January 2016 Pulmonary Case of the Month

Kathryn E. Williams, MB

Karen L. Swanson, DO 

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 64-year-old man was seen in June 2015 with a nonproductive cough.

Past Medical History, Social History and Family History

He has no significant past medical history. He is a former smoker. Family history is positive for coronary artery disease

Physical Examination

Decreased breath sounds over the right hemithorax with dullness to percussion. Otherwise, the physical exam is unremarkable.

Radiography

A chest radiograph was performed (Figure 1).

Figure 1. Initial PA chest radiograph.

The chest radiograph shows which of the following? (Click on the correct answer to proceed to the second of five panels)

1. There is a large mass in the right upper lobe
2. There is a loculated pleural effusion
3. There is volume loss in the right upper lobe
4. 1 and 3
5. All of the above

Cite as: Williams KE, Swanson KL. January 2016 pulmonary case of the month. Southwest J Pulm Crit Care. 2016;12(1):1-5. doi: http://dx.doi.org/10.13175/swjpcc158-15 PDF 

Interval Development of Multiple Sub-Segmental Pulmonary Embolism in Mycoplasma Pneumoniae Bronchiolitis and Pneumonia

Peter V. Bui¹

Sapna Bhatia²

Ali I. Saeed²

¹Department of Internal Medicine

²Division of Pulmonary, Critical Care, and Sleep Medicine

The University of New Mexico

Albuquerque, NM, USA

Abstract

Introduction: Cases of pulmonary embolism (PE) concurrent with Mycoplasma pneumoniae infection are rare in the medical literature. We describe a patient with M. pneumoniae bronchiolitis and pneumonia who developed multiple right-sided, sub-segmental PE.

Case Description: A 54-year-old man presented following one week of respiratory and constitutional symptoms. He was admitted for respiratory distress and started on ceftriaxone, azithromycin, and oseltamivir. Because of a lack of clinical improvement, antibiotics were escalated to vancomycin and piperacillin-tazobactam. M. pneumoniae IgM and IgG serologies returned positive, and antibiotics were narrowed to azithromycin, with clinical improvement and gradual decrease in supplemental oxygen requirement. One week into the hospitalization, the patient abruptly developed an increased oxygen requirement. Computed tomography angiography (CTA) of the chest found stable M. pneumoniae bronchiolitis and pneumonia and the interval development of multiple right-sided, sub-segmental PE. He was treated with unfractionated and then low-molecular-weight heparin as a bridge to warfarin, azithromycin, and a prednisone taper. In the outpatient setting, repeat CTA revealed resolution of M. pneumoniae infection and PE. 

Discussion: Although the mechanism and association are unclear, other case reports have proposed that M. pneumoniae infection promotes hypercoagulability or a prothrombotic state, predisposing patients to thromboembolism. In a patient with M. pneumoniae infection who develops sudden respiratory distress or failure despite appropriate treatment, clinicians should have a high suspicion for PE, and a CTA should be considered as part of further evaluation.

Introduction

Mycoplasma pneumoniae is one of thirteen Mycoplasma species isolated from humans and less commonly causes lower respiratory tract infections, of which atypical pneumonia occurs at higher rates (1). These lower respiratory tract infections have been reported to present similarly to other disease processes such as asthma and pulmonary embolism (PE) (2, 3). M. pneumoniae pneumonia typically has a benign course with low mortality. A study by von Baum et al. found a mortality of 0.7% in patients with M. pneumoniae pneumonia, with the deaths occurring in hospitalized patients (4). Despite this low mortality, rare complications may contribute to morbidity and mortality, although to what degree, if any, is unclear. A case report in the medical literature describes a PE and a hypercoagulable state associated with M. pneumoniae pneumonia in an adult during the peri-infectious period (5). We present a case with radiographic evidence of the interval development of multiple segmental PE in a patient with M. pneumoniae bronchiolitis and pneumonia.

Case Description

A 54-year-old man with a 15-pack-year smoking history, positive purified protein derivative treated with isoniazid, occupational exposures including asbestos and dust, and a current history of ethanol abuse presented to the emergency department with a one-week history of a productive cough with yellow sputum, weakness, shortness of breath, and dyspnea on exertion. He also noticed diffuse papular cutaneous lesions over his back.

In the emergency department, he was hypoxic with a need for supplemental oxygen. Cardiopulmonary examination was unremarkable. Initial laboratory studies including complete blood count, chemistry panel, and hepatic function panel were notable for a leukocytosis of 13.6 k/μL with a neutrophilia of 83%, aspartate transaminase of 108 units/L, alanine transaminase of 152 units/L, alkaline phosphatase of 175 units/L, and total bilirubin of 1.5 mg/dL, and creatine kinase of 563 units/L. Conventional chest radiograph (Figure 1) showed a left lower lobe infiltrate.

Figure 1. Conventional chest radiograph on day zero of the hospitalization. The images show a left lower lobe infiltrate.

The patient was admitted to the hospital and started on ceftriaxone and azithromycin for community-acquired pneumonia as well as oseltamivir over concerns for influenza.

During the initial hospitalization, the patient required supplemental oxygen for hypoxia with a rapid increase in fractional inspired oxygen (F_iO₂) to maintain oxygen saturation above 90%. Because of a lack of clinical improvement, antibiotics were broadened to include vancomycin and piperacillin-tazobactam. Since he continued to require a F_iO₂ of 60% on day four of the hospitalization, additional workup for atypical bacterial, viral, and fungal pathogens were performed after consultation with pulmonology. Acid-fast bacillus cultures and stains were negative. Sputum cultures were not obtained. An arterial blood gas prior to evaluation by Pulmonology found a pH of 7.42, partial pressure of carbon dioxide of 38 mmHg, partial pressure of oxygen of 86 mmHg, HCO₃ of 24 mmol/L, and F_iO₂ of 95%. Computed tomography (CT) of the chest (Figure 2) showed extensive bronchiolitis with focal areas of consolidation involving bilateral lower lobes.

Figure 2. Computed tomography of the chest on day four of the hospitalization. The image shows an extensive bronchiolitis with focal areas of consolidation involving bilateral lower lobes.

Oseltamivir was discontinued after the respiratory viral panel returned negative. Broad spectrum antibiotics were narrowed to azithromycin after M. pneumoniae IgM and IgG serologies returned positive. His oxygen requirement gradually improved over the next two days, and he was transitioned to nasal cannula.

