLE. We describe a case of newly diagnosed lupus presenting as COP.

Case Report

An 18-year-old woman with no significant past medical history presented to the Emergency Department complaining of generalized malaise, cough and fever for 4 days. Her cough was productive with white to brownish sputum. She complained of chest heaviness/pressure with inability to take deep breaths. Her only reported sick contact was her mother who had the “flu” one week prior to the onset of her illness. She denied any illicit drug use, alcohol or smoking, as well as any recent travel or exotic pet exposure. On admission, her vital signs were: temperature 38.4°C, pulse rate 129 bpm, blood pressure 159/108 mmHg, respiratory rate 29 rpm and oxygen saturation 94% on room air. On physical exam, the patient was in moderate distress with tenderness to palpation over her muscles. Left anterior cervical adenopathy was present and lung auscultation revealed coarse bilateral crackles. She was alert and oriented times 3 with no neurological deficits. 

Laboratory data on admission: white blood cell count 5100/µL with 43% bands, hemoglobin 10.6 g/dL, platelets 125 x 10⁹/L, blood urea nitrogen 37mg/dL, and creatinine 2.0 mg/dL. Urinalysis revealed a large amount of microscopic blood, small amount of leukocyte esterase, moderate bacteria and protein > 300 mg/dl. ABG of pH 7.39/pCO2 28 mm Hg/pO2 of 68 mm Hg on 2L/min by nasal cannula. Initial chest radiograph (CXR) demonstrated bilateral perihilar infiltrates (Figure 1).   

  

Figure 1. CXR on admission.

She was started on ceftriaxone and azithromycin with a working diagnosis of sepsis secondary to community-acquired pneumonia with impending respiratory failure.

She continued to be febrile, hypoxic and tachycardic. A 4-day follow-up CXR demonstrated interval worsening of bilateral airspace disease (Figure 2).

Figure 2. CXR on hospital day 4.

Despite antibiotic therapy for 5 days she was intubated due to continued deterioration. Diagnostic bronchoscopy was performed showing a positive mycoplasma IgM, while samples for bacterial, viral and fungal sources as well blood cultures were negative. GMS stain for Pneumocystis was also negative. At this time infectious disease recommended switching the antibiotics to vancomycin and aztreonam.  

The patient continued to have persistent anemia, thrombocytopenia and urine containing large amounts of protein raising suspicion for an autoimmune hemolytic anemia with bone marrow failure. Rheumatologic panel revealed ANA titer of 2,560 (normal <40), anti-ds DNA antibody >300 IU/ml (normal <10) and normal complement C3,C4. HIV testing was non reactive. Per rheumatology's recommendations, she was started on methylprednisolone 1 g daily for 3 days and later switched to prednisone 100 mg daily and 600 mg cytoxan for the working diagnosis of systemic lupus erythematosus (SLE). After about 1 week of persistent extensive bilateral lung infiltrates and continued ventilator dependence, an open lung biopsy was performed which demonstrated bronchoalveolar tissue showing organizing pneumonia of unknown etiology (Figure 3). No histological findings for vasculitis or alveolar hemorrhage were identified.

 

Figure 3. Panel A: patchy fibroblastic plugs in bronchioles and alveolar ducts (bronchiolitis obliterans) (black arrows). Panel B: Organizing pneumonia within alveoli (black circle).

She was diagnosed with SLE involving multiple organs, which included lung, kidneys and bone marrow. Prednisone 100 mg daily was continued for 2 weeks. Broad spectrum antibiotics were discontinued, but she finished a 2 week coarse of azithromycin for the positive mycoplasma antibodies. Her respiratory status gradually improved and she was extubated on her 14th hospital day. As an outpatient, prednisone was tapered slowly over the next 2 months to 10 mg daily and then she was transitioned to mycophenolate. Follow-up CXR showed resolution of the airspace disease (Figure 4).

Figure 4. CXR 2 months after admission to ICU.

Discussion

Cryptogenic organizing pneumonia is a noninfectious inflammatory pulmonary process that leads to the formation of fibromyxoid connective tissue plugs that adhere to the walls of the alveolar ducts and alveoli (1,2,4). COP can be idiopathic or secondary to several etiologies, including drug toxicity, infection, connective tissue diseases (CTD), malignancy and bone marrow transplantation (6). The diagnosis of SLE-related COP is rare with no cohort studies showing a dominant type of CTD resulting in COP.

Oymak S et al. (8) reviewed etiologic and clinical features in 26 patients with COP and found that 58% were idiopathic. The other 42% were secondary, but the causes were not described. Yoo JW et al. (9) further compared cryptogenic organizing pneumonia and connective tissue disease-related organizing pneumonia (CTD-OP). The study showed rheumatoid arthritis, Sjogren’s syndrome and polymyositis/dermatomyositis were predominant types of CTD and no patients were mentioned with SLE (9). Other studies mention polymyalgia rheumatica and SLE as potential causes of COP, but there are no reported cases of the two entities presenting together in adults (10-12). 

The mechanism by which SLE can lead to the development of COP is unknown. Otsuka et al. (13) suggested that elevated antiphospholipid antibodies contribute to the development of Masson bodies, macrophages and fibrin found within pulmonary alveoli, due to an inhibited inflammatory repair mechanism within the airways, which may contribute to the development of COP. The hypothesis of epithelial damage by the immune system is supported by the response to steroid therapy, which prevents and/or resolves deposition of IgM, IgG and infiltration of plasma cells into the bronchiolar walls (14,15).

The development of SLE-related COP remains a rare entity. Our patient’s presentation was unique in that COP was the initial manifestation of her SLE. Additionally, the pattern of airspace disease on chest radiograph was atypical for organizing pneumonia, which usually presents as either peripheral or peribronchiolar areas of consolidation. As more cases arise, our understanding of the mechanism and timing of the disease will hopefully become more apparent.

References

1. Epler GR, Colby TV, McLoud TC, Carrigton CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985;312:152-8. [CrossRef] [PubMed]
2. Colby TV. Pathologic aspects of bronchiolitis obliterans organizing pneumonia. Chest 1992;102:38S-43S. [CrossRef] [PubMed]
3. Epler GR. Bronchiolitis obliterans organizing pneumonia. Arch Intern Med. 2001;161:158-64. [CrossRef] [PubMed]
4. Moore SL. Bronchiolitis obliterans organzining pneumonia: a late complication of stem cell transplantation. Clin J Oncol Nurs. 2003;7(6):659-62. [CrossRef] [PubMed]
5. Cordier JF. Organizing pneumonia. Thorax 2000;55:318-28. [CrossRef] [PubMed]
6. Roberton B, Hansell D. Organizing pneumonia: a Kaleidoscope of concepts and morphologies. Eur Radiol 2011;21:2244-54. [CrossRef] [PubMed]
7. Takada H, Saito Y, Nomura A, Ohga S, Kuwano K, Nakashima N, Aishima S, Tsuru N, Hara T. Bronchiolitis obliterans organizing pneumonia as an initial manifestation in systemic lupus erythematosus. Pediatr Pulmonol. 2005;40:257-260. [CrossRef] [PubMed]
8. Oymak S, Demirbas HM. Mavili E, Akgun H, Gulmex I, Demir R, Ozesmi M. Bronchiolitis obliterans organizing pneumonia. Respiration. 2005;72:254-62. [CrossRef]  [PubMed]
9. Yoo JW, Song JW, Jang SJ, Lee CK, Kim MY, Lee HK, Jegal Y, Kim DS. Comparison between cryptogenic organizing pneumonia and connective tissue disease-related organizing pneumonia. Rheumatology 2011;50:932-8. [CrossRef] [PubMed]
10. Douglas WW, Tazelaar HD, Hartman TE, Hartman RP, Decker PA, Schroeder DR, Ryu JH. Polymyositis-dermatomyositis-associated interstitial lung disease. Am J Respir Crit Care Med. 2001;164(7):1182-5. [CrossRef] [PubMed]
11. Katzenstein ALA, Myers J, Prophet WD, Corley LS 3rd, Shin MS. Bronchiolitis obliterans and usual interstitial pneumonia. Am J Surg Pathol. 1986;10:373-81. [CrossRef] [PubMed]
12. Lynch D. Lung disease related to collagen vascular disease. J Thorac Imaging. 2009;24(4):299-309. [CrossRef] [PubMed]
13. Otsuka F, Amano T, Hashimoto N, Takahashi M, Hayakawa N, Makino H, OtaZ, Ogura T. Bronchiolitis obliterans organizing pneumonia associated with systemic lupus erythematosus with antiphopholipid antibody. Intern Med. 1996;35:341-4. [CrossRef] [PubMed]
14. Myers JL, Katzenstein AL. Ultrastructural evidence of alveolar epithelial injury in idiopathic bronchiolitis obliterans-organizing pneumonia. Am J Pathol. 1988;132(1):102-9. [PubMed]
15. Ippolito JA, Palmer L, Spector S, Kane PB, Goveric PD. Bronchiolitis obliterans organizing pneumonia and rheumatoid arthritis. Semin Arthritis Rheum. 1993;23(1):70-8. [CrossRef] [PubMed]

Reference as: Jedd A, Kolli S, Liao T, Oliva I. Systemic lupus erythematosus presenting as cryptogenic organizing pneumonia: case report. Southwest J Pulm Crit Care. 2015;10(2):87-92. doi: http://dx.doi.org/10.13175/swjpcc164-14 PDF 

February 2015 Pulmonary Case of the Month: Severe Asthma

Suresh Uppalapu, MD
Sunil Santhanakrishnan, MD
Rajeev Saggar, MD

Banner Good Samaritan Medical Center

Phoenix, AZ

History of Present Illness

A 50-year-old  African-American woman  with a history of asthma presented to the emergency department with a chief complaint of shortness of breath for 2 weeks. She reported some chest tightness, wheezing  and dry cough. She denied fever, chills, myalgias or arthralgias  at the time of admission.

PMH, SH and FH

In addition to asthma, she has a past medical history of type 2 diabetes mellitus, hypertension, and multiple sclerosis. She admitted to social smoking but states she quit 6 to 7 months ago. She denies alcohol, recreational drug use, or a family history of early coronary artery disease, strokes or cancers. 

Medications

• Montelukast 10 mg daily
• Salmeterol/fluticasone 250/50 inhaled twice a day
• Albuterol inhaler as needed for shortness of breath
• Metformin 500 mg bid.
• Dimethyl fumarate 240 mg bid.
• Omega 3 fish oil.
• Calcium carbonate 600 mg daily
• Naproxen 500 mg BID
• Lisinopril 10 mg daily
• Hydrochlorothiazide 25 mg daily.

Physical Exam

Vitals: Temperature 37.2º C, respiratory rate 33 breaths/min, heart rate 112 beats/min, blood pressure 152/80 mm Hg, SpO2 80% on room air but 98% on 3 liters/min by nasal cannula.

General: Mild respiratory distress.

Lungs: Diminished breath sounds diffusely with mild wheezing.

The rest of her exam was within normal limits.

Laboratory/EKG/Chest Radiography

White blood cells 8.1 X 10³ cells/microliter, hemoglobin 13.9 g/dL, hematocrit 41.7, platelets 289,000 cells/microliter.

Electrolytes blood urea nitrogen, creatinine, glucose, troponin, and brain naturetic peptide were within normal limits

EKG showed sinus tachycardia but was otherwise normal.

Chest x-ray was interpreted as normal.

A thoracic CT scan showed wispy infiltrates but no evidence of pulmonary embolism or other abnormalities.

Which of the following is appropriate management at this time? (Click on the correct answer to proceed to the second of four panels)

1. Bronchodilators
2. Discharge the patient to home
3. Intravenous corticosteroids
4. 1 and 3
5. All of the above

Reference as: Uppalapu S, Santhanakrishnan S, Saggar R. February 2015 pulmonary case of the month: severe asthma. Southwest J Pulm Crit Care. 2015;10(2):57-62. doi: http://dx.doi.org/10.13175/swjpcc010-15 PDF

January 2015 Pulmonary Case of the Month: More Red Wine, Every Time

Uzair Ghori, MD (UGhori@salud.unm.edu)

Shozab Ahmed, MD  (Sahmed@salud.unm.edu)

University of New Mexico

Albuquerque, New Mexico

History of Present Illness

A 41-year-old man travelling from Texas to Las Vegas, Nevada presents to the Emergency Room in Albuquerque, New Mexico with petechial rash, photophobia and headache of 2 weeks duration. The patient complains of general malaise, arthralgia, trouble sleeping, shortness of breath associated with cough and intermittent bilateral lower extremity swelling of 3 weeks duration.

PMH, SH & FH

The patient was prescribed lisinopril and metformin for hypertension and diabetes mellitus, respectively. He admitted occasional drinking, smoking a variable quantity for 30 years but currently not smoking. He denied any illicit drug use.

Physical Exam

Vitals: Heart Rate-92, Blood Pressure-116/45 mm Hg, Respiratory Rate-44 breaths/min, Temperature- 37.2ºC, SpO2-98% on non-rebreather mask.

General: His mental status was not altered.

HEENT: No papilledema was appreciated on eye exam.

Neck: JVP not appreciated.

Lungs: he had diminished breath sounds bilaterally on auscultation.

Heart: His heart had a regular rate and rhythm with no murmurs rubs or gallops.

Abdomen: No abdominal distention or lower extremity edema appreciated.

Skin: A petechial rash was noted most prominently in the lower extremities.