On day seven of his hospitalization, the patient suddenly developed moderate respiratory distress with an increase in oxygen requirement. CT angiography (CTA) of the chest (Figure 3) done at this juncture showed unchanged parenchymal findings with interval development of multiple sub-segmental pulmonary emboli in the right lung.

Figure 3. Computed tomography angiography of the chest on day five of the hospitalization. The images show unchanged parenchymal findings with interval development of multiple sub-segmental pulmonary emboli in the right lung (see white arrows in Figure 3A).

Doppler ultrasound found no evidence of deep venous thrombosis (DVT) in both lower extremities. He was subsequently started on therapeutic anticoagulation with unfractionated heparin and then low-molecular-weight heparin as a bridge to warfarin. The patient subsequently improved on a 14-day course of azithromycin 500 mg orally once daily and 3-month tapered course of prednisone 60 mg orally once daily for M. pneumoniae infection, a 3-month course of warfarin for the PE, and supplemental oxygen. During follow-up in the outpatient setting, CTA of the chest showed the infection and PE to have resolved, and all therapies related to the infection and PE were discontinued.

Discussion

We herein describe a case of M. pneumoniae bronchiolitis and pneumonia complicated by right-sided PE. The reported occurrences of venous thromboembolism (VTE) during M. pneumoniae infection are limited to case reports. In our review of the literature, we found one case of M. pneumoniae infection associated with PE in the adult population. Ascer et al. (5) presented the case of a 28-year-old male with right-sided pneumonia and right-sided PE who was found to have antiphospholipid antibodies. For the PE, this patient was successfully treated with recombinant tissue-type and plasminogen activator and heparin and was discharged with hydroxychloroquine sulphate, aspirin, and warfarin. However, Ascer did not publish additional follow up for this seemingly prothrombotic state. In a case without PE, Senda et al. (6) reported on a 21-year-old patient with a left middle cerebral artery embolus and DVT in bilateral femoral veins in the setting of a M. pneumoniae infection. This patient had a transient increase in prothrombin time, partial thromboplastin time, fibrin/fibrinogen degradation products, thrombin-antithrombin III-complex, antiphospholipid antibodies, and IgM anticardiolipin antibodies and decrease in protein C activity.

The pediatric medical literature has additional case reports linking M. pneumoniae to PE. Brown et al. (7) described a 6-year-old male child with M. pneumoniae pneumonia, right-sided ileofemoral thrombosis, and right-sided PE found to have anticardiolipin IgG and IgM antibodies, lupus anticoagulant, and acquired activated protein C resistance. This prothrombotic state subsequently resolved after treatment of the infection with antibiotics and the PE with unfractionated heparin and then dalteparin. In another case report, during workup for a 13-year-old male child with right-sided PE in the setting of a left lower lobe M. pneumoniae pneumonia, Graw-Panzer et al. (8) found lupus anticoagulant, anticardiolipin IgG and IgM antibodies, and an underlying protein S deficiency. The transient prothrombotic markers returned to normal levels during subsequent follow-up for his acute illness.

M. pneumoniae pulmonary infections have been reported in the pediatric medical literature to be associated with an underlying hypercoagulability. Creagh et al. (9) reported on a left femoral vein thrombosis in a 10-year-old female with M. pneumoniae pneumonia who was found to have type I familial antithrombin III deficiency. In another case report of two children describing splenic infarcts associated with M. pneumoniae pneumonia, Witmer et al. (10) found elevated D-dimer, lupus anticoagulant, and elevated anticardiolipin and β2-glycoprotein antibodies that resolved following successful treatment of the infection with antibiotics and a three-month course of anticoagulation and, in one patient, an additional course of aspirin (10). No specific etiology was found for the infarctions, but Witmer et al. attributed the infarctions to possible thrombosis. Other case reports in the pediatric literature that found antiphospholipid antibodies include a patient with cardiac thrombus and internal carotid artery occlusion (11, 12). However, in their report of right popliteal artery thrombosis in a 5-year-old male child with M. pneumoniae pneumonia and right popliteal artery thrombosis, Joo et al. (13) did not find abnormalities in their limited hypercoagulability workup.

Our lack of hypercoagulability workup limits comparison with the available medical literature. We did not perform a hypercoagulability workup because the patient did not meet any Wells criteria and did not have a family history of hypercoagulability. Based on the available case reports, the underlying pathophysiology can be inferred to be related to a transient formation of antiphospholipid antibodies during a M. pneumoniae infection. Additionally, the thromboembolism can be expected to occur within a short period of time following the onset of symptoms. The rate that hypercoagulability occurs in infected patients and the practical clinical relevance of such a prothrombotic state without or without an inherited or congenital deficiency are unknown at this time. These questions would benefit from further investigation.

An alternative interpretation is a preexisting hypercoagulability may predispose patients to M. pneumoniae infection, which can exacerbate the hypercoagulability, further increasing the risk of VTE. This interpretation may be relevant for the patients of Graw-Panzer et al. (8) and Creagh et al. (9) who had underlying hypercoagulable conditions and subsequently suffered M. pneumoniae infection and then developed VTE. The Worcester Venous Thromboembolism study found an association between infection and VTE, and Rosendaal’s review of the literature found an association between hypercoagulability and increased risk of thrombosis (14-16). With the available case reports and epidemiological studies, this alternative interpretation has not been elucidated.

In this report, we described the interval development of PE in a patient with M. pnuemoniae bronchiolitis and pneumonia. The mechanism for the hypercoagulability during M. pneumoniae infection is unclear. A CTA of the chest should be obtained if a patient with M. pneumonia infection fails to show clinical improvement or suddenly develops clinical worsening of his or her respiratory status, so as to exclude PE. However, clinicians should take into account that Mycoplasma pneumonia may present with the symptoms of PE (3).

Acknowledgements

We would like to acknowledge Cecelia Kieu for assisting in the preparation of the figures for this manuscript.