Based on the initial presentation the most appropriate investigations would be? (Click on the correct answer to proceed to the 2nd of 6 panels)

1. CBC, CT head, echocardiogram, blood cultures, metabolic panel, inflammatory markers
2. CBC, UA, lumbar puncture, chest x-ray, inflammatory markers, metabolic panel
3. Echocardiogram, CBC, UA, venous blood gases, bronchoscopy, CT head
4. Stress test, CXR, inflammatory markers, lumbar puncture, ultrasound abdomen, metabolic panel
5. UA, lumbar Puncture, bronchoscopy, echocardiogram, CT head, inflammatory markers 

Reference as: Ghori U, Ahmed S. January 2015 pulmonary case of the month: more red wine, every time. Southwest J Pulm Crit Care. 2015;10(1):1-7. doi: http://dx.doi.org/10.13175/swjpcc155-14 PDF

December 2014 Pulmonary Case of the Month: Bronchiolitis in Adults

Kashif Yaqub, MD

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 61-year-old man was admitted to the hospital with cough, dyspnea and hypoxemia. He had some prior respiratory symptoms about a month prior to admission, but his symptoms worsened recently. He was seen in Family Medicine Clinic on the day of admission and noted to have saturations of 88 – 89%.

A thoracic CT scan was done shortly after his initial symptoms but was negative for lung consolidation or pulmonary embolus. He currently was having fever with temperatures of 99 to 103 degrees and cough that was only slightly productive.

PMH, FH, SH

He had a history of hypertension and obstructive sleep apnea although he was not using continuous positive airway pressure (CPAP).

Medications

• nifedipine
• lisinopril/hydrochlorothiazide
• cough medication

Physical Examination

      General: SpO2 95% on 2l/min by nasal cannula

      Chest: his breath sounds were coarse, but there were no wheezes or crackles.       

      Cardiovascular: regular rate and rhythm with no murmur noted

      Extremities: no clubbing, cyanosis or edema.

      Skin: no rashes noted.

Laboratory

      CBC: Hemoglobin 15.1 d/dL,  WBC 15.3 x 10³ cells/µL, no eosinophilia.

      Procalcitonin: 0.22 ng/mL (normal < 0.15 ng/mL).    

      Nasopharyngeal swab: PCR negative for pertussis, chlamydophila and           mycoplasma pneumonia.

Radiography

His thoracic CT scan at the initial presentation of his illness about a month prior to admission was reviewed (Figure 1).

Figure 1. Representative images from thoracic CT scan in lung windows done about one month prior to admission.

Which of the following are appropriate at this time? (Click on the correct answer to proceed to the next panel)

1. Cocci serology
2. Empirically begin antibiotics for community-acquired pneumonia
3. Repeat the thoracic CT scan
4. Sputum culture
5. All of the above

Reference as: Yaqub K, Wesselius LJ. December 2014 pulmonary case of the month: bronchiolitis in adults. Southwest J Pulm Crit Care. 2014;9(6):297-301. doi: http://dx.doi.org/10.13175/swjpcc149-14 PDF 

November 2014 Pulmonary Case of the Month: BAL Eosinophilia

Salma Imran Patel, MD, MPH

Lewis J. Wesselius, MD

Laszlo T. Vaszar, MD

Departments of Internal Medicine and Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 62 year-old- was admitted to the hospital for 2 weeks of worsening cough, yellowish sputum production, shortness of breath and pleuritic chest pain. The patient has had asthma since the 1970s and presently uses salmeterol/fluticasone and albuterol as a rescue inhaler. He was intubated once four years ago, and has had a total of three hospitalizations for his asthma and 15 courses of prednisone. He is sensitive to cold/hot air, all animals, aspirin and acetaminophen.

PMH, FH, SH

In addition to the asthma, he has a history of type 2 diabetes mellitus, hypertension, gastroesophageal reflux disease, and chronic abdominal pain.

Physical Examination

Vital signs: T 36.6º C, HR 98, BP129/69, RR 20 and SPO2 96% on 2 L of oxygen by nasal cannula. He was mildly distressed and coughing. His pulmonary exam showed diffuse inspiratory and expiratory wheezes. The remainder of his exam was unremarkable.

Laboratory

Significant findings on laboratory evaluation include an elevated white blood cell count of 13,400 cells/ɥL, an elevated absolute eosinophil count of 2,820 eosinophils/ɥL, an elevated glucose of 131 mg/dL, and a low sodium of 120 mEq/L.

Imaging

A thoracic CT scan was performed (Figure 1).

Figure 1. Representative images in lung windows from thoracic CT scan.

Which of the following best describes the CT scan? (click on the correct answer to proceed to the next panel)

1. Cavitary changes in both apices
2. Central consolidation
3. Fibrotic changes at the bases
4. Peripheral opacities
5. Normal

Reference as: Palel SI, Wesselius LJ, Vasczar LT. November 2014 pulmonary case of the month: BAL eosinophilia. Southwest J Pulm Crit Care. 2014;9(5):251-6. doi: http://dx.doi.org/10.13175/swjpcc136-14 PDF

How Does Genetics Influence Valley Fever? Research Underway Now To Answer This Question

John N. Galgiani, MD

Valley Fever Center for Excellence

The University of Arizona Colleges of Medicine

Tucson and Phoenix, Arizona

Introduction

Of the roughly 150,000 new infections of coccidioidomycosis (Valley Fever) that occur each year, there is an enormous range of severity and outcomes. As depicted in Figure 1, approximately a third seek medical attention because of a significant illness and even fewer of these are accurately diagnosed and reported to state officials (1).

Figure 1. Severity and outcomes of coccidioidomycosis (Valley Fever).

The community-acquired pneumonia syndrome that most symptomatic patients experience often takes many weeks to many months to completely resolve and is anything but trivial (2). Even so, for most patients, the illness is eventually self-limited whether treated or not.

In contrast, a relatively small proportion of all infections result in the spread through the blood stream beyond the lungs (extrathoracic dissemination) to produce progressive tissue destruction in skin, bones, joints, the central nervous system, and almost any other part of the body. As a result, about 160 persons die of Valley Fever each year (3).  What accounts for this striking spectrum of disease has been the subject of speculation for decades. Now two research programs have been initiated to try to answer this question.

Genetic Differences Among Persons Is The Prime Suspect

For many infectious diseases, the size of the microbial inoculum determines whether disease will result. Indeed, there are very good examples of this when the exposure to coccidioidal spores is very high. For example, when archeologists or construction projects involve soil rich in spores of Coccidioides spp., infection rates are higher and symptomatic illness is more common than found in the general population within endemic regions (4-6).  However, in such clusters, there is little or no evidence that high inoculum is more likely to result in extrathoracic dissemination.

Another possible source of differences in disease severity could be due to differences among strains of Coccidioides spp. While this cannot be entirely ruled out, the evidence that exists is not supportive. For example, in the clusters of infections cited above where likely most infections came from genetically similar spores, there is still a wide spectrum of illness. Similarly, in laboratory accidents where all persons are definitely exposed to the same strain, there are also diverse clinical manifestations (7).

In contrast to inoculum and fungal virulence, several lines of evidence implicate genetic differences among individuals as a factor responsible for disseminated infection. First and most apparent, normal control of coccidioidal infection is critically dependent on competent cellular immunity. When this is severely compromised either by an underlying disease such as AIDS (8, 9) or by immunosuppression for organ transplantation or treatment of autoimmune disorders (10-12), coccidioidal infections are very much more likely to result in extrathoracic dissemination. That broad immunosuppression is a major risk factor for disseminated Valley Fever opens up the possibility that more subtle differences in the immune response to coccidioidal infection could account for differences in disease severity. 

Secondly, men are much more likely to develop disseminated coccidioidal infection than women. Evidence for this comes from the enrollment statistics for clinical trials conducted by the Mycoses Study Group for patients with disseminated coccidioidal infection where between 1988 and 2007 three-quarters of 367 subjects were male (13-17).  Similar results are apparent in other reports as well (18-20). 

Thirdly, at least one specific genetic marker, that of B and AB blood groups, has been associated with disseminated infection (19, 21). This is not likely to be a causal relationship but does clearly suggest a genetic component.

Finally, numerous studies have implicated increased risk of certain ethnic groups for disseminated infection, most notably those of African and Filipino ancestry (22). Estimates of how much more susceptible African-Americans are to developing disseminated disease range as high as 41.9 times more than Caucasians (Table 1).

An Arizona Department of Health Services presentation in 2011 based upon chart review of reported cases found dissemination in Blacks was 25% compared to 6% in Whites, roughly a four-fold increase in incidence of dissemination. The denominator for these statistics was all cases reported to the state and therefore avoid referral bias and some other confounding factors in earlier studies.

Despite all of these associations suggesting a genetic component to a risk for disseminated infection, there have been essentially no observations as to which specific genes are involved and how genetic differences affect disease susceptibility. Dr. Stephen Holland, a physician scientist and his colleagues at the National Institutes for Health have recently identified in a small number of patients specific gene mutations which appear responsible for more severe infections. The mutated genes were the interferon-gamma receptor 1 (28), the interleukin-12 receptor beta (29), and STAT1 (30). 

As important as these findings are, all of the patients described in these reports are not typical of most patients who experience disseminated coccidioidomycosis. The patient with the interferon-gamma receptor 1 deficiency had two other opportunistic mycobacterial infections at other times in his life, and multiple opportunistic infections are not typical for patients with disseminated Valley Fever. The patients with the interleukin-12 beta deficiency were siblings from a consanguineous family. Disseminated coccidioidomycosis is very uncommon in multiple members of the same family. The two patients with the STAT1 mutation had a clinical presentation that included disseminated infection but also included a consumptive pulmonary process that was strikingly devoid of cavitation. However, Dr. Holland has identified additional patients who appear to have functional immunologic deficits, even thought he and his team were unable to determine the genetic basis for those altered responses (31). 

Two Studies Now Underway Involving Arizonans To Better Understand The Genetics Of Disseminated Valley Fever

Encouraged by his recent findings, Dr. Holland has written a clinical research protocol specifically addressing patients with disseminated coccidioidomycosis. The program, entitled “The Pathogenesis and Genetics of Disseminated Coccidioidomycosis,” is open to any person over the age of 2 years who has culture or histologic proof of disseminated Valley Fever. Persons who have an already identified immunosuppressing condition or who have a medical or psychiatric condition that would interfere with providing informed consent would not be appropriate for this study. If informed consent is given, subjects will initially have blood specimens collected locally for shipment to the NIH. Then, depending upon initial results, subjects may be invited to visit the NIH for additional testing. After the initial visit, study related expenses, including travel and treatment of the disseminated Valley Fever infection, will be paid by the NIH (initial travel expenses may be covered for indigent subjects). Dr. Holland’s study is open to patients throughout the United States. However, for those close enough to down town Phoenix, it will be possible to have the initial blood and urine specimens obtained and shipment arranged by the NIH laboratory located on the Indian Health Hospital campus.  This protocol was initiated in the fall of 2014 and is currently active.

A second research initiative is investigating the increased susceptibility of those with African ancestry. Despite the findings shown in Table 1 above, an underlying problem with all estimates of increased frequency of disseminated coccidioidomycosis in African-Americans is that the relation of self-identified race/ethnicity (SIRE) is a poor surrogate for ancestral genetic origins. Genetic heterogeneity within each racial and ethnic grouping may bias associations in genetic association studies, generating both false-positive and false-negative results (32-36). Variations in the distribution of single nucleotides polymorphisms (SNPs), called ancestry informative markers (AIMs), have been found which describe the architecture of genome variations between populations (37). This discovery has led to an approach which circumvents the genetic ambiguity of SIRE categorizations.  One of the benefits of AIMs is that relatively few markers are required (about 1,500 AIMs for African-Americans) to effectively screen the entire genome. As such, we expect it to identify large chromosomal regions of differential ethnic ancestry in clinical samples. 

For this second study, anyone who is self-declared of African ancestry who has laboratory confirmed coccidioidal infection is eligible. For those who have not experienced disseminated infection, an adequate length of time off antifungal therapy is necessary (nominally two years (38)) to determine if disseminated infection is not likely to occur. Consenting subjects will be asked for a sample of saliva for genetic testing. They may also be asked for a blood specimen in the future for laboratory studies of their leukocyte response to coccidioidal antigens. Collaborators for this study are in both Phoenix and in Tucson.

Any Arizona clinician interested in referring a patient for potential inclusion in either study can contact the Valley Fever Center for Excellence at the Arizona Health Sciences Center in Tucson or the Valley Fever Center in Phoenix located at St. Joseph’s Hospital and Medical Center at their respective phone or FAX contact numbers:

Summary

After decades of interest and speculation about what possible genetic influences are involved in determining the severity of Valley Fever infections, there are now two separate studies underway to address this question, each taking a different and complementary approach. At the very least, such information would be valuable for risk stratification, either for persons wanting that information before travelling to the coccidioidal endemic area or early in the course of a new coccidioidal infection. However, depending upon the success of this research, understanding the genetics could possibly suggest new therapeutic options. Most helped by this work will be Arizonans where two-thirds of all Valley Fever infections in the United States occur.