References

1. Cha SI, Shin KM, Kim M, Yoon WK, Lee SY, Kim CH, Park JY, Jung TH. Mycoplasma pneumoniae bronchiolitis in adults: Clinicoradiologic features and clinical course. Scand J Infect Dis. 2009;41(6-7):515-9. [CrossRef] [PubMed]
2. Vasudevan VP, Suryanarayanan M, Shahzad S, Megjhani M. Mycoplasma pneumonia bronchiolitis mimicking asthma in an adult. Respir Care. 2012;57(11):1974-6. [CrossRef] [PubMed]
3. Simmons BP, Aber RC. Mycoplasma pneumoniae pneumonia. Symptoms mimicking pulmonary embolism with infarction. JAMA. 1979;241(12):1268-9. [CrossRef] [PubMed]
4. von Baum H, Welte T, Marre R, Suttorp N, Luck C, Ewig S. Mycoplasma pneumoniae pneumonia revisited within the German Competence Network for Community-acquired pneumonia (CAPNETZ). BMC Infect Dis. 2009;9;62. [CrossRef] [PubMed]
5. Ascer E, Marques M, Gidlund M. M pneumonia infection, pulmonary thromboembolism and antiphospholipid antibodies. BMJ Case Rep. 2011;2011. [CrossRef] [PubMed]
6. Senda J, Ito M, Atsuta N, Watanabe H, Hattori N, Kawai H, Sobue g. Paradoxical brain embolism induced by Mycoplasma pneumoniae infection with deep venous thrombosis. Intern Med. 2010;49(18):2003-5. [CrossRef] [PubMed]
7. Brown SM, Padley S, Bush A, Cummins D, Davidson S, Buchdahl R. Mycoplasma pneumonia and pulmonary embolism in a child due to acquired prothrombotic factors. Pediatr Pulmonolo. 2008;43(2):200-202. [CrossRef] [PubMed]
8. Graw-Panzer KD, Verma S, Rao S, Miller ST, Lee H. Venous thrombosis and pulmonary embolism in a child with pneumonia due to Mycoplasma pneumoniae. J Natl Med Assoc. 2009;101(9):956-8. [PubMed]
9. Creagh MD, Roberts IF, Clark DJ, Preston FE. Familial antithrombin III deficiency and Mycoplasma pneumoniae pneumonia. J Clin Pathol. 1991;44:870-1. [CrossRef] [PubMed]
10. Witmer CM, Steenhoff AP, Shah SS, Raffini LJ. Mycoplasma pneumoniae, splenic infarct, and transient antiphospholipid antibodies: a new association? Pediatrics. 2007;119:292–5. [CrossRef] [PubMed]
11. Bakshi M, Khemani C, Vishwanathan V, Anand RK. Mycoplasma pneumonia with antiphospholipid antibodies and a cardiac thrombus. Lupus 2006;15:105–6. [CrossRef] [PubMed]
12. Tanir G, Aydemir C, Yilmaz D, Tuygun N. Internal carotid artery occlusion associated with Mycoplasma pneumoniae infection in a child. Turk J Pediatr. 2006;48(2):166-71. [PubMed]
13. Joo CU, Kim JS, Han YM. Mycoplasma pneumoniae induced popliteal artery thrombosis treated with urokinase. Postgrad Med J. 2001;77:723–724. [CrossRef] [PubMed]
14. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet. 1999;353(9159):1167-73. [PubMed]
15. Spencer FA, Emery C, Joffe SW, Pacifico L, Lessard D, Reed G, Gore JM, Goldberg RJ. Incidence rates, clinical profile, and outcomes of patients with venous thromboembolism. The Worcester VTE study. J Thromb Thrombolysis. 2009;28(4):401-9. [CrossRef] [PubMed]
16. Spencer FA, Emery C, Lessard D, Anderson F, Emani S, Aragam J, Becker RC, Goldberg RJ. The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med. 2006;21(7):722-7. [CrossRef] [PubMed]

Cite as: Bui PV, Bhatia S, Saeed AI. Interval development of multiple sub-segmental pulmonary embolism in Mycoplasma pneumoniae bronchiolitis and pneumonia. Southwest J Pulm Crit Care. 2015;11(6):277-83. doi: http://dx.doi.org/10.13175/swjpcc152-15 PDF 

December 2015 Pulmonary Case of the Month

Zachary M. Berg, MD

Kashif Yaqub, MD 

Brian Wojek, MD

Khang Tran, MD

Karen L. Swanson, DO

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

The patient is a 70-year-old man with a history of a chronic dry cough for 5 years, who presented to the emergency department with worsening cough and shortness of breath.

Two weeks prior to symptom onset, was on trip in the United Kingdom, he developed gastroenteritis which spontaneously resolved.

Past Medical History, Social History, and Family History

• Old healed TB scar with positive PPD at 17 years of age prior to joining Air Force.  No treatment given and patient was asymptomatic from a pulmonary point of view since then.
• Squamous cell carcinoma of the skin on the scalp, status post excision complicated by osteomyelitis, status post surgical graft from hip with prolonged course of IV antibiotics in 2010.
• Fractured left clavicle, status post repair 20 years ago.
• Hay fever.
• Hyperlipidemia.
• Squamous cell carcinoma removed from left arm.
• Varicose veins, lower extremity.
• Married. Retired police officer. Does not smoke.
• Family history is noncontributory

Physical Examination

• General:  In moderate respiratory distress.  
• Vitals: SpO2 on room air of 65%, 94% on high flow oxygen.  Blood pressure 124/84, afebrile  
• Lungs:  Fine bibasilar crackles posteriorly.  
• Heart: Regular rhythm without murmur.
• The remainder of the physical examination was normal.

Laboratory Evaluation

• CBC: unremarkable except white blood cell count 20.5 x 10³ cells/ɥL, neutrophil predominant
• BNP: 366 pg/mL
• Mycobacterium Quantiferon: Positive
• Mycoplasma IgM: Positive at 1.18 U/L

Radiography

Initial chest x-ray is shown in Figure 1.

Figure 1. Initial chest x-ray.

What is the best next step in the patient's evaluation? (Click on the correct answer to proceed to the second of five panels)

1. Begin erythromycin or doxycycline for Mycoplasma pneumonia
2. Begin heparin for presumptive pulmonary embolism
3. Thoracic CT scan
4. 1 and 3
5. All of the above

Cite as: Berg ZM, Yaqub K, Wojek B, Tran K, Swanson KL. December 2015 pulmonary case of the month. Southwest J Pulm Crit Care. 2015;11(6):240-5. doi: http://dx.doi.org/10.13175/swjpcc146-15 PDF

November 2015 Pulmonary Case of the Month

Kristal Choi, MD

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 66 year-old woman was admitted to neurology with acute-onset dysarthria, right facial droop, and right-sided hemiparesis as a stroke alert. She also had a nonproductive cough and intermittent dyspnea for 4 months.