References

1. CDC. Increase in reported coccidioidomycosis - United States, 1998-2011. MMWR Morb Mortal Wkly Rep. 2013;62:217-21. [PubMed]
2. Tsang CA, Anderson SM, Imholte SB, Erhart LM, Chen S, Park BJ, et al. Enhanced surveillance of coccidioidomycosis, Arizona, USA, 2007-2008. Emerg Infect Dis. 2010;16(11):1738-44. [CrossRef] [PubMed]
3. Huang JY, Bristow B, Shafir S, Sorvillo F. Coccidioidomycosis-associated Deaths, United States, 1990-2008. Emerg Infect Dis. 2012;18(11):1723-8. [CrossRef] [PubMed]
4. Werner SB, Pappagianis D, Heindl I, Mickel A. An epidemic of coccidioidomycosis among archeology students in northern California. N Engl J Med. 1972;286:507-12. [CrossRef] [PubMed]
5. Coccidioidomycosis in travelers returning from Mexico--Pennsylvania, 2000. MMWR Morb Mortal Wkly Rep. 2000;49(44):1004-6. [PubMed]
6. Cairns L, Blythe D, Kao A, Pappagianis D, Kaufman L, Kobayashi J, et al. Outbreak of coccidioidomycosis in Washington State residents returning from Mexico. Clinical Infectious Diseases. 2000;30(1):61-4. [CrossRef] [PubMed]
7. Stevens DA, Clemons KV, Levine HB, Pappagianis D, Baron EJ, Hamilton JR, et al. Expert opinion: what to do when there is Coccidioides exposure in a laboratory. Clin Infect Dis. 2009;49(6):919-23. [CrossRef] [PubMed]
8. Fish DG, Ampel NM, Galgiani JN, Dols CL, Kelly PC, Johnson CH, et al. Coccidioidomycosis during human immunodeficiency virus infection. A review of 77 patients. Medicine (Baltimore). 1990;69:384-91. [CrossRef] [PubMed]
9. Singh VR, Smith DK, Lawerence J, Kelly PC, Thomas AR, Spitz B, et al. Coccidioidomycosis in patients infected with human immunodeficiency virus: Review of 91 cases at a single institution. Clin Infect Dis. 1996;23(3):563-8. [CrossRef] [PubMed]
10. Taroumian S, Knowles SL, Lisse JR, Yanes J, Ampel NM, Vaz A, et al. Management of coccidioidomycosis in patients receiving biologic response modifiers or disease-modifying antirheumatic drugs. Arthritis Care Res (Hoboken). 2012;64(12):1903-9. [CrossRef] [PubMed]
11. Vucicevic D, Carey EJ, Blair JE. Coccidioidomycosis in liver transplant recipients in an endemic area. Am J Transplant. 2011;11(1):111-9. [CrossRef] [PubMed]
12. Vikram HR, Blair JE. Coccidioidomycosis in transplant recipients: a primer for clinicians in nonendemic areas. Curr Opin Organ Transplant. 2009;14(6):606-12. [CrossRef] [PubMed]
13. Galgiani JN, Stevens DA, Graybill JR, Dismukes WE, Cloud GA. Ketoconazole therapy of progressive coccidioidomycosis. Comparison of 400- and 800-mg doses and observations at higher doses. Am J Med. 1988;84(3 Pt 2):603-10. [CrossRef] [PubMed]
14. Graybill JR, Stevens DA, Galgiani JN, Dismukes WE, Cloud GA, NAIAD Mycoses Study Group. Itraconazole treatment of coccidioidomycosis. Am J Med. 1990;89:282-90. [CrossRef] [PubMed]
15. Galgiani JN, Catanzaro A, Cloud GA, Higgs J, Friedman BA, Larsen RA, et al. Fluconazole therapy for coccidioidal meningitis. The NIAID-Mycoses Study Group. Ann Intern Med. 1993;119(1):28-35. [CrossRef] [PubMed]
16. Galgiani JN, Catanzaro A, Cloud GA, Johnson RH, Williams PL, Mirels LF, et al. Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group. Ann Intern Med. 2000;133(9):676-86. [CrossRef] [PubMed]
17. Catanzaro A, Cloud GA, Stevens DA, Levine BE, Williams PL, Johnson RH, et al. Safety, tolerance, and efficacy of posaconazole therapy in patients with nonmeningeal disseminated or chronic pulmonary coccidioidomycosis. Clin Infect Dis. 2007;45(5):562-8. [CrossRef] [PubMed]
18. Foley CGT, C.A.;Christ,C.;Anderson,S.M. Impact of disseminated coccidioidomycosis in Arizona, 2007-2008. Proceedings of the 55th Annual Coccidioidomycosis Study Group. University of California at Davis, Davis California: Coccidioidomycosis Study Group; 2011:8.
19. Cohen IM, Galgiani JN, Potter D, Ogden DA. Coccidioidomycosis in renal replacement therapy. Arch Intern Med. 1982;142:489-94. [CrossRef] [PubMed]
20. Flynn NM, Hoeprich PD, Kawachi MM, Lee KK, Lawrence RM, Goldstein E, et al. An unusual outbreak of windborne coccidioidomycosis. N Engl J Med. 1979;301(7):358-61. [CrossRef] [PubMed]
21. Deresinski SC, Pappagianis D, Stevens DA. Association of ABO blood group and outcome of coccidioidal infection. Sabouraudia. 1979;17:261-4. [CrossRef] [PubMed]
22. Pappagianis D, Lindsay S, Beall S, Williams P. Ethnic background and the clinical course of coccidioidomycosis [letter]. Am Rev Respir Dis. 1979;120:959-61. [PubMed]
23. Smith CE, Beard RR, Whiting EG, Rosenberger HG. Varieties of coccidioidal infection in relation to the epidemiology and control of the disease. Am J Public Health. 1946;36:1394-402. [CrossRef] [PubMed]
24. Pappagianis D. Epidemiology of coccidioidomycosis. Curr Top Med Mycol. 1988;2:199-238. [CrossRef] [PubMed]
25. Rosenstein NE, Emery KW, Werner SB, Kao A, Johnson R, Rogers D, et al. Risk factors for severe pulmonary and disseminated coccidioidomycosis: Kern County, California, 1995-1996. Clin Infect Dis. 2001;32(5):708-15. [CrossRef] [PubMed]
26. Crum NF, Lederman ER, Stafford CM, Parrish JS, Wallace MR. Coccidioidomycosis: A Descriptive Survey of a Reemerging Disease. Clinical Characteristics and Current Controversies. Medicine (Baltimore). 2004;83(3):149-75. [CrossRef] [PubMed]
27. Drake KW, Adam RD. Coccidioidal meningitis and brain abscesses: analysis of 71 cases at a referral center. Neurology. 2009;73(21):1780-6. [CrossRef] [PubMed]
28. Vinh DC, Masannat F, Dzioba RB, Galgiani JN, Holland SM. Refractory disseminated coccidioidomycosis and mycobacteriosis in interferon-gamma receptor 1 deficiency. Clin Infect Dis. 2009;49(6):e62-5. [CrossRef] [PubMed]
29. Vinh DC. Coccidioidal meningitis: disseminated disease in patients without HIV/AIDS. Medicine (Baltimore). 2011;90(1):87. [CrossRef] [PubMed]
30. Sampaio EP, Hsu AP, Pechacek J, Bax HI, Dias DL, Paulson ML, et al. Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol. 2013;131(6):1624-34. [CrossRef] [PubMed]
31. Duplessis CA, Tilley D, Bavaro M, Hale B, Holland SM. Two cases illustrating successful adjunctive interferon-gamma immunotherapy in refractory disseminated coccidioidomycosis. J Infect. 2011;63(3):223-8. [CrossRef] [PubMed]
32. Bonilla C, Boxill LA, Donald SA, Williams T, Sylvester N, Parra EJ, et al. The 8818G allele of the agouti signaling protein (ASIP) gene is ancestral and is associated with darker skin color in African Americans. Hum Genet. 2005;116(5):402-6. [CrossRef] [PubMed]
33. Caulfield T, Fullerton SM, Ali-Khan SE, Arbour L, Burchard EG, Cooper RS, et al. Race and ancestry in biomedical research: exploring the challenges. Genome Med. 2009;1(1):8. [CrossRef] [PubMed]
34. Choudhry S, Coyle NE, Tang H, Salari K, Lind D, Clark SL, et al. Population stratification confounds genetic association studies among Latinos. Hum Genet. 2006;118(5):652-64. [CrossRef] [PubMed]
35. Shriver MD, Parra EJ, Dios S, Bonilla C, Norton H, Jovel C, et al. Skin pigmentation, biogeographical ancestry and admixture mapping. Human Genet. 2003;112(4):387-99. [PubMed]
36. Tsai HJ, Choudhry S, Naqvi M, Rodriguez-Cintron W, Burchard EG, Ziv E. Comparison of three methods to estimate genetic ancestry and control for stratification in genetic association studies among admixed populations. Hum Genet. 2005;118(3-4):424-33. [CrossRef] [PubMed]
37. Kittles RA, Weiss KM. Race, ancestry, and genes: implications for defining disease risk. Annu Rev Genomics Hum Genet. 2003;4:33-67. [Pubmed]
38. Ampel NM, Giblin A, Mourani JP, Galgiani JN. Factors and outcomes associated with the decision to treat primary pulmonary coccidioidomycosis. Clin Infect Dis. 2009;48(2):172-8. [CrossRef]

Reference as: Galgiani JN. How does genetics influence valley fever? research underway now to answer this question. Southwest J Pulm Crit Care. 2014;9(4):230-7. doi: http://dx.doi.org/10.13175/swjpcc137-14 PDF

October 2014 Pulmonary Case of the Month: A Big Clot

G. Zacharia Reagle DO

Eyad Almasri MD

Stuart J. Maxwell MD

Departments of Internal Medicine, Division of

Pulmonary and Critical Care

and Emergency Medicine

UCSF Fresno

Fresno, CA

History of Present Illness:

A 63 year-old man was brought to the emergency department (ED) with a report of acute onset of dyspnea. The dyspnea had started at rest less than one hour prior to ED presentation. It quickly progressed to severe respiratory distress. His initial vital signs were recorded as a BP of 124/69, pulse of 112, respiratory rate of 26 with an oxygen saturation (SpO₂) of 88% on 15 liters per minute (lpm) of oxygen via a non-rebreather mask. He was placed on non-invasive ventilation with intermittent episodes of brief desaturation into the 60% range. He was subsequently intubated without incident. Immediately following intubation he experienced a pulseless electrical activity (PEA) cardiopulmonary arrest.

Past Medical History:

• Diabetes mellitus
• Coronary Artery Disease
• Hypertension
• Deep Venous Thrombosis

Past Surgical History:

• Coronary Artery Bypass Graft – 2 vessel

Medications:

• Atorvastatin 40mg PO daily
• Insulin glargine 10u SQ daily
• Lisinopril 10mg PO daily
• Warfarin – had been stopped due to difficulty with compliance.

Social History:

• Married
• Owns and manages a series of used car lots.
• Lifetime non-smoker
• Reports a remote history of chronic alcohol use, but quit in 2005 when he was diagnosed with coronary artery disease.
• He denied illicit drug use.

Physical Exam:

General: Intubated, on a fentanyl infusion at 50mcg per hour.

Vitals: BP: 122/63 HR: 123 RR: 24 T: 35.6

HEENT: NC/AT, PERRL, neck supple without JVD noted.

Lungs: equal chest expansion was noted with clear lung sounds.

Heart: Tachycardic and regular with a good S1 and S2, no murmurs or             gallops were appreciated.

Abdomen: soft, obese, good bowel sounds.

Extremities: cold to the touch with no edema, or clubbing.

Neurological: Nonfocal exam with suppressed Glasgow Coma Scale after       sedation for intubation.

Skin: No rashes noted.

Laboratory:

Complete Blood Count (CBC): White blood cell count (WBC) 8.8 x 1000 cells/µL, hemoglobin 14.6 g/dL,   hematocrit 43.7, platelets 191,000 cells/µL

Chemistry: Sodium 139 meq/L, potassium 3.6 meq/L, chloride 106 meq/L, bicarbonate (CO2) 19 meq/L, blood urea nitrogen (BUN) 20 mg/dL, creatinine 0.7 mg/dL, glucose 459 mg/dL, magnesium 2.0 meq/L, phosphorus 3.4 mg/dL

Liver Function Tests: Albumin 4.1 g/dL, ALP 59 U/L, AST 30 U/L ALT 31 U/L. total bilirubin 0.4 mg/dL

Coagulation: Prothrombin time 13.9 seconds, INR 1.1, activated partial thromboplastin time (aPTT) 24.2 seconds

Troponin: 0.007 ng/ml

Brain naturetic peptide (BNP): 39 pg/ml

Arterial Blood Gases (ABG): pH 7.27, pCO2 38, pO2 38

Imaging:

The patient was immediately taken for a chest CT pulmonary angiogram. As he was on the CT scan table, the CT technician discovered that his IV line was malfunctioning. Before the line could be replaced, he had several non-contrast chest CT cuts obtained (Figure 1).  

Figure 1. Images A & C are non-contrast cuts while images B & D are comparison cuts that became available after the contrast study was obtained.

How often are intravascular filling defects seen on non-contrast chest CT images and what is the positive predictive value (PPV) of non-contrast images for pulmonary embolism (PE)? (Click on the correct answer to proceed to the next panel)

1. Filling defects are often seen on non-contrast CT images and are diagnostic for pulmonary embolism.
2. Filling defects can be seen on non-contrast images but have a low PPV.
3. Filling defects indicating pulmonary embolism are never seen on non-contrast images.
4. Filling defects indicating pulmonary embolism are sometimes seen on non-contrast images and have a high PPV for PE.

Reference as: Reagle GZ, Almasri E, Maxwell SJ. October 2014 pulmonary case of the month: a big clot. Southwest J Pulm Crit Care. 2014;9(4):199-207. doi: http://dx.doi.org/10.13175/swjpcc118-14 PDF

September 2014 Pulmonary Case of the Month: A Case for Biblical Scholars

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 66-year-old man was seen in consultation. He had been followed since 1998 for bronchiectasis. He had a prior history of multiple skin infections with abscess formation requiring drainage beginning when he was in his 20's. He presented with increased recent sputum production, greenish in color.

PMH, FH, SH

He had a history of multiple skin infections, multiple pneumonias and osteomyelitis in addition to the bronchiectasis. There was a positive family history of coronary artery disease and childhood cancer in a sister. He had smoked cigars in the remote past, but none since the age of 25.

Physical Examination

•       General: short stature, scoliosis, SpO2 98% on RA.
•       Chest: few scattered crackles, no wheezes.
•       Cardiovascular: regular rate and rhythm with no murmur noted.
•       Extremities: No clubbing, cyanosis or edema.

Spirometry

      FVC 69% of predicted; FEV1 76% of predicted.