Past Medical History, Social History and Family History

• She has a history of hypertension and hyperlipidemia. 
• She smoked 1-2 packs/day for 15 years but quit 35 years ago. She drinks two glasses of wine per day.
• There is a family history of bowel and breast cancer.

Physical Examination

• Vital signs: T 36.8, HR 81, BP 129/75, RR 18, O2 sat 93% RA
• General: No acute distress. Awake and alert.
• Heart, abdomen, and lungs: No significant abnormalities
• Neurological: Mild right-sided nasolabial fold flattening.  Evidence of ptosis o the right eyelid. Hemiparesis on the right, the arm greater than leg. Sensation intact. Dysmetria on the right upper and lower extremities.

Laboratory Evaluation

• CBC: Hemoglobin 11.9 g/dL, white blood cells (WBC) 7,900 cells/mcL, platelets 290,000 cells/mcL
• Basic metabolic panel: Na+ 139 mEq/L, K+ 4 mEq/L, Cl- 100 mEq/L , bicarbonate 22 mEq/L, creatinine 0.7 mg/dL

Radiography

A head CT angiogram (CTA) was performed (Figure 1).

Figure 1. Representative images from CTA of the head.

Which of the following should be done next? (Click on the correct answer to proceed to the second of six panels)

1. Administer an intravenous injection of tissue plasminogen activator (TPA)
2. Administer detachable coils (coiling or endovascular embolization) or stereotactic radiosurgery
3. Begin an anti-convulsant and dexamethasone
4. 1 and 3
5. All of the above

Cite as: Choi K, Wesselius LW. November 2015 pulmonary case of the month. Southwest J Pulm Crit Care. 2015;11(5):200-8. doi: http://dx.doi.org/10.13175/swjpcc134-15 PDF

Why Chronic Constipation May be Harmful to Your Lungs: A Case Report and Review of Lipoid Pneumonia and Mycobacterium fortuitum Leading to Acute Respiratory Failure and Septic Shock

Sandra Till, DO

Manoj Mathew, MD 

Da-Wei Liao, MD

Christina Ramirez, MD 

Banner University Medical Center

Phoenix, AZ

Case Report

A 43 year-old female with a past medical history of right-sided hemiparesis secondary to motor vehicle accident 17 years prior presented a two week history of cough, fever and right-sided pleuritic chest pain. Her baseline status included using a wheelchair, living alone at home and working as a teacher.

On admission she had a temperature of 39.6º C, was tachycardia and hypotensive requiring vasopressors. Labs were remarkable for a white count of 25,000 cells/mcL. Chest x-ray showed right-sided infiltrate and pleural effusion (Figure 1).

Figure 1. Chest x-ray on presentation.

Bronchoscopy and thoracentesis was performed upon admission. The pleural fluid wasexudative with a glucose of 78 and no suggestion of loculations on chest x-ray or ultrasound. The patient was started on therapy for community-acquired pneumonia.

On day 4 after admission, the patient had increasing sinus tachycardia, hypotension and was worsening despite being on antimicrobial therapy. A CT angiogram of the chest was performed (Figure 2).

Figure 2. Initial CT scan on day 4 of admission. Panel A: axial view showing pneumonia and right pleural effusion. Panel B: coronal view.

CT angiogram was negative for pulmonary embolism and a percutaneous chest tube was placed on day 4 for drainage of pleural effusion due to development of loculations. On day 7, the pleural fluid from initial thoracentesis grew acid-fast bacteria identified as Mycobacterium fortuitum.

Bronchoscopy was performed on day 8 and there was no endobronchial obstruction.

Bronchoscopic alveolar lavage cultures grew Mycobacterium fortuitum. She had no history of bronchiectasis, skin infection, or immunoglobulin deficiency. Treatment with amikacin and levofloxacin was initiated based on susceptibilities.

The pleural chest tube was removed on day 14 (Figure 3). At this time the patient was transferred to a skilled nursing facility.

Figure 3. CT scan on day 13 prior to chest tube removal. Panel A: axial view. Panel B: coronal view.

The patient continued antibiotic treatment for Mycobacterium fortuitum with amikacin and levofloxacin, however, serial sputum cultures remained positive. On day 25, in the skilled nursing facility, the patient developed respiratory failure due to increased right effusion and worsening pneumonia. She was transferred to our facility were she was intubated and a new right-sided chest tube was placed. After placement of chest tube and drainage the right lung did not expand. Decompensation was felt to be related to the inadequate evacuation of the empyema with plans to solely continue antimicrobial therapies by the outside facility.

Figure 4. CT scan on day 30 showing trapped lung. Panel A: axial view. Panel B: coronal view. 

Repeat pleural fluid cultures and BAL once again grew Mycobacterium fortuitum. She was taken for decortication and right middle and lower lobe resection by thoracic surgery. Due to extensive disease the patient required right thoracotomy, decortication, parietal pleurectomy, right middle lobectomy, and wedge resection of a right lower lobe lung abscess.

The lung pathology is shown below and was consistent with lipoid pneumonia (Figure 5).

Figure 5. Panels A & B: CD 163 stains showing lipid present within histiocytes. Panels C & D: histology demonstrating severe lipoid pneumonia. Panels E & F: Granulomatous inflammation with giant cells. Panel G: pleura. Panel H: abscess.

There were no mycobacteria cultured on the lung biopsy. There were areas of both acute and chronic fibrosis noted on pathology report along with areas of acute interstitial pneumonitis and granulomatous inflammation.

During post-operative phase the patient confirmed that she was drinking mineral oil chronically for treatment of constipation. Repeat sputum cultures 7 days post operatively were negative for Mycobacterium fortuitum. She continued to improve with treatment of Mycobacterium fortuitum and postoperative cultures remained negative. She was able to liberate from the ventilator and returned home at after a prolonged course of rehabilitation.