Which of the following should be performed at this time? (Click on the correct answer to proceed to the next panel)

1. Immunocompromised evaluation
2. Sputum culture
3. Thoracic CT scan
4. 1 and 3
5. All of the above

Reference as: Wesselius LJ. September 2014 pulmonary case of the month: a case for biblical scholars. Southwest J Pulm Crit Care. 2014;9(3):146-50. doi: http://dx.doi.org/10.13175/swjpcc108-14 PDF

Role of Endobronchial Ultrasound in the Diagnosis and Management of Bronchogenic Cysts: Two Case Descriptions and Literature Review

Rene Franco-Elizondo MD

Soumya Patnaik MD

Kuan-Hsiang Gary Huang MD, PhD

Jorge Mora MD

Albert Einstein Medical Center

Philadelphia, Pennsylvania

Abstract

Imaging studies, such as high resolution computerized tomography (HRCT) and magnetic resonance imaging (MRI) facilitate the evaluation of mediastinal masses. However, the definite characterization of such masses can be ascertained only after tissue sampling is obtained and analyzed. Some mediastinal masses, like bronchogenic cysts, can be misdiagnosed as solid masses or lymphadenopathy in imaging studies, due to the variable densities of the cyst contents. More invasive tests, like fine needle aspiration or surgical resection of the bronchogenic cyst, may be necessary when HRCT fails to provide an initial diagnosis. We describe two such cases seen at our institution that highlight the implications of establishing a diagnosis of bronchogenic cyst with endobronchial ultrasound (EBUS) - trans-bronchial needle aspiration (TBNA) and discuss the possible therapeutic utility of EBUS-TBNA in select patients with bronchogenic cysts.

Abbreviation List

BAL - Bronchoalveolar lavage

CNS - Coagulase-negative Staphylococcus

CT – Computed tomography

EBUS - Endobronchial ultrasound

EUS – Endoscopic ultrasound

FOB - Fiberoptic bronchoscopy

HRCT - High resolution computerized tomography

MRI - Magnetic resonance imaging

RUL – Right upper lobe

TBNA - Trans-bronchial needle aspiration

VATS - Video-assisted thoracoscopic surgery

Introduction

Modern imaging, particularly high-resolution computed tomography (HRCT) and magnetic resonance imaging facilitate the evaluation of mediastinal masses. However, definite characterization is possible only after tissue sampling is obtained, typically through fine-needle aspiration or surgical resection. Herein, we report two cases of patients with mediastinal masses, where HRCT failed to provide a diagnosis. Bronchogenic cysts in both patients were ultimately diagnosed by endobronchial ultrasound (EBUS) and trans-bronchial needle aspiration (TBNA). The implications of establishing a diagnosis of bronchogenic cyst via EBUS-TBNA and therapeutic approaches are discussed.

Case 1

A 68-year-old African American woman with hypertension, diabetes mellitus type 2 and end-stage renal disease, on home hemodialysis, presented to the hospital with central stabbing chest pain, radiating to the back, accompanied by shortness of breath. An initial HRCT chest performed to rule out aortic dissection revealed a large subcarinal mass, measuring 2.3 cm x 6.5 cm x 3.8 cm (AP x transverse x height), that splayed the carina, exerting mass effect on the esophagus, raising suspicion of malignancy (Figure 1).

Figure 1. Subcarinal mass. Density ranged from 25-80 Hounsfield Units.

A separate 2.2 cm x 1.7 cm right paratracheal mass, mediastinal lymphadenopathy and many small prevascular lymph nodes were noted. These clinical and imaging findings were concerning for possible lymphoma.

A fiberoptic bronchoscopy (FOB), followed by blind TBNA of the subcarinal space using a Wang needle was attempted. Both, bronchoalveolar lavage (BAL) and TBNA were unrevealing. The patient was found to have persistent coagulase-negative Staphylococcus (CNS) bacteremia, with the first blood cultures being positive at the time of admission. A thorough evaluation, which included an echocardiogram and abdominal HRCT, failed to reveal a source of bacteremia, which was ultimately thought to be related to hemodialysis. Arrangements for outpatient EBUS evaluation of the mediastinal mass and lymphadenopathy were made and the patient was discharged.

A week later, she was readmitted for hypertensive emergency. EBUS was performed during this hospitalization and a cystic mass with heterogeneous-containing material was detected in the subcarinal space (Figure 2).

Figure 2 EBUS image of bronchogenic cyst and adjacent subcarinal lymph node.

The needle aspirate was sent for histological analysis and culture, but it was not possible to drain this cystic structure. Cytopathologic analysis showed bronchial and ciliated cells with abundant mucoid material and a diagnosis of bronchogenic cyst was made. Interestingly, the cultures from the aspirated material grew CNS. The patient was discharged with plans for a video-assisted thoracoscopic surgery (VATS) resection of the bronchogenic cyst as an outpatient.

Five days later, the patient was readmitted with symptoms that were concerning for sepsis, and was thus re-started on broad-spectrum antibiotics. She was found to have Enterobacter intermedius bacteremia. She subsequently underwent VATS, with direct aspiration of the bronchogenic cyst. A resection was not performed due to technical difficulties encountered during VATS. Purulent fluid was retrieved from the cyst and Enterobacter intermedius was identified upon analysis and culture of the cyst content. The patient had no further episodes of bacteremia after eight months of follow-up.

Case 2

A 43-year-old woman without significant past medical history was referred to our institute, for evaluation of a pretracheal lymph node seen on a chest HRCT (Figure 3) done for evaluation of new onset dyspnea and wheezing. Upon auscultation, a localized wheeze was noted with deep inspiration in the right upper chest. Her physical exam was otherwise unremarkable.

Figure 3. Chest CT showing subcarinal lymphadenopathy and mass. Density of mass 9-95 Hounsfield units.

A bronchoscopic exam with EBUS evaluation of lymphadenopathy was scheduled. On FOB, the patient was found to have an incidental endobronchial mass occluding the anterior segment of the right upper lobe. EBUS exam revealed an enlarged subcarinal lymph node (8 mm) with an adjacent cystic space containing homogenous hypoechoic material (Figure 4).

Figure 4. EBUS of bronchogenic cyst. A) Cyst prior to aspiration. B) Collapsed cystic cavity with enlarged lymph node now visible.

Both the lymph node and cystic space were sampled. Ten mL of serous fluid was aspirated from the cystic space, resulting in obliteration of the cavity, as visualized on the ultrasound (Figure 5).

Figure 5.Serous aspirate from cystic cavity.

Full mediastinal staging was done, and only station 11R lymph nodes were found to be enlarged and were sampled. Endobronchial biopsies, brushings and BAL were obtained from RUL endobronchial lesion. The patient was discharged home on empiric antibiotics (amoxicillin/clavulanate) for aspirated bronchogenic cyst. Subsequent fluid analysis revealed abundant macrophages and lymphocytes, consistent with cystic fluid content. Cultures of the fluid were positive for Streptococcus viridians. Lymph node sampling failed to reveal any evidence of malignancy. Interestingly, endobronchial mass biopsies, brushings and fluid cytology also failed to show evidence of malignancy. Only reactive inflammatory cells and benign bronchial elements were detected. The patient was continued on antibiotics for ten days without any evidence of infection.

A repeat bronchoscopy was performed to re-sample the endobronchial lesion. Benign elements were confirmed on the repeat biopsy. Follow up imaging has not been performed to evaluate fluid re-accumulation, since the patient has remained asymptomatic for two months.

Discussion

Mediastinal bronchogenic cysts are congenital anomalies of tracheobronchial origin; they are believed to be a result of an abnormal budding process during the development of foregut. They are often asymptomatic at presentation but can become symptomatic in 30% to 80% of cases due to infection or other complications like compressive efforts (1).

These cysts, being lined by secretary respiratory epithelium, consist of fluid of water density; however, the amount of proteinous mucus and calcium oxalate crystals in them can vary, affecting the imaging features on CT/MRI. A chest CT may reveal spherical masses with water or soft–tissue attenuation. A chest CT may misdiagnose them as soft-tissue masses in about 43% of patients. High attenuation on a chest CT can be a result of calcium oxalate or protein content, or can be due to infection of the cyst content (2, 3).

Due to the variable density in the cyst’s content, bronchogenic cysts can be misdiagnosed as masses or lymphadenopathy on non-invasive testing, as noted in our patients. EBUS can be of great help in diagnosing these lesions. Ultrasound provides an excellent delineation between tissues of different densities, and the absence of flow with color Doppler allows for differentiation from vascular structures. Ultrasonography allows a better delineation of cystic lesions and characterization of their contents (e.g. hypoechoic, isoechoic, heterogeneous, etc.), thereby providing useful diagnostic information. Needle aspiration of cyst contents can bring about not only cytological confirmation of the diagnosis, but also identification of complications such as infected bronchogenic cysts.

Our cases highlight the usefulness of EBUS in the diagnosis of bronchogenic cysts. In the first case, the diagnosis of bronchogenic cyst was made only after EBUS imaging and content aspiration were obtained, despite the initial chest HRCT specifically done to evaluate this mass. In the second case, EBUS imaging established the diagnosis in the absence of any suggestive findings on the HRCT.

The treatment of choice remains the complete surgical resection of the secreting mucosal lining, particularly in complicated cysts (11, 12). However, some authors have reported cases of successful treatment of bronchogenic cysts with EBUS-guided aspiration (4-8). In one case, a patient was followed up for eighteen months without evidence of recurrence (8). The rationale behind this approach is that complete drainage of the cyst obliterates the cyst cavity and prevents further fluid re-accumulation. In our first case, though complete drainage was not achieved with EBUS due to its thick mucoid content, aspiration of the cyst by VATS resulted in resolution without fluid re-accumulation. In our second case, resolution of the cyst was achieved via EBUS-TBNA drainage. These cases underscore the usefulness of aspiration of bronchogenic cysts as an alternative therapeutic approach to surgery in certain scenarios.

Contrary to the above mentioned cases, other case reports have pointed out life-threatening complications after bronchogenic cyst drainage with EBUS-guided FNA, such as pneumonia (9) or purulent pericardial effusion (10). As mentioned elsewhere, empiric antibiotic therapy should be given when a cystic lesion is drained via EBUS-TBNA (13). It should be noted, however, that in some of these case reports, infection post-EBUS-TBNA occurred despite giving empiric antibiotics (9), as in our first case.

The risk of infection should be underscored, as evidenced by the first case; particularly the less frequently reported possibility of bronchogenic cyst infection from bacteremia. The initial EBUS-TBNA cyst aspirate grew CNS, similarly to the blood cultures that were obtained prior to the blind TBNA sample of the mediastinal lesion. This suggests that the contamination of the cyst content could have been due to seeding from CNS bacteremia. However, the final VATS aspirate of the cyst grew Enterecoccus intermedius, which was likely to have been introduced by the EBUS-TBNA at the time of diagnosis. This infection occurred despite the use of antibiotics before and after the procedure. In this regard, the available literature is scant. In a study conducted by Steinfort et al. (14), incidence of bacteremia after EBUS-TBNA was found to be 7%, comparable to reported incidence of bacteremia from regular FOB. It is important to note that although none of these patients experienced clinical signs of infection, none of the biopsies were taken from cystic structures. Data evaluating EBUS-TBNA of mediastinal cystic lesions is conflicting. In a report of 22 patients undergoing EUS-TBNA of suspected mediastinal cyst and receiving periprocedural antibiotics, no infectious complications were found (15). However, several case reports of serious infectious complications after EBUS-TBNA have also been published (16).

Conclusion

Diagnosis of bronchogenic cysts cannot always be made with commonly used chest-imaging modalities such as X-ray or CT. EBUS has proven to be a useful diagnostic tool in the evaluation of some mediastinal masses. Although surgical resection remains the treatment of choice, complete aspiration, by VATS or EBUS, can be a successful therapeutic alternative in patients who are not candidates for surgery. However, the risks should be carefully assessed in each patient, with particular awareness of potential infectious complications. When this approach is taken, empiric antibiotics are recommended.

References

1. St-Georges R, Deslauriers J, Duranceau A, Vaillancourt R, Deschamps C, Beauchamp G, Pagé A, Brisson J. Clinical spectrum of bronchogenic cysts of mediastinum and lung in adult. Ann Thorac Surg. 1991;52:6-13. [CrossRef] [PubMed]
2. Mc Adams HP, Kirejczyk WM, Rosado-de-Christenson ML, Matsumoto S. Bronchogenic cyst: imaging features with clinical and histopathological correlation. Radiology. 2000;217:441-6. [CrossRef] [PubMed] 
3. Patel SR, Meeker DP, Biscotti CV, Kirby TJ, Rice TW. Presentation and management of bronchogenic cysts in adult. Chest 1994;106:79-85. [CrossRef] [PubMed] 
4. Aragaki-Nakahodo AA, Guitron-Roig J, Eschenbacher W, Benzaquen S, Cudzilo C. Endobronchial ultrasound-guided needle aspiration of a bronchogenic cyst to liberate from mechanical ventilation: case report and literature review. J Bronchology Interv Pulmonol. 2013;20(2):152-4. [CrossRef] [PubMed]
5. Meseguer SM, Franco-Serrano J. Drainage of a mediastinal cyst by endobronchial ultrasound-guided needle aspiration. Arch Bronconeumol. 2010;46(4):207-8. [CrossRef]  [PubMed]
6. Dhand S and Krimsky W. Bronchogenic cyst treated by endobronchial ultrasound drainage. Thorax. 2008;63(4):386. [CrossRef] [PubMed]
7. Galluccio G, Lucantoni G. Mediastinal bronchogenic cyst's recurrence treated with EBUS-FNA with a long-term follow-up. Eur J Cardiothoracic Surg. 2006; 29(4):627-9. [CrossRef] [PubMed]
8. Casal RF, Jimenez CA, Mehran RJ, Eapen GA, Ost D, Sarkiss M, Morice RC. Infected mediastinal bronchogenic cyst successfully treated by endobronchial ultrasound-guided fine-needle aspiration. Ann Thorac Surg. 2010; 90(4):e52-3. [CrossRef] [PubMed]
9. Hong G, Song J, Lee KJ, Jeon K, Koh WJ, Suh GY, Chung MP, Kim H, Kwon OJ, Um SW. Bronchogenic cyst rupture and pneumonia after endobronchial ultrasound-guided transbronchial needle aspiration: a case report. Tuberc Respir Dis (Seoul). 2013;74(4):177-80. [CrossRef] [PubMed] 
10. Gamrekeli A, Kalweit G, Schäfer H, Huwer H. Infection of a Bronchogenic cyst after ultrasonography-guided fine needle aspiration. Ann Thorac Surg. 2013;95(6):2154-5. [CrossRef] [PubMed]
11. Cioffi U, Bonavina L, De Simone M, Santambrogio L, Pavoni G, Testori A, Peracchia A. Presentation and surgical management of bronchogenic and esophageal duplication cysts in adults. Chest. 1998;113(6):1492-6. [CrossRef] [PubMed] 
12. Anantham D, Phua GC, Low SY, Koh MS. Role of endobronchial ultrasound in the diagnosis of bronchogenic cysts. Diagn Ther Endosc. 2011, 2011:468237. [CrossRef] [PubMed]
13. Haas AR. Infectious complications from full extension endobronchial ultrasound transbronchial needle aspiration. Eur Respir J. 2009;33(4):935-8. [CrossRef] [PubMed]
14. Steinfort DP, Johnson DF, Irving L.B. Incidence of bacteraemia following endobronchial ultrasound-guided transbronchial needle aspiration. Eur Respir J. 2010:36(1):28-32. [CrossRef] [PubMed] 
15. Fazel A, Moezardalan K, Varadarajulu S, Draganov P, Eloubeidi MA. The utility and the safety of EUS-guided FNA in the evaluation of duplication cysts.GastrointestEndosc. 2005; 62(4):575-80. [CrossRef] [PubMed]
16. Jenssen C, Alvarez-Sánchez M. V., Napoléon B and Faiss S. Diagnostic endoscopic ultrasonography: assessment of safety and prevention of complications. World J Gastroenterol. 2012;18(34):4659–76. [CrossRef] [PubMed]