Lipoid Pneumonia and Associated Mycobacterial Infection

The association between acid-fast bacteria and lipoid pneumonia was first reported in 1925 and since case reports have been noted. In 1953, a case report and literature review documented six cases of “saprophytic” mycobacteria was noted in conjunction with lipoid pneumonia. It was observed at this time that the fatty environment of lipoid pneumonia might assist with the growth of mycobacterium (1). Since then, intermittent case reports have been published reporting lipoid pneumonia with atypical mycobacteria.

There are two main categories of lipoid pneumonia, endogenous and exogenous. The endogenous form is also known as cholesterol pneumonia or golden pneumonia. It is associated with lysis of lung tissue distal to obstruction due to malignancy, fat storage disease such as Neiman-Pick or Gaucher's, medications and therapies including chemotherapeutic agents, amiodarone and radiation therapy. Pulmonary alveolar proteinosis has also been reported in idiopathic cases with granulomatosis with polyangiitis and connective tissue diseases (2-4). In polarized light microscopy after staining with sulfuric and acetic acid, the sample reveals cholesterol crystals, which is diagnostic of endogenous lipoid pneumonia (3).

Exogenous lipoid pneumonia occurs when external substances enter the lungs due to inhalation or aspiration (3). Cases have been reported from mineral oil, paraffin use, oil based nasal drops, total parenteral nutrition, mineral oil nose drops, black fat tobacco smoking, milk, and liquid hydrocarbons used by flame blowers (2-6). The pulmonary reaction to each substance varies. For example, mineral oils are fairly inert and less likely to produce alveolar inflammation, where milk fats are hydrolyzed by lung lipases leading to a significant inflammatory response (2).

The clinical presentation and appearance of lipoid pneumonia is variable from consolidation to effusion to nodule. Nodules from lipids may have elevated standardized uptake value (SUV) on positron emission tomography (PET) scan. The BAL from lipoid pneumonia may demonstrate lipid laden foamy macrophages (2). Mineral oil granuloma (paraffinoma) also can present as a spiculated mass mimicking malignancy.

Mineral oil is notorious for causing lipoid pneumonia by aspiration for several reasons. First, it floats on the column of undigested material in the esophagus so it is first to be aspirated (5); secondly, it impairs phagocytosis at the alveolar level; and lastly, it inhibits the cough reflex and motor function of ciliated mucosa (7).

The impairment of phagocytosis associated with lipoid pneumonia is thought to be a contributing factor in why atypical mycobacterium strives in the lipid rich environment of lipoid pneumonia (5,6). Malnutrition is also thought to be a component of risk as it due to impairment in cell mediated immunity (6). Lipid acts as mechanical protection for the mycobacteria favoring tissue necrosis facilitating secondary infection. Also it is thought that lipids may activate the cell walls of the atypical mycobacteria leading to increased virulence of the mycolic acids within the wall of the bacteria (8).

Mycobacterium fortuitum rarely causes pulmonary disease unless associated with lipoid pneumonia. This is often related to gastroesophageal disease and chronic vomiting and aspiration of contents. It is typically associated with skin and soft tissue infections and is a rapid growing mycobacterium and most frequently found in water and soil (2,8,9)

This case demonstrates an atypical presentation of lipoid pneumonia and Mycobacterium fortuitum infection leading to septic shock and ventilator failure. Although the association of lipoid pneumonia and mycobacterial infections is well documented, the rapid and acute decline in this patient’s clinical status is unusual. This can be attributed to incomplete drainage of the initial empyema prior to transfer to the skilled nursing facility.

The etiology of the lipoid pneumonia was chronic aspiration of mineral oil producing an ideal environment for growth of Mycobacterium fortuitum. The absence of bronchiectasis, immunoglobin deficiency, skin infections should prompt further evaluation for abnormal lung architecture serving as a nidus for Mycobacterium fortuitum Infection. In our case, failure to improve is attributed to a persistent nidus for infection. We advocate resection of diseased lung segments of lipoid pneumonia to facilitate successful treatment of Mycobacterium fortuitum. In conclusion, if a patient has lipoid pneumonia with signs of clinical infection, the possibility of rapidly growing mycobacterium such as M. fortuitum should be considered.

References

1. Gibson JB. Infection of the lungs by saprophytic mycobacteria in achalasia of the cardia, with report of a fatal case showing lipoid pneumonia due to milk. J Pathol Bacteriol. 1953;65(1):239-51. [CrossRef] [PubMed]
2. Hasan A, Swamy T. Nocardia and Mycobacterium fortuitum infection in a case of lipoid pneumonia. Respiratory Medicine CME 2011: 75-78. [CrossRef]
3. Betancourt SL, Martinez-Jimenez S, Rossi SE, Truong MT, Carrillo J, Erasmus JJ. Lipoid pneumonia: spectrum of clinical and radiologic manifestations. AJR Am J Roentgenol. 2010;194(1):103-9. [CrossRef] [PubMed]
4. Harris K, Chalhoub M, Maroun R, Abi-Fadel F, Zhao F. Lipoid pneumonia: a challenging diagnosis. Heart Lung. 2011;40(6):580-4. [CrossRef] [PubMed]
5. Hughes RL, Freilich RA, Bytell DE, Craig RM, Moran JM. Clinical conference in pulmonary disease. Aspiration and occult esophageal disorders. Chest. 1981;80(4):489-95. [CrossRef] [PubMed]
6. Tranovich VL, Buesching WJ, Becker WJ. Pathologic quiz case. Chronic pneumonia after gastrectomy. Pathologic diagnosis: chronic aspiration lipoid pneumonia with Mycobacterium abscessus. Arch Pathol Lab Med. 2001;125(7):976-8. [PubMed]
7. Jouannic I, Desrues B, Léna H, Quinquenel ML, Donnio PY, Delaval P. Exogenous lipoid pneumonia complicated by Mycobacterium fortuitum and Aspergillus fumigatus infections. Eur Respir J. 1996;9(1):172-4. [Pubmed]
8. Couto SS, Artacho CA. Mycobacterium fortuitum pneumonia in a cat and the role of lipid in the pathogenesis of atypical mycobacterial infections. Vet Pathol. 2007;44(4):543-6. [CrossRef] [PubMed]
9. Vadakekalam J, Ward MJ. Mycobacterium fortuitum lung abscess treated with ciprofloxacin. Thorax. 1991;46(10):737-8. [CrossRef] [PubMed] 

Cite as: Till S, Mathew M, Liao D-W, Ramirez C. Why chronic constipation may be harmful to your lungs: a case report and review of lipoid pneumonia and mycobacterium fortuitum leading to acute respiratory failure and septic shock. Southwest J Pulm Crit Care. 2015;11(4):193-9. doi: http://dx.doi.org/10.13175/swjpcc118-15 PDF 

Traumatic Hemoptysis Complicating Pulmonary Amyloidosis

Erwan Oehler, MD¹

Charlotte Courtois, MD² 

Florent Valour, MD¹

¹Department of Internal Medicine

²Department of Pulmonary Medicine

French Polynesia Hospital Center

98716 Pirae, Tahiti

French Polynesia

Case Presentation

We present a 74-year-old man admitted to hospital for a fall occurring at home. His past medical history included histologically-proven pulmonary amyloidosis followed for fifteen years (Figure 1A), without involvement of other organs.

Figure 1A. Frontal chest radiography shows bilateral confluent, somewhat nodular and dense-appearing opacities with a background of faint linear and reticular opacities.

At admission, he complained of left chest pain related to a rib fracture (Figure 1B, arrow).

Figure 1B. Detail radiograph of the left upper thorax shows a fracture (arrow) of a posterolateral rib, superimposed on the background of dense-appearing linear and nodular parenchymal disease.

The next day, he presented with moderate hemoptysis, prompting performance of thoracic CT (Figure 1C and D) which showed a cavity filled with material of soft tissue attenuation.

Figure 1C and D. Axial thoracic CT displayed in soft tissue windows shows extensive bilateral nodular hyperattenuating tissue consistent with alveolar septal / diffuse pulmonary parenchymal amyloidosis. A cystic lesion with internal, dependent soft tissue attenuation (arrow, D) is present, consistent with a hematoma.

This soft tissue-filled cavity was located at the same level as the rib fracture, surrounded by calcified tissue, and presumably reflected a pulmonary parenchymal hematoma resulting from traumatically induced laceration of the inelastic calcified lung tissue.

Discussion

Pulmonary amyloidosis is a rare disease resulting from the extracellular deposition of insoluble fibrillar proteins aggregating in a β–pleated sheet configuration (1). Amyloidosis is classified according to the chemistry of the amyloid protein as AA secondary amyloidosis (SAA protein) -often related to chronic inflammatory disease- AL amyloidosis (monoclonal immunoglobulin light chains of the lambda or kappa type)-secondary to B lymphoproliferative disorders-and hereditary or familial amyloidosis (transthyretin and gelsolin). Dialysis-associated amyloidosis (βR₂R microglobulinemia) and “senile” amyloidosis SAA (wild-type transthyretin) are also recognized. Pulmonary amyloidosis may occur in three forms: tracheobronchial, nodular parenchymal and alveolar septal / diffuse parenchymal patterns (2). The two first forms (which include primitive pulmonary amyloidosis) are often remain localized to the respiratory system, whereas the alveolar septal / diffuse parenchymal form of amyloidosis, whose prognosis is more severe, often presents in a systemically. Parenchymal amyloid nodules grow slowly and generally remain asymptomatic but patients may also present with dyspnea, cough, hemoptysis or recurrent pneumonia (3).

References

1. Chu H, Zhao L, Zhang Z, Gui T, Yi X, Sun X. Clinical characteristics of amyloidosis with isolated respiratory system involvement: A review of 13 cases. Ann Thorac Med. 2012 (4):243-9. [CrossRef] [Pubmed]
2. Gilmore JD, Hawkins PN. Amyloidosis and the respiratory tract. Thorax. 1999;54:444-51. [CrossRef] [PubMed]
3. Vieira IG, Marchiori E, Zanetti G, Cabral RF, Takayassu TC, Spilberg G, Batista RR. Pulmonary amyloidosis with calcified nodules and masses - a six-year computed tomography follow-up: a case report. Cases J. 2009;2:6540. [CrossRef] [PubMed]

Cite as: Oehler E, Courtois C, Valour F. Traumatic hemoptysis complicating pulmonary amyloidosis. Southwest J Pulm Crit Care. 2015;11(4):173-5. doi: http://dx.doi.org/10.13175/swjpcc133-15 PDF

Staphylococcus aureus Sternal Osteomyelitis: a Rare Cause of Chest Pain

Manjinder Kaur DO

Courtney Walker DO

Emily S. Nia MD

Jeffrey R. Lisse MD

Department of Medicine

Banner University Medical Center

Tucson, AZ USA

Abstract

Chest pain is a common presenting symptom with a broad differential. Life-threatening cardiac and pulmonary etiologies of chest pain should be evaluated first. However, it is critical to perform a thorough assessment for other sources of chest pain in order to limit morbidity and mortality from less common causes. We present a rare case of a previously healthy 45 year old man who presented with focal, substernal, reproducible chest pain and Staphylococcus aureus bacteremia who was later found to have primary Staphylococcus aureus sternal osteomyelitis.

Case Report

A 45 year old previously healthy man presented to the emergency department with sudden onset substernal chest pain of two days duration. The pain was described as constant, achy, worsened with movement, and improved with lying still.  Palpation of the manubrium reproduced pain and was associated with an appreciable “bump”. The patient denied recent trauma or surgery and reported no fevers, weight loss, night sweats, cough, or history of intravenous drug use. He had multiple tattoos covering his thorax and abdomen obtained while incarcerated twenty years prior to admission. On examination, the patient was uncomfortable due to severe sternal pain. He was diaphoretic, tachycardic, tachypneic, and afebrile. His manubrium was tender to palpation and the overlying skin was warm and mildly swollen without apparent erythema, induration, or drainage. Laboratory results were remarkable for leukocytosis of 18,4000/uL with 92% neutrophils, serial troponins less than 0.01 ng/mL, ESR 15 mm/hr, c-reactive protein (CRP) 13.40 mg/dL, nonreactive HIV antibodies, and positive hepatitis C virus (HCV) antibody with detectable but unquantifiable HCV RNA. Electrocardiogram showed normal sinus rhythm without ischemia. Bibasilar atelectasis was appreciated on chest x-ray and chest CT with contrast revealed no bone or chest wall lesions. Sternum MR with contrast (Figure 1) showed enhancing edema in the subcutaneous soft tissues overlying the sternomanubrial joint with extension into the pectoralis major musculature symmetrically without abscess or bony involvement.