Reference as: Franco-Elizondo R, Patnaik S, Huang K-H G, Mora J. Role of endobronchial ultrasound in the diagnosis and management of bronchogenic cysts: two case descriptions and literature review. Southwest J Pulm Crit Care. 2014;9(2):115-22. doi: http://dx.doi.org/10.13175/swjpcc096-14 PDF

Azathioprine Associated Acute Respiratory Distress Syndrome: Case Report and Literature Review

Dmitriy Scherbak, D.O.

Ruth Wyckoff, M.D.

Clement Singarajah, M.D.

Phoenix VA Healthcare System

Phoenix, AZ

Abstract

A 58-year-old Caucasian man treated with azathioprine to prevent rejection of an orthotopic liver transplant, presented to the Carl Hayden VA Medical Center with rapid respiratory decline and appeared septic. He required urgent intubation, mechanical ventilator support and empiric antibiotics. His clinical picture and imaging studies were consistent with acute respiratory distress syndrome; however, extensive infectious work up failed to reveal an offending organism. Review of his current medications implicated azathioprine and upon discontinuation of this agent, the patient made a rapid recovery. He was subsequently extubated, transferred out of the ICU and soon discharged home in good health.

Prescribed for organ transplant rejection and a wide array of autoimmune diseases, azathioprine has been rarely correlated with pneumonitis and rapid respiratory failure. No reported cases were found in which azathioprine was used to treat liver transplant rejection and associated with development of the adult respiratory distress syndrome (ARDS). However, there have been ARDS cases in which azathioprine was used for other purposes. We review all the available cases of azathioprine associated ARDS. The patients in these reports had similar clinical symptoms on presentation as our patient: hypoxia, febrile episodes and rapid development of ARDS with no infectious etiology. Most notable is the rapid resolution of ARDS after discontinuation of azathioprine.

Although azathioprine toxicity related respiratory failure is rare, this correlation should still be considered in the differential for immunosuppressed patients presenting with rapid pulmonary decline. Further studies are needed and warranted to better correlate this connection, but it is imperative to recognize that the relationship exists.

Introduction

Since its first use in 1961, azathioprine (a derivative of 6-mercaptopurine) has been used as a steroid sparing immunosuppressive agent in numerous disorders including prevention of graft rejection for solid organ transplantation (1-2). Azathioprine side effects are commonly gastrointestinal complaints such as nausea and vomiting, occurring in ~19% of patients. Laboratory abnormalities such as leukopenia are also common (17%) with thrombocytopenia and anemia being less common (3-4%) (3). Hepatotoxicity has been reported as well. Pulmonary toxicity is not usually noted as a side effect (1). Sixteen cases have been reported in the literature implicating azathioprine with pulmonary toxicity (1-2, 4-12). In 10 of these cases, the patient developed acute respiratory distress syndrome (ARDS) (1,2,6,8,9,11).

Pulmonary infections have been the leading cause of complications in immunosuppressed recipients of solid organs (13). Therefore, when a patient presents with respiratory distress, an abnormal chest x-ray and fevers, such infections are high on the differential, but the possibility of lung injury resulting from the immunosuppressive agent is often overlooked (1). We present a case of azathioprine induced ARDS in a liver transplant recipient and review the available ARDS cases associated with azathioprine use.

Case Report

We present a 58-year-old white man with a past medical history of end-stage liver disease due to hepatitis C cirrhosis and hepatocellular carcinoma who received an orthotopic liver transplant (OLT) 9 months prior to presentation. He was being treated with azathioprine 150mg daily and tacrolimus 1.5 mg daily to prevent rejection. He presented to the emergency department 9 months after his transplant with shortness of breath and increasing hypoxia. He was admitted to the intensive care unit where he developed respiratory failure that night requiring intubation and ventilator support. He had fevers as high as 105.1⁰F. He had pancytopenia with white blood cell count (WBC) 2.3 thousand cells at presentation, hemoglobin (HGB) 9.8 g/dL and platelets (PLT) 119 thousand cells.

Chest x-ray showed bilateral patchy pulmonary infiltrates. CT of the chest was done as well showing bilateral ground glass opacities and diffuse scattered pulmonary consolidations (Figure 1).

Figure 1. Representative images from chest CT with contrast done on admission showing diffuse ground glass opacities and scattered pulmonary consolidations.

Since he was immunosuppressed he was started on empiric antibiotic coverage with vancomycin, levofloxacin, pipercillin/tazobactam, gancyclovir and fluconazole. Trimethoprim-sulfamethoxazole was added on day 2 of hospitalization. A bronchoscopy with bronchial alveolar lavage (BAL) was done prior to antibiotics. Cell count and differential showed 160 white blood cells, 11% segmented neutrophils and 3% eosinophils, the other 86% of cells were pulmonary macrophages/monocytes and reactive respiratory epithelial cells. No organisms or evidence of malignancy were seen. BAL cultures showed no growth on bacterial, viral, acid fast or mycology cultures. Influenza A and B and a pneumocystis smear were also negative. Blood cultures were taken twice during the patient’s hospitalization during febrile episodes and showed no growth both times in two sets of cultures. On day 6 of hospitalization anti-microbial therapy was discontinued.

The patient’s clinical status continued to deteriorate. Chest x-rays continued to show increasing bilateral pulmonary infiltrates (Figure 2).

Figure 2. Chest x-ray at worst (hospital day 8) showing worsening bilateral pulmonary infiltrates.

The diagnosis of acute respiratory distress syndrome (ARDS) was established. His ventilator settings followed the NHLBI ARDS Network protocol, and on day 6 he was even placed in a prone position. On day 7 of hospitalization his white blood cell count dropped to a nadir of 0.5 thousand cells, hemoglobin dropped to 6.5 g/dL and platelets down to 69 thousand cells). Azathioprine was discontinued due to the pancytopenia and due to finding a few case reports in which it was implicated in ARDS. Within 3 days of azathioprine discontinuation (day 10 of hospitalization), the patient’s chest x-rays and pulmonary function had dramatically improved and he was successfully extubated by the fifth day of azathioprine being withdrawn (day 12 of hospitalization). Daily chest x-rays showed continued resolution of infiltrates (Figure 3).

Figure 3. Chest x-ray from hospital day 15 showing dramatic improvement of infiltrates after azathioprine discontinuation.

He improved rapidly and was discharged from the ICU on day 17 and discharged home from the hospital on day 18 with complete resolution of his pulmonary symptoms. His azathioprine was not restarted but he resumed tacrolimus for immunosuppression. Six months after admission, the patient was in good health with no clinical symptoms.

Discussion

Azathioprine is a nitroimidazole derivative of 6-mercaptopurine (4). It was first used in 1961 and has since become a common medication for treatment of numerous auto-immune disorders and as an immunosuppressant in transplant recipients (1). It has been described to have several reversible dose dependent side effects including bone marrow suppression, hepatotoxicity, anorexia, nausea and vomiting (4). Hypersensitivity reactions have also been described and include fevers, rigors, arthralgia, myalgia, cutaneous reactions, headaches, interstitial nephritis, pancreatitis, dyspnea, cough and pneumonitis (1-4, 6).

In our case the patient developed pneumonitis and ARDS which resolved rapidly after the discontinuation of azathioprine. A review of the literature using broad search terms in OVID, Pub-Med and Google Scholar revealed only 10 articles constituting 16 cases of pulmonary toxicity linked to azathioprine. Detailed analysis showed only 5 reported cases of ARDS linked to azathioprine toxicity (2,6,8,9,11), and a single case series of 7 cases of which 2 also have an infectious etiology (1). Data from these cases are summarized on table 1.

Table 1. Cases of Azathioprine induced ARDS in the literature.

The four remaining articles not appearing in table 1 were excluded because they either represented an immediate hypersensitivity reaction to azathioprine or had infectious pneumonitis which could have contributed to the development of ARDS (4,5,10,12).

Neither our case nor those in the literature contain irrefutable proof that azathioprine was directly responsible for lung injury. However, the similarities between the cases in which the patient survived lead us to conclude that azathioprine is involved in this adverse reaction. First, all 8 cases in which the patient survived show a rapid improvement within one to two weeks after discontinuation of azathioprine. Second, all of these patients present in the same way with hypoxia, pulmonary infiltrates, and fevers. Third, none of the cases show any other possible causes and the ones that go to biopsy have non-specific findings (UIP or diffuse alveolar damage) (1,2,6,7,11). These observations are circumstantial, but the diagnosis of drug-induced pulmonary toxicity is usually based on clinical history of drug exposure and the absence of other known causative agents. Additionally, diffuse interstitial pulmonary disease is the most common form of lung pathology caused by drugs (1,14).

Leukopenia or pancytopenia were present in our case as well as 4 of the 10 reported cases (6,8,9,11). No other side effects from azathioprine were reported in any of the cases. Therefore ARDS is likely a unique effect and unrelated to other potential side effects of azathioprine. The dose of azathioprine was widely variable in the known cases (25-150mg daily) leading us to believe that the development of ARDS is not dose-dependent. All of the cases had patients who had been on azathioprine for months (years in one case) prior to developing pneumonitis or ARDS, leading us to speculate that ARDS is not an acute hypersensitivity. It may be that ARDS development is a function of dose effect over time.

Although there are very few reported cases, It is possible that azathioprine induced lung injury is more common than it appears. When an immunosuppressed patient presents with respiratory distress, some form of infectious etiology is usually involved and the immunosuppressants are often discontinued (1). It is possible that in some of these cases azathioprine itself is the cause or may at least contribute to the development of ARDS. We believe it is important that azathioprine lung toxicity be included in the differential for ARDS causes because prompt discontinuation of azathioprine has led to rapid recovery and good outcome in 8 of the 10 known cases (1,2,6,8,9,11).

Acknowledgments

Sarah Waybright, Pharm.D. and Lindsay Kittler, Pharm.D. The clinical pharmacists who noted case reports of azathioprine causing pulmonary toxicity and recommended it’s discontinuation in our patient.

References

1. Bedrossian CW, Sussman J, Conklin RH, Kahan B. Azathioprine-associated interstitial pneumonitis. Am J of Clin Pathol. 1984;82(2):148-54. [PubMed]
2. Weisenburger DD. Interstitial pneumonitis associated with azathioprine therapy. Am J of Clin Pathol. 1978;69(2):181-5. [PubMed]
3. Whisnant JK, Pelkey J. Rheumatoid arthritis: treatment with azathioprine (IMURAN (R)). Clinical side-effects and laboratory abnormalities. Ann Rheum Dis. 1982;41:44-47. [CrossRef] [PubMed]
4. Stetter M, Schmidl M, Krapf R. Azathioprine hypersensitivity mimicking Goodpasture's syndrome. Am J of Kidney Dis. 1994;23(6):874-7. [CrossRef] [PubMed]
5. Krowka MJ, Breuer RI, Kehoe TJ. Azathioprine-associated pulmonary dysfunction. Chest. 1983;83(4):696-8. [CrossRef] [PubMed]
6. Rubin G, Baume P, Vandenberg R. Azathioprine and acute restrictive lung disease. Aust N Z J Med. 1972 Aug;2(3):272-4. [CrossRef] [PubMed]
7. Bidinger JJ, Sky K, Battafarano DF. Henning JS. The cutaneous and systemic manifestations of azathioprine hypersensitivity syndrome. [Review] J Am Acad Dermatol. 2011;65(1):184-91. [CrossRef] [PubMed]
8. Carmichael DJS, Hamilton DV, Evans DB, Stovin PGI, Calne RY. Interstitial pneumonitis secondary to azathioprine in a renal transplant patient. Thorax. 1983;38:951-952. [CrossRef] [PubMed]
9. Perreaux F, Delphine Z, Capron F, Trioche P, Odievre M, Labrune P. Azathioprine-induced lung toxicity and efficacy of cyclosporine a in a young girl with type 2 autoimmune hepatitis. J Ped Gastroenterol Nutr. 2000;31:190-192. [CrossRef]
10. Ananthakrishnan AN, Attila T, Otterson MF, Lipchik RJ, Massey BT, Komorowski RA, Binion DG. Severe pulmonary toxicity after azathioprine/6-mercatopurine initiation for treatment of inflammatory bowel disease. J Clin Gastroenterol. 2007;41(7):682-688. [CrossRef] [PubMed]
11. Brown AL, Corris PA, Ashcroft T, Wilkinson R. Azathioprine-related interstitial pneumonitis in a renal transplant recipient. Nephrol Dial Transplant. 1992;7:362-364. [PubMed]
12. Frost J, Carion G, Mazer J. A case of azathioprine hypersensitivity syndrome, acute respiratory distress syndrome, and shock. Crit Care Med Suppl. 2011;32(12):926.
13. De Gasperi A, Feltracco P, Ceravola E, Mazza E. Pulmonary complications in patients receiving a solid-organ transplant. Curr Opin Crit Care. 2014;20(4):411-419. [CrossRef] [PubMed]
14. Camus P, Fanton A, Bonniaud P, Camus C, Foucher P. Interstitial lung disease induced by drugs and radiation. Respir. 2004;71:01-326. [CrossRef] [PubMed]

Reference as: Scherbak D, Wyckoff R, Singarajah C. Azathioprine associated acute respiratory distress syndrome: case report and literature review. Southwest J Pulm Crit Care. 2014;9(2):94-100. doi: http://dx.doi.org/10.13175/swjpcc087-14 PDF

August 2014 Pulmonary Case of the Month: A Physician's Job is Never Done

Elijah Poulos, MD^*

Kristine Saunders, MD^†

Pulmonary and Critical Care Medicine*

Department of Pathology^†

Phoenix VA Medical Center

Phoenix, AZ

History of Present Illness

A 75-year-old man presented with recurrent minimally productive cough, dyspnea, fatigue, low-grade fevers, and weight loss in November 2013. The patient had been treated twice as an outpatient with antibiotics in the previous 6 weeks for pneumonia.

PMH, FH, SH

The patient has a history of obstructive sleep apnea but is not compliant with his prescribed continuous positive airway pressure. He also as a history of obesity, dyslipidemia, and peripheral vascular disease.

There is no significant family history.  

He is a retired brick layer with a 50 pack-year smoking history but quit a few weeks prior to admission.  He drinks a case of beer/week.

Physical Examination

VS stable. There were no significant findings on physical examination.

Radiography

A chest radiograph (Figure 1) was performed.

Figure 1. Admission PA (Panel A) and lateral (Panel B) chest radiograph.

What should be done next? (Click on the correct answer to proceed to the next panel)

1. Bronchoscopy with bronchoalveolar lavage
2. Bronchoscopy with transbronchial biopsy
3. Needle biopsy
4. Thoracentesis
5. Video-assisted thorascopic surgery (VATS)

Reference as: Poulos E, Saunders K. August 2014 pulmonary case of the month: a physician's job is never done. Southwest J Pulm Crit Care. 2014;9(2):59-67. doi: http://dx.doi.org/10.13175/swjpcc098-14 PDF

July 2014 Pulmonary Case of the Month: Where Did It Come From?

Colin B. Fitterer, MD

James M. Parish, MD

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 67 year old man presented with worsening cough and shortness of breath. He has a history of metastatic colon cancer first diagnosed in 2010. He was treated with radiation and chemotherapy (FOLFOX) but unfortunately developed new pulmonary nodules in October, 2013 which were metastatic colon cancer on biopsy. In February 2014 he developed a right parietal brain mass which was resected. Thoracic CT scan at that time showed progression of the pulmonary nodules. He has also noted a 30 pound weight loss over the past 6 months and an enlarging right supraclavicular lymph node.

PMH, FH, SH

In addition to the colon cancer, he has previous diagnoses of type 2 diabetes mellitus, hypertension, allergic rhinitis, and vitamin D deficiency. He is married and a recently retired railroad engineer. He has no history of tobacco use. There is a positive family history of lung cancer but no colon cancer.

Physical Examination

Vital Signs:  Temperature 36.8, pulse 98, respirations 18, blood pressure 144/70, SpO2 91% on 3 L via nasal cannula.

Pertinent findings include:

• A large firm and fixed right supraclavicular lymph node that is nonpainful on palpation.
• Diminished breath sounds across all right posterior lung fields with dullness to percussion. 
• Palpable liver edge is palpable approximately 2cm below the right costal margin.

Laboratory Analysis

Admission laboratory values include a hemoglobin of 11.1 g/dL but with a normal white blood cell count and platelet count. Electrolytes, blood urea nitrogen, creatinine, and liver enzymes were all within normal limits.  Serum chemistries are within normal limits.

Radiography

A chest x-ray (Figure 1A) and chest CT (Figure 1B) were performed.

Figure 1. Admission AP (Panel A) and representative image from the thoracic CT scan (Panel B).

Which of the following is the best interpretation of the radiographic findings? (Click on the correct answer to proceed to the next panel)

1. Large right pleural effusion
2. Right lung atelectasis
3. Right lung pneumonia
4. Right lung pulmonary edema
5. None of the above

Reference as: Fitterer CB, Parish JM. July 2014 pulmonary case of the month: where did it come from? Southwest J Pulm Crit Care. 2014;8(6):1-7. doi: http://dx.doi.org/10.13175/swjpcc080-14 PDF

June 2014 Pulmonary Case of the Month: "Petrified"

Steven W. Purtle, MD

University of Colorado Hospital, Denver, CO

steven.purtle@ucdenver.edu

History of Present Illness

A 52 year old expatriated Iraqi man presents to pulmonary clinic with complaints of chronic dyspnea. While a young man living in Iraq, he had been disqualified from service in the Iraqi Air Force after a screening chest x-ray was found to be abnormal. He had no respiratory symptoms at the time of his disqualification, and he remained asymptomatic for the next twenty five years. Beginning five years ago, he had an insidious onset of breathlessness and exertional intolerance. Over the past several years, he has developed diffuse pleuritic chest pain, non-productive cough, and fatigue. He denies any fevers, chills, night sweats, arthralgias, rash, or visual symptoms. After moving to Denver, Colorado three years ago, he has developed a continuous oxygen requirement of two liters per minute.

PMH, FH, SH

He has no significant past medical or family history. While living in Iraq, he worked as a photographer, but he is currently unemployed. He is a lifelong non-smoker and uses no illicit drugs. He has never had any pets. He denies any exposure to inorganic dusts.

Medications

None

Physical Examination

Physical examination reveals a thin, middle-aged man in no acute distress. Vital signs were notable for an oxygen saturation of 90% on 2 liters per minute of supplemental oxygen. Pulmonary examination was notable for fine inspiratory crackles heard best at the bilateral bases. There was no clubbing or peripheral edema. The remainder of his physical examination was unremarkable.

Laboratory Analysis

Serum chemistries are within normal limits. Complete blood count shows a normal white blood cell count, hematocrit, and platelet count.

Pulmonary Function Tests

Pulmonary functions tests are shown in Figure 1.

Radiography

A chest x-ray (Figure 2) and chest CT (Figures 3 and 4) were performed.

Figure 2. Admission AP (Panel A) and lateral (Panel B) chest x-ray.

Figure 3. Static thoracic CT images displayed in lung windows (Panels A-D) and soft tissue windows (Panels E-H).

Figure 4. Movies of thoracic CT scan in lung windows (Panel A, top) and soft tissue windows (Panel B, bottom).

Which of the following features best describes the pattern seen on the patient’s chest CT? (Click on the correct answer to proceed to the next panel)

1. Diffuse microcalcifications
2. Honeycombing
3. Mosaicism
4. Patchy ground glass opacifications
5. Pleural plaques

Reference as: Purtle SW. June 2014 pulmonary case of the month: "petrified". Southwest J Pulm Crit Care. 2014;8(6):299-304. doi: http://dx.doi.org/10.13175/swjpcc069-14 PDF

May 2014 Pulmonary Case of the Month: Stress Relief

Robert W. Viggiano, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 62 year old man was referred for an abnormal CT scan of the chest. He was found to have an abnormality in the lung as an incidental finding on a CT scan of the abdomen done 6 months earlier for abdominal pain. A CT-guided needle biopsy was performed but revealed only scant tissue and no diagnosis was made.

The patient was asymptomatic without dyspnea, wheezing or cough. He had no fevers, chills, history of pneumonia or sinus disease. He denied any symptoms of gastroesophageal reflux disease (GERD), regurgitation, dysphagia or aspiration.

PMH, FH, SH

The patient had a small melanoma excised from his arm several months earlier. Family history was noncontributory. He smoked a pack per day for 7 years but quit over 30 years earlier. He does not drink.

Medications

• Vitamins
• Mineral oil laxative

Physical Examination

Physical examination was unremarkable.

Radiography

A CT scan of the chest was performed (Figure 1).

Figure 1. Representative images from the thoracic CT scan. Panels A-E: lung windows. Panels F-J: Corresponding soft tissue windows.

The thoracic CT shows which of the following abnormalities? (Click on the correct answer to proceed to the next panel)

1. Left lower lobe mass
2. Mediastinal mass
3. Right middle lobe mass
4. 1 and 3
5. All of the above

Reference as: Viggiano RW. Pulmonary case of the month: stress relief. Southwest J Pulm Crit Care. 2014;8(5): . doi: http://dx.doi.org/10.13175/swjpcc046-14 PDF

Giant Cell Myocarditis: A Case Report and Review of the Literature

Nathan Spence, MD

Karen Niehaus, MD

Leonardo Macias, MD

Bart Cox, MD

University of New Mexico Hospital

Albuquerque, New Mexico, United States

Introduction 

First described by Saltykow in 1905 (1), Giant cell myocarditis (GCM) is a rare but highly lethal disease. Until the 1980s the diagnosis of GCM was determined at autopsy (2). It often affects young patients (mean age of 42.6 + 12.7 years),  and appears to occur in men and women equally. The occurrence of GCM in minority patients has not been previously described (3). The most common presenting symptom is heart failure (75%), though ventricular tachycardia (14%), chest pain with ECG findings of acute myocardial infarction (6%) and complete heart block (5%) may also occur. Treatment often involves an immunosuppressive regimen as a bridge to heart transplantation. The prevalence of GCM is known primarily from autopsy studies (i.e., 0.051% in India, 0.007% in England,  and 0.023% in Japan) (4-6). In the largest GCM observational study yet published, the rate of death or cardiac transplantation was 89 percent, with a median survival of 5.5 months from the onset of symptoms to the time of death or transplantation (3). Few cases with the successful treatment of GCM have been reported (7). Here we describe a case of GCM in a Hispanic female, the first to our knowledge, in which immediate diagnosis and initiation of an immunosuppressive regimen led to a favorable hospital course, whereby she was clinically stabilized and able to be transferred for transplant evaluation.

Case

A 56-year-old Hispanic female with a past medical history significant only for hypertension presented to our emergency department for evaluation of a non-productive cough over the last 3 days, which was associated with a headache, runny nose, myalgias, nausea, vomiting, chest pain, increased dyspnea on exertion, and lower extremity edema. On initial evaluation, heart rate was 86, blood pressure was 131/84, temperature was 37.4 degrees Celsius, oxygen saturation 96% on room air. Physical exam revealed a patient in moderate distress, a pericardial friction rub, clear lungs, and trace lower extremity edema. Laboratory testing revealed a leukocytosis of 12,800/mm³ (normal < 10,600/mm³), troponin I of 3.020 ng/mL (normal < 0.06 ng/mL), N-Terminal-Pro-BNP of 9,775 pg/mL (normal < 125 pg/mL), elevated ESR of 43 mm/hr (normal < 15mm/hr), elevated CRP of 3.6mg/dL (normal < 1 mg/dL), and a mild eosinophilia of 6% (normal < 5%).  Respiratory viral panel was negative. Chest X-Ray revealed a globular cardiac silhouette without definite evidence of congestion. Twelve-lead electrocardiogram revealed normal sinus rhythm with a new left bundle branch block. Cardiac catheterization revealed no significant coronary stenosis, with a left ventricular end diastolic pressure (LVEDP) of 22 mmHg. Upon admission to the floor, diuresis and titration of guideline based medications for dilated cardiomyopathy were begun, but were promptly discontinued due to development of hypotension. Transthoracic echocardiography (TTE) displayed severe hypokinesis of the basal inferoseptum and inferior wall of the left ventricle. Estimated ejection fraction was 35%, with mild to moderate mitral regurgitation. Blood pressure stabilized on day 2 of admission. Cardiac MR (CMR) with gadolinium was ordered, which did not show definite myocardial delayed enhancement (i.e., no evidence of infarction, myocarditis. See Figure 1).

Figure 1 Cardiac Magnetic Resonance Imaging. (A) Two chamber delayed post-gadolinium inversion recovery view. (B) Two chamber delayed post-gadolinium phase sensitive inversion recovery view.

On day 3 of hospitalization, the patient suddenly developed complete heart block, became hypotensive and confused. As a result, a temporary venous pacemaker (TVP) was placed, and endomyocardial biopsy (EMB) was performed. Five specimens were obtained. Pulmonary capillary wedge pressure was measured at 32 mmHg, with a Fick cardiac output 3.01 L/min and cardiac index of 1.77 L/min/m². Due to persistent hypotension in the cath lab, a dopamine drip was begun, a Swan-Ganz catheter was placed, and the patient was transferred to the Medical Intensive Care Unit for further hemodynamic monitoring and treatment. That afternoon, GCM was diagnosed by pathology (see Figure 2).

Figure 2 Pathology. (A) Infiltration of cardiac muscle tissue by an inflammatory infiltrate. (B) Massive myocyte necrosis with giant cells among the inflammatory infiltrate. (C) Rare eosinophils are seen among the inflammatory infiltrate. (D) Giant cell among the inflammatory infiltrate.

An immunosuppressive regimen of corticosteroids, azathioprine,  and cyclosporine was promptly initiated. Thereafter, over the course of 3 days, clinical symptoms  and hemodynamics improved significantly. TVP was removed, inotropic support was weaned off, and ACE inhibitor and diuretics were titrated. Beta-blockers were withheld out of concern for recent complete heart block and use of inotropic support. On hospital day 10, the patient was transferred, in stable condition, to be evaluated for heart transplantation, and/or mechanical circulatory support. At the outside center, she had an ICD placed for primary prevention, was maintained on the three drug immunosuppression regimen, continued to do well clinically, and was listed for transplant.