Figure 1. Sagittal and axial T2 fat sat images (A and B) demonstrate inflammatory changes involving the soft tissues overlying the sternum including the pectoralis muscles bilaterally. Sagittal and axial T1 post contrast images (C and D) demonstrate avid enhancement involving the soft tissues overlying the sternum consistent with phlegmonous change without a rim enhancing loculated fluid collection to suggest an abscess formation. No underlying osseous involvement is present. A tissue marker corresponds to the patient’s site of pain. 

On day two of admission, blood culture results were reported positive for Staphylococcus aureus oxacillin susceptible (MSSA). Positive blood cultures persisted despite appropriate antibiotics. A transesophageal echocardiogram (TEE) was performed and showed no vegetations. Although chest imaging was negative for osteomyelitis, the persistent bacteremia and focal sternomanubrial pain was clinically suggestive of primary sternal osteomyelitis. The patient was discharged to home and completed a six week course of intravenous cefazolin for presumed MSSA sternal osteomyelitis.  

Repeat MR sternum performed eight weeks after initial presentation showed osteomyelitis across the sternomanubrial joint with improved soft tissue edema
(Figure 2).

Figure 2. Sagittal and axial T2 fat sat images (A and B) demonstrate interval improvement in inflammatory changes involving the soft tissues overlying the sternum with persistent edema present at the sternomanubrial joint (red arrow). Sagittal T1 image (C) demonstrates focal hypointense bone marrow about the sternomanubrial joint (red arrow). Sagittal and axial T1 post contrast images (D and E) demonstrate enhancement of the sternomanubrial joint (red arrow). Overall findings are consistent with osteomyelitis of the sternomanubrial joint.

Given that the patient had completed six weeks of parenteral antibiotic therapy, his sternal chest pain had resolved, and CRP had normalized, additional antibiotics were not prescribed and the patient was asked to follow up with his primary care provider as needed. There was no incidence of further complication and the patient was diagnosed with primary MSSA sternal osteomyelitis.

Discussion       

Primary osteomyelitis of the sternum in immunocompetent patients is extremely rare, accounting for 0.3% of all cases of osteomyelitis reported in the literature (1). Common risk factors for primary sternal osteomyelitis are trauma, pneumonia, diabetes, immunodeficiency, or history of IV drug use (2,3). Our patient had none of these risk factors. Risks for secondary sternal osteomyelitis are due to complications from sternal incision post-thoracic surgery(1-3). Staphylococcus aureus is the most common organism of both primary and secondary sternal osteomyelitis (2).

Early diagnosis of acute osteomyelitis is critical in order to prevent necrosis of bone, as well as other local and systemic complications, from delayed antibiotic therapy. Multiple imaging modalities are available to confirm the presumed clinical diagnosis of osteomyelitis. MRI is 82% to 100% sensitive and 75% to 96% specific and is considered the gold standard in diagnosis of acute osteomyelitis (4). However, as evidenced by our case, imaging findings may lag behind clinical presentation. Clinicians need to consider primary osteomyelitis in the differential diagnosis of a young patient who presents with focal sternal chest pain, swelling, and bacteremia. A strong index of suspicion for acute osteomyelitis is needed in order to promptly initiate antibiotic therapy to reduce morbidity and mortality associated with untreated osteomyelitis (1,2).

References

1. de Nadai TR, Daniel RF, de Nadai MN, da Rocha JJ, Féres O. Hyperbaric oxygen therapy for primary sternal osteomyelitis: a case report. J Med Case Rep. 2013;7:167. [CrossRef] [PubMed]
2. Gill EA Jr, Stevens DL. Primary sternal osteomyelitis. West J Med. 1989;151(2):199-203. [PubMed]
3. Vacek TP, Rehman S, Yu S, Moza A, Assaly R. Another cause of chest pain: Staphylococcus aureus sternal osteomyelitis in an otherwise healthy adult. Int Med Case Rep J. 2014;7:133-7. [CrossRef] [PubMed]
4. Pineda C, Espinosa R, Pena A. Radiographic imaging in osteomyelitis: the role of plain radiography, computed tomography, ultrasonography, magnetic resonance imaging, and scintigraphy. Semin Plast Surg. 2009;23(2):80-9. [CrossRef] [PubMed] 

Cite as: Kaur M, Walker C, Nia ES, Lisse JR. Staphylococcus aureus sternal osteomyelitis: a rare cause of chest pain. Southwest J Pulm Crit Care. 2015;11(4):167-70. doi: http://dx.doi.org/10.13175/swjpcc131-15 PDF  

Safety and Complications of Bronchoscopy in an Adult Intensive Care Unit

Aarthi Ganesh, MBBS¹

Nirmal Singh, MBBS, MPH²

Gordon E. Carr, MD¹

¹Department of Pulmonary & Critical Care

²Department of Internal Medicine

University of Arizona

Tucson, Arizona

Abstract

Background: Bronchoscopy is a common procedure performed in adult intensive care units (ICU). However, very few studies report the safety and complications of the bronchoscopy and related procedures performed on critically ill patients. The primary aim of this study was to determine the incidence of complications following ICU bronchoscopy.

Methods: We conducted a retrospective chart review of patients admitted to an adult ICU and underwent bronchoscopy with or without bronchoalveolar lavage (BAL) and other bronchoscopic procedures. Data included patient demographics, APACHE II score, hemodynamics, comorbidities, type of ventilation and procedure performed. Data from BAL, including cellular differential and microbiology, were also collected.

Results: We identified 120 patient charts between November 2011 to March 2012. The most common procedure was bronchoscopy with BAL (62%) to evaluate for pneumonia (58%). Other procedures included transbronchial biopsy, APC and cryotherapy, balloon and stent placement, endobronchial biopsy and EBUS. Complications occurred in 18% of the patients, with hypoxia being the most common (7.5%). No deaths occurred related to the procedures. Nine percent of patients who had BAL or inspection had complications compared to 29% who underwent other procedures. Subgroup analysis conducted on patients undergoing BAL revealed significantly higher neutrophil counts (p=0.001) and higher APACHE II score (p=0.02) among those with BAL positive for bacteria and co-infection.