Discussion

Several autoimmune disorders have been associated with GCM, which include inflammatory bowel disease, thyroiditis, and thymoma (8). Our patient did not have a history of autoimmune disease, and the laboratory tests to detect such during her hospitalization were negative. Evidence suggests that GCM is an autoimmune disorder dependent on CD4-positive T lymphocytes and anti-myosin autoantibodies (8). Early diagnosis leading to appropriate treatment, as in our case, appears to be imperative for a favorable clinical outcome. Treatment with a combination of immunosuppressives has been shown to improve survival, compared with those not receiving immunosuppressive regimens (12.3 months vs. 3.0 months, p=0.001) (3). If patients live long enough to receive heart transplantation, longer term survival is possible. For that reason, it is a Class I (level of evidence B) guideline recommendation to perform EMB in the setting of unexplained, new-onset heart failure of < 2 weeks' duration associated with a normal sized or dilated left ventricle in addition to hemodynamic compromise (9). The sensitivity of EMB for GCM is 80% to 85% in subjects who subsequently die or undergo heart transplantation (2). Therefore, in the appropriate clinical setting, EMB may drastically alter treatment and provide important prognostic information. The pathological hallmark of GCM is the presence of multinucleated giant cells and a lymphocytic inflammatory infiltrate, associated with myocyte necrosis (10-12). CMR may display delayed myocardial enhancement to support the diagnosis of myocarditis, though a non-diagnostic study, as in our case, does not rule it out.   

We encountered, to our knowledge, the first case of GCM in a patient of Hispanic ethnicity, who presented with the classic associated symptoms of heart failure, hemodynamic collapse, and complete heart block, and whose clinical course was favorably improved by early diagnosis and initiation of an immunosuppressive regimen. CMR did not identify myocarditis. However, this case illustrates the importance of including GCM in the differential diagnosis when a patient presents with suggestive clinical features and is not responding to current evidence based treatment for acute decompensated heart failure.

References

1. Saltykow S. Uber Diffuse Myokarditis. Virchows Archiv fur Pathologische Anatomie. 1905;182:1-39. [CrossRef]
2. Shields RC, Tazelaar HD, Berry GJ, Cooper LT. The role of right ventricular endomyocardial biopsy for idiopathic giant cell myocarditis. J Card Fail. 2002;8:74-88. [CrossRef] [PubMed] 
3. Cooper LT, Berry GJ, Shabetai R. Idiopathic giant-cell myocarditis - natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators. N Engl J Med. 1997;336:1860-6.[CrossRef] [PubMed]
4. Vaideeswar P, Cooper L. Giant cell myocarditis: clinical and pathological disease characteristics in an indian population. Cardiovasc Pathol. 2013;22:70-4. [CrossRef] [PubMed]  
5. Whitehead R. Isolated myocarditis. Brit Heart J 1965;27:220-30. [CrossRef] [PubMed]
6. Okada R, Wakafuji S. Myocarditis in autopsy. Heart Vessels 1985; Suppl 1:23-9. [CrossRef]
7. Desjardins V, Pelletier G, Leung TK, Waters D. Successful treatment of severe heart failure caused by idiopathic giant cell myocarditis. Can J Cardiol. 1992;8:788-92. [PubMed] 
8. Cooper L, ElAmm C. Giant Cell Myocarditis: Diagnosis and treatment. Herz. 2012;37:632-6. [CrossRef] [PubMed] 
9. Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease. A scientific statement from the American heart association, the American college of cardiology, and the European society of cardiology. J Am Coll Cardiol. 2007;50(19):1914-31. [CrossRef] [PubMed] 
10. Davies M, Pomerance A, Teare R. Idiopathic giant cell myocarditis - a distinctive clinico-pathological entity. Br Heart J. 1975;37:192-5. [CrossRef] [PubMed] 
11. Davidoff R, Palacios I, Southern J, Fallon JT, Newell J, Dec GW. Giant cell versus lymphocytic myocarditis. A comparison of their clinical features and long-term outcomes. Circulation. 1991;83:953-61. [CrossRef] [PubMed] 
12. Ren H, Poston RS Jr, Hruban RH, Baumgartner WA, Baughman KL, Hutchins GM. Long survival with giant cell myocarditis. Mod Pathol. 1993;6:402-7. [PubMed] 

Reference as: Spence N, Niehaus K, Macias L, Cox B. Giant cell myocarditis: a case report and review of the literature. Southwest J Pulm Crit Care. 2014;8(4):247-51. doi: http://dx.doi.org/10.13175/swjpcc052-14 PDF

April 2014 Pulmonary Case of the Month: DIP-What?

Lewis Wesselius MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 53 year old woman from Indiana was seen who had a history of nonproductive cough for several years.  She had a prior diagnosis of asthma but continued to have cough despite asthma treatment.  She was also treated for gastroesophageal reflux and had a Nissen fundoplication.  This resolved in some improvement in the cough. In May 2013 she noted increasing dyspnea on exertion.

An echocardiogram was performed which was notable for a 16% left ventricular ejection fraction. A thoracic CT demonstrated some nodules and a question was raised of sarcoidosis. She was admitted to a hospital in Indiana and had a biventricular pacemaker placed. Bronchoscopy with transbronchial biopsy was performed with no diagnostic findings. No granulomas were seen on the biopsy. Bronchoalveolar lavage showed a CD4/CD8 ration of 0.84. Optic nerve swelling was noted at that time. Due to the cardiac, pulmonary, and optic nerve findings a clinical diagnosis of sarcoidosis with a dilated cardiomyopathy was made and she was treated with prednisone initially, then a combination of prednisone and methotrexate.

PMH, FH, SH

Her past medical history was as above and family history was noncontributory. She does not smoke or drink.

Medications

• Methotrexate 15 mg weekly
• Prednisone 5 mg daily
• Furosemide 40 mg daily
• Potassium chloride 20 meq daily

Physical Examination

Afebrile. SpO2 96% on room air. The physical exam was unremarkable.

Which of the following should be performed at this time?

1. Pulmonary function testing
2. Repeat echocardiogram
3. Repeat thoracic CT scan
4. 1 and 3
5. All of the above

Reference as: Wesselius LJ. April 2014 pulmonary case of the month: DIP-what? Southwest J Pulm Crit Care. 2014;8(4):195-203. doi: http://dx.doi.org/10.13175/swjpcc024-14 PDF

Wireless Capsule Endo Bronchoscopy

 David M. Baratz, MD

Sandra Till, DO

Banner Good Samaritan Medical Center

Phoenix, AZ

Case Presentation

History of Present Illness

A 67 year-old man presents 10 days after swallowing a capsule endoscopy camera that was never retrieved.  The wireless capsule was swallowed asymptomatically for evaluation of heme positive stools after negative upper and lower endoscopies. Patient noted that the evening after swallowing the camera he developed mild shortness of breath and cough. The cough and shortness of breath were persistent and worsened while lying down and when moving positions. He denied prior issues with swallowing or aspiration.

Review of Systems

Negative other than what is noted above.

PMH, SH, and FH

Past medical history: coronary artery disease, peripheral vascular disease, hyperlipidemia

Surgical history: femoral-popliteal bypass, previous shoulder and back surgery

Social history: 1 pack/day of cigarettes for 50 years, prior alcohol usage but not current, no illicit drugs

Family history: no pulmonary diseases

Physical Exam

Vital signs: temperature 36.7º C, heart rate 86 beats per minute, respiratory rate 15 breaths/min, blood pressure 156/69, and oxygen saturation 97% while breathing  room air

Lungs: bilateral wheezing with left greater than right.

Otherwise examination was normal.

Radiography

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

Figure 1. Chest x-ray with capsule in left main bronchus (arrow).

A thoracic CT scan is shown in Figure 2.

Figure 2. Thoracic non-contrast CT scan with capsule in left main bronchus (arrow).

Bronchoscopy was performed under general anesthesia using a laryngeal mask airway (LMA). Bronchoscopic examination revealed a white capsule lodged in left main bronchus (Figure 3).

Figure 3. Bronchoscopy with capsule in left main bronchus.

A mesh basket was used to retrieve of the capsule from the left main bronchus, but in the carina the capsule slipped out of the basket. Attempts to use snare and retrieval forceps failed due to the slippery plastic housing covering the capsule.  The mesh basket was used again with capture of the capsule. Once the capsule was retrieved, the LMA was removed to avoid en bloc damage to the vocal cord while removing the capsule. The LMA was then reinserted for continued ventilation after the capsule had been obtained.

Figure 4. Intact capsule after removal.

Literature Review

Capsule endoscopy has been available since 2001 and is used for the evaluation of obscure gastrointestinal bleeding and iron deficiency anemia. The retention rate is 1-2%, with capsules typically found in diverticula, hernias, or other bowel abnormalities (1-3). It is reported that approximately 2% of patients will have difficulty or inability to swallow the capsule.  Review of 13 available cases of aspiration of wireless endoscopy capsules revealed that about 50% of the time capsules are spontaneously expulsed by coughing, and the other half requiring bronchoscopic intervention for removal (Table 1).

Table 1. Summary of cases with aspirated wireless endoscopy capsules.

Risks for aspiration include underlying neurologic disease, elderly patients, and patient with previous difficulties with swallowing. Signs of capsule aspiration vary from asymptomatic to shortness of breath, cough, and tachypnea (1-12).

The capsule is a wirelesses, 11 mm X 26 mm capsule with a miniature video camera, light emitting diodes, batteries, transmitter, and an antenna. It is slippery, nonbiodegradable, has plastic housing, and weighs less than 4 grams (13).

This case represents a rare, but important complication of wireless capsule endoscopy requiring evaluation and possible intervention. Although this complication is rare, it is likely we will see increasing frequency as capsule utilization increases.

References

1. Guy T, Jouneau S, D'Halluin PN, Lena H. Asymptomatic bronchial aspiration of a video capsule. Interact Cardiovasc Thorac Surg. 2009;8(5):568-70. [CrossRef] [PubMed] 
2. Depriest K, Wahla AS, Blair R, Fein B, Chin R Jr. Capsule endoscopy removal through flexible bronchoscopy. Respiration. 2010;79(5):421-4. [CrossRef] [PubMed] 
3. Koulaouzidis A, Pendlebury J, Douglas S, Plevris JN. Aspiration of video capsule: rare but potentially life-threatening complication to include in your consent form. Am J Gastroenterol. 2009;104(6):1602-3. [CrossRef] [PubMed] 
4. Choi HS, Kim JO, Kim HG, Lee TH, Kim WJ, Cho WY, Cho JY, Lee JS. A case of asymptomatic aspiration of a capsule endoscope with a successful resolution. Gut Liver. 2010;4(1):114-6. [CrossRef] [PubMed]
5. Buchkremer F, Herrmann T, Stremmel W. Mild respiratory distress after wireless capsule endoscopy. Gut. 2004;53(3):472. [CrossRef] [PubMed]
6. Ding NS, Hair C, De Cruz P, Watson J. Education and Imaging. Gastrointestinal: symptomatic bronchial aspiration of capsule endoscope - a significant complication. J Gastroenterol Hepatol. 2013;28(5):761. [CrossRef] [PubMed]
7. Nathan SR, Biernat L. Aspiration--an important complication of small-bowel video capsule endoscopy. Endoscopy. 2007;39 Suppl 1:E343. [CrossRef] [PubMed] 
8. Pezzoli A, Fusetti N, Carella A, Gullini S. Asymptomatic bronchial aspiration and prolonged retention of a capsule endoscope: a case report. J Med Case Rep. 2011;5:341. [CrossRef] [PubMed] 
9. Schneider AR, Hoepffner N, Rösch W, Caspary WF. Aspiration of an M2A capsule. Endoscopy. 2003;35(8):713. [CrossRef] [PubMed] 
10. Bredenoord AJ, Stolk MF, Al-toma A.Tabib S, Fuller C, Daniels J, Lo SK. Unintentional video capsule bronchoscopy. Eur J Gastroenterol Hepatol. 2009;21(5):593. [CrossRef] [PubMed] 
11. Tabib S, Fuller C, Daniels J, Lo SK.Sepehr A, Albers GC, Armstrong WB. Asymptomatic aspiration of a capsule endoscope. Gastrointest Endosc. 2004;60(5):845-8. [CrossRef] [PubMed]
12. Sepehr A, Albers GC, Armstrong WB. Aspiration of a capsule endoscope and description of a unique retrieval technique. Otolaryngol Head Neck Surg. 2007;137(6):965-6. [CrossRef] [PubMed]
13. Kelley SR, Lohr JM. Retained wireless video enteroscopy capsule: a case report and review of the literature. J Surg Educ. 2009;66(5):296-300. [CrossRef] [PubMed]

Reference as: Baratz DM, Till S. Wireless capsule endo bronchoscopy. Southwest J Pulm Crit Care. 2014;8(3):183-7. doi: http://dx.doi.org/10.13175/swjpcc014-14 PDF

Elevated Tumor Markers In Coccidioidomycosis of the Female Genital Tract

Ying Wu, MD¹

Stacy Arnold²

Tim Kuberski, MD³

¹Department of Internal Medicine and the ³Section of Infectious Disease

Maricopa Medical Center

Phoenix, Arizona

²University of Arizona College of Medicine Phoenix

Phoenix, Arizona

Abstract

The female genital tract is rarely involved by coccidioidomycosis. We describe a woman with disseminated coccidioidomycosis involving the female pelvic organs associated with elevated tumor markers CA 125 and CA 19-9. She had no fevers and the initial clinical suspicion was a malignancy because of the elevated tumor markers. At exploratory laparotomy a total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed because of the suspicion of a malignancy. Subsequent pathology demonstrated coccidioidomycosis involving the female genital tract and no malignancy. The abnormal CA 125 and CA 19-9 returned to normal after surgical resection and treatment of the coccidioidomycosis.

Introduction

Dissemination of coccidioidomycosis to the female genital tract is an unusual complication of that fungal infection (1). This report describes a woman with disseminated coccidioidomycosis which mimicked a malignancy of the female genital tract. The initial clinical suspicion was a malignancy because of the elevation of carbohydrate antigen tumor markers CA125 and CA19-9.

Case Report

A 48-year-old Hispanic woman with a history of adult onset diabetes and menorrhagia presented with left lower quadrant pain.  She denied fever, chills or sweats.  She gave no history of “Valley Fever” or pneumonia.  Physical examination was significant for left lower quadrant abdominal tenderness without rebound or guarding.  CT of the abdomen and pelvis showed free fluid within the pelvis, masses within the uterus, left hydronephrosis and bilateral cystic masses of the adnexa. She was anemic and thrombocytopenic with a hemoglobin of 7.8 g/dL and platelet count of 51,000/mm³.  She received blood and platelet transfusions and was given oral prednisone 80 mg once daily for five days which was associated with improvement of her platelet count to normal. Certain tumor markers were found to be elevated a CA 125 of 475.7 (normal range: 0-35 U/mL) and CA 19-9 of 133 (normal range: 0–37 U/mL). A carcinoembryonic antigen (CEA) was not elevated 1.9 (normal range 0-2.5 ng/ml). Her diabetes was controlled. The left hydronephrosis was treated with a ureteral stent and nephrostomy.  An endometrial biopsy was consistent with benign endocervical and endometrial tissue.  Percutaneous drainage of the left ovarian cyst fluid showed no malignant cells and no abscess.  A plain chest x-ray was interpreted as normal, however a CT scan of the chest showed a left lower lobe lesion which was biopsied and found to be consistent with an old Coccidioides granuloma.  Because of the concern for a pelvic malignancy, an exploratory laparotomy was done and a total hysterectomy with bilateral salpingo-oophorectomy was performed.  The pathology of the surgical specimen showed Coccidioides with necrotizing granulomas and spherules in the round ligament, uterus, endometrium, bilateral ovaries and fallopian tubes (Figure 1).

Figure 1.  Hematoxylin and eosin stain of round ligament showing necrotizing granulomas associated with Coccidioides spherules (arrows). Empty Coccidioides  spherule in inset.

Following the operation, she was started on oral fluconazole 400mg daily and followed as an outpatient. Her complement fixation titer for Coccidioides was positive at 1:64 on discharge, increased to 1:256 one month later and then declined to 1:8 five months later. At five months follow-up she was asymptomatic and back to her premorbid state. She was to remain on fluconazole indefinitely.  Postoperatively the CA 125 and CA 19-9 returned to normal at 12.3 and 12.0 respectively after fifty days (Table 1). 

Table 1. Tumor Marker Values Before and Fifty Days After Surgical Resection.

                          

Discussion 

Dissemination of Coccidioides to the female pelvic organs is unusual. In a series of 142 necropsies of patients who died of coccidioidomycosis, none of the thirty-three females had involvement of the genital tract (2).  Presumptively the fungus spreads endogenously from the lung as in our patient. It is notable that the lung lesion in this patient was initially thought to be a malignancy. However, when “old Coccidioides granuloma” was reported, it was not associated with her genital tract problem by the treating physicians. We were able to find seventeen previously reported cases of coccidioidomycosis involving the female genital tract since the first report in 1929 (3-7). In those cases of Coccidioides involving the genital tract, there was no combination of investigations or clinical features that were sensitive enough to diagnose the female genital tract infection preoperatively. In fourteen of the eighteen patients (including our patient) with Coccidioides serologic test results, thirteen had a positive titer of 1:16 or greater (3-6).

In all eighteen cases the diagnosis of Coccidioides involving the genital tract was made only post-operatively after the microscopic examination of surgical specimens. Treatment of female genital tract coccidioidomycosis generally requires surgical resection of the involved tissues and antifungal agents (3). Cure of pelvic coccidioidomycosis by surgical resection alone, without antifungal therapy, has been reported in at least 5 cases (3,7). However, deaths attributable to disseminated coccidioidomycosis with involvement of the genital tract despite treatment and surgery have been reported (8). Quantitative serologic testing can be useful in making the diagnosis and following the response to treatment. The complement fixation titers to Coccidioides would be expected to decrease with treatment and clinical improvement. Our patient’s complement fixation titer went from a high of 1:256 to 1:8 after surgical resection and five months of treatment. In general, patients with disseminated coccidioidomycosis will respond to fluconazole, but the duration of therapy can be protracted for years.

Early in the course of our patient’s workup, she was found to have elevated CA 125 and CA 19-9 levels, raising the suspicion of a malignancy. In general, tumor markers should not be used as a screening test for malignancy and are most useful for following the response to treatment. In this patient the response was to antifungal therapy rather than chemotherapy. We believe the tumor markers were elevated due to the inflammatory response to the Coccidioides infection (4,9). CA 125 is most commonly monitored in the management of ovarian carcinoma.  However, it is only 75-80% sensitive in patients with ovarian cancer and can also be elevated in a variety of benign conditions such as infection (10).  In addition to the ovarian cancer cells, benign endometrial and peritoneal mesothelial cells can also secrete CA 125 (11). It appears that any process causing serosal inflammation may elevate CA 125. Thus non-tumorous conditions such as pelvic tuberculosis can result in sufficient inflammation to cause an increased CA 125 level (12). CA 19-9 is a serum marker associated with pancreatic cancer, but it also can be elevated in non-cancerous conditions such as pancreatitis, endometriosis and in diabetics with poor glycemic control (10,13).

Both CA 125 and CA 19-9 can be elevated in noncancerous conditions such as infection and presumed to be the reason for the elevation in our patient. Her surgical histopathology showed concomitant endometriosis of the round ligament, uterine serosa and both ovaries (Figure 2).

Figure 2. Hematoxylin and eosin stain of ovary showing changes consistent with endometriosis (arrow).

This was in addition to the necrotizing granulomas containing Coccidioides spherules (Figure 1). Increased levels of CA 125 have been reported previously in three patients with Coccidioides involving pelvic organs (4,5,7), but there have been no reports of elevated serum CA 19-9 levels.  Endometriosis alone can cause both CA 125 and CA 19-9 to be increased (14,15), however the mechanism by which these markers become elevated is not completely understood. It has been postulated that chronic inflammation causes an epithelial reaction that results in the leakage of the tumor markers into the circulation (14,15).  Endometriosis due to a variety of infectious etiologies can cause serum CA 125 levels to be elevated and they can precipitously decrease following surgical intervention, as in our patient (4,5). CA 19-9 levels have also been found to return to normal following surgical intervention for endometriosis (16). We presume that the elevated tumor markers in our patient were the result of similar inflammatory mechanisms observed for both CA 125 and CA 19-9. We suspect the reason that CA 19-9 levels have not been reported previously is that this test would be ordered less frequently in patients suspected of having a pelvic malignancy. Our patient had a normal CEA level consistent with a lack of involvement of the gastrointestinal tract by coccidioidomycosis.

Another potential source of Coccidioides infecting the female genital tract is sexual transmission. We could find no references to document sexual transmission of Coccidioides. However, transmission from a man with prostate involvement to a woman who developed an infection of her genital tract could occur, but our patient’s husband had no prostate disease, no history of Valley Fever and his Coccidioides serology was negative. Coccidioides has been documented to mimic a variety of malignancies such as breast cancer, bronchogenic carcinoma, osteosarcoma and lymphoma (6). It is notable that the first reported case of coccidioidomycosis in 1892 was initially misdiagnosed as mycosis fungoides (6). Coccidioidomycosis is known to have protean manifestations and in this patient it mimicked a female genital tract malignancy. This case is unique because a Coccidioides infection was documented and associated with the elevation of tumor markers CA 19-9 and CA 125, which returned to normal following treatment and surgical resection of the involved tissues. Involvement of the female genital tract by coccidioidomycosis may be uncommon, but in endemic areas it should be a consideration in the differential diagnosis in women with a suspected pelvic malignancy and elevated levels of CA 125 and CA 19-9.

References

1. Saw EC, Smale LE, Einstein H, Huntington RW,Jr. Female genital coccidioidomycosis. Obstet Gynecol. 1975;45:199-202. [PubMed] 
2. Huntington RW Jr., Waldmann WJ, Sargent JA, O'Connell H, Wybel R, Croll D. pathological and clinical observations in 142 cases of fatal coccidioidomycosis on necropsy. In Ajello L, ed. Proceedings of the Second Coccidioidomycosis Symposium. Tuscon, The University of Arizona Press.1967:143-167.
3. Chowfin A, Tight R. Female genital coccidioidomycosis (FGC), Addison's disease and sigmoid loop abscess due to Coccidioides immites; case report and review of literature on FGC. Mycopathologia. 1999;145:121-126. [CrossRef] [PubMed]
4. Ellis MW, Dooley DP, Sundborg MJ, Joiner LL, Kost ER. Coccidioidomycosis mimicking ovarian cancer. Obstet Gynecol. 2004;104:1177-1179. [CrossRef] [PubMed] 
5. Micha JP, Goldstein BH, Robinson PA, Rettenmaier MA, Brown JV. Abdominal/pelvic Coccidioidomycosis. Gynecol Oncol. 2005;96:256-258. [CrossRef] [PubMed]
6. Crum-Cianflone NF, Truett AA, Teneza-Mora N, et al. Unusual presentations of coccidioidomycosis: a case series and review of the literature. Medicine (Baltimore). 2006;85:263-277. [CrossRef] [PubMed] 
7. Smith G, Hoover S, Sobonya R, Klotz SA. Abdominal and pelvic coccidioidomycosis. Am J Med Sci. 2011;341:308-311. [CrossRef] [PubMed]
8. Bylund DJ, Nanfro JJ, Marsh WL,Jr. Coccidioidomycosis of the female genital tract. Arch Pathol Lab Med. 1986;110:232-235. [PubMed] 
9. Bast RC,Jr, Xu FJ, Yu YH, Barnhill S, Zhang Z, Mills GB. CA 125: the past and the future. Int J Biol Markers. 1998;13:179-187. [PubMed] 
10. Cancer antigen 125. In: Ferri FF, ed. Ferri's Clinical Advisor 2013 : 5 Books in 1. 1st ed. St. Louis, Mo: Elsevier Mosby; 2013:1452-1453.
11. Sevinc A, Camci C, Turk HM, Buyukberber S. How to interpret serum CA 125 levels in patients with serosal involvement? A clinical dilemma. Oncology. 2003;65:1-6. [CrossRef] [PubMed] 
12. Sheth SS. Elevated CA 125 in advanced abdominal or pelvic tuberculosis. Int J Gynaecol Obstet. 1996;52:167-171. [CrossRef] [PubMed]
13. Yu H, Li R, Zhang L, Chen H, Bao Y, Jia W. Serum CA19-9 level associated with metabolic control and pancreatic beta cell function in diabetic patients. Exp Diabetes Res. 2012;2012:745189. [CrossRef] [PubMed] 
14. Kurata H, Sasaki M, Kase H, Yamamoto Y, Aoki Y, Tanaka K. Elevated serum CA125 and CA19-9 due to the spontaneous rupture of ovarian endometrioma. Eur J Obstet Gynecol Reprod Biol. 2002;105:75-76. [CrossRef]  [PubMed]
15. Park BJ, Kim TE, Kim YW. Massive peritoneal fluid and markedly elevated serum CA125 and CA19-9 levels associated with an ovarian endometrioma. J Obstet Gynaecol Res. 2009;35:935-939. [CrossRef] [PubMed] 
16. Takemori M, Sugimura K. Ovarian chocolate cyst with markedly elevated serum CA19-9 level: a case report. Eur J Obstet Gynecol Reprod Biol. 1991;42:241-244. [CrossRef] [PubMed] 

Reference as: Wu Y, Arnold S, Kuberski T. Elevated tumor markers in coccidiomyocosis of the female genital tract. Southwest J Pulm Crit Care. 2014;8(3):170-5. doi: http://dx.doi.org/10.13175/swjpcc179-13 PDF

March 2014 Pulmonary Case of the Month: The Cure May Be Worse Than the Disease

Sudheer Penupolu, MD 

Philip J. Lyng, MD

Lewis J. Wesselius, MD 

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 51 year old woman was seen with a chief complaint of gradually increasing shortness of breath. She was at baseline five months prior to presentation but noticed dyspnea on minimal exertion initially at a higher altitude, gradually progressing to dyspnea at rest. She was tried on 2 courses of antibiotics with no significant improvement. In addition to the dyspnea, she has some non productive cough but no fevers.

PMH, SH, FH

She had a renal transplant in 1997 for IgA disease and has a history of type II diabetes and hypertension.

She is a life long nonsmoker and has only occasional alcohol use. She is employed as a utility designer and has no exposure to any dusts, fumes or exotic animals.

Family history is noncontributory.

Medications

• Atenolol
• Lasix
• Prednisone 2 mg q daily
• Rosuvastatin
• Sirolimus 2 mg po q daily

There have been no changes in the doses in the past few years.

Physical Examination

Physical examination reveals no abnormalities and her lung auscultation is clear.

Laboratory

Her complete blood count (CBC), urinanalysis, liver function tests, and calcium were all within normal limits.

Radiology

An x-ray of the chest is shown in Figure 1. 

Figure 1. Initial PA chest radiograph.

Which of the below is the best interpretation of her chest x-ray?

1. Cardiomegaly
2. Left upper lobe consolidation
3. Normal
4. Right upper lobe consolidation
5. All of the above

Reference as: Penupolu S, Lyng PJ, Wesselius LJ. March 2014 pulmonary case of the month: the cure may be worse than the disease. Southwest J Pulm Crit Care. 2014;8(3):142-51. http://dx.doi.org/10.13175/swjpcc005-14 PDF