Conclusion: Bronchoscopy with BAL and inspection is relatively safe procedure even in critically ill patients. However, other interventional bronchoscopic procedures should be performed with caution in the ICU.

Abbreviations:

ICU: Intensive care unit

BAL: Bronchoalveolar lavage

EBUS: Endobronchial Ultrasound

APC: Argon Plasma Coagulation

SBP: Systolic Blood Pressure

CI: Confidence Interval

IP: Interventional pulmonary

MAP: Mean arterial pressure

SD: Standard deviation

CHF: Congestive heart Failure

COPD: Chronic Obstructive Pulmonary Disease

ILD: Interstitial Lung Disease

ET: Endotracheal

Introduction

Fiberoptic bronchoscopy is a commonly performed procedure in the medical intensive care unit (ICU). Prior studies have indicated that bronchoscopy is generally safe, making it a relatively low-risk procedure in appropriately selected ICU patients (1-3). Most prior studies reporting the safety of bronchoscopy were performed in early 1990s. The rates of complications or adverse events in these earlier studies ranged from 2% to 40% (2,4-6). The primary aim of this study was to assess the incidence of complications in ICU patients undergoing bronchoscopy in the contemporary era.

Methods

The study was approved by the Institutional Review Board at the University of Arizona. We conducted a retrospective chart review of patients, 18 years or older, admitted to the adult medical intensive care unit, who underwent bronchoscopy with or without bronchoalveolar lavage (BAL) and other bronchoscopic procedures from November 1, 2011 to March 31, 2012. The other bronchoscopic procedures included transbronchial biopsies, endobronchial ultrasound (EBUS) guided biopsy, argon plasma coagulation (APC) and cryotherapy, balloon dilatation with stenting, and endobronchial biopsy. We excluded patients with incomplete charts, and patients who had bronchoscopy as a part of percutaneous tracheostomy procedure. Data included patient demographics, APACHE II scores, hemodynamics, co-morbidities, type of ventilation, type of procedure performed and the complications. Sedation used in the procedures included propofol or midazolam with fentanyl for analgesia. BAL results, including cellular differential and microbiology studies, were also collected. We used pre-specified definitions to assess for complications. We defined hypotension as reduction in systolic blood pressure (SBP) by >20 mm Hg or when a patient required vasopressors to maintain a mean arterial pressure (MAP) > 60 mm Hg during or after the procedure. Hypoxia was defined by drop in saturation to < 90% or when the FiO2 requirement increased by > 20% for more than 2 hours after the procedure. Hemorrhage was indicated as per the procedure note by the bronchoscopist or when the note indicated use of epinephrine or when additional procedures needed to be performed to control the bleeding. During the procedure all the patients FiO2 was increased but was turned down to their previous ventilatory settings unless there was significant hypoxia.

Statistical analysis was performed using STATA/IC 13.1 (StataCorp LP, Texas). Numerical variables are expressed as mean ± standard deviation (SD). Ninety-five percent confidence intervals (CIs) were calculated where appropriate. Univariate comparisons between patients who did and did not develop complications were calculated using a χ2 test or Fischer's exact test for categorical variables and a 2-sample t test for continuous variables applying central limit theorem. All statistical testing was two-tailed with significance level set at the alpha level of ≤0.05.

Results

We identified 140 patients who underwent ICU bronchoscopy during the study period. Eighteen patients were excluded due to incomplete information. Two charts were excluded as the bronchoscopy was performed for percutaneous tracheostomy. Table 1 shows the baseline characteristics of patients undergoing ICU bronchoscopy.

Table 1. Baseline Characteristics of Patients Prior to Bronchoscopy

Key: CAD: Coronary Artery Disease

        CHF: Congestive Heart Failure

        COPD: Chronic obstructive pulmonary disease

        FiO2: Oxygen required

        ILD: Interstitial Lung Disease

        MAP: Mean arterial pressure

        NM Disease: Neuromuscular disease

Sixty-nine percent of the patients were male and average age was 52 ± 16 years. The average APACHE II score was 18 ± 6 with a median of 18 and 88% of the patients were intubated and mechanically ventilated. The mean percentage oxygen (FiO2) requirement in the patients prior to the procedure was 63% ± 26. Sixty-three percent of the patients were immunocompromised, likely related to the large proportion of lung transplant recipients in our study population. Fifty-four percent also had chronic lung disease including chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). Other common co-morbidities included cardiovascular disease including congestive heart failure (CHF) and arrhythmias, malignancy and neuromuscular diseases. Table II shows the indications for ICU bronchoscopy. The most common indication for the procedure was to evaluate for pneumonia or infiltrate in 87 cases (72%), followed by atelectasis/ collapse/ secretions in 19 cases (15.8%) (Table 2).

Table 2. Indications For Procedures

Other indications included tracheal or airway diseases, which included tracheal stenosis, upper airway obstruction, tracheal mass and bronchopleural fistula in 11 (8%) and hemoptysis (2%). The most common procedures performed were bronchoscopy with BAL in 75 (62%) and inspection in 31 (26%) (Table 3).

Table 3. Procedures

Key:  APC: Argon plasma coagulation

         BAL: Bronchoalveolar lavage

         Cryo: Cryotherapy

         EBUS: Endobronchial ultrasound

         ET: Endotracheal tube

Other procedures included transbronchial biopsy, APC and cryotherapy, balloon and stent placement, endobronchial biopsy and EBUS.

Table 4 shows the complications resulting from ICU bronchoscopy in this study population.

Table 4. Complications

Twenty two complications occurred during or within 2 hours after the procedure (18%), with hypoxia being the most common (7.5%). Hypoxia in two patients occurred secondary to hemorrhage. Pneumothorax was seen in one patient who underwent transbronchial biopsy with no fluoroscopic guidance. Hypotension which needed treatment with fluids or vasopressors occurred in 5.8% and hemorrhage in 3.3%. Hemorrhage was unrelated to coagulopathy in the patients. Significant bradycardia requiring treatment with atropine occurred in one patient. No deaths were reported related to the procedures. None of the procedures had to be terminated secondary to the complications. More adverse events were seen among the patients who underwent other bronchoscopic procedures (29%) than those undergoing BAL or inspection only (9%), though this was not statistically significant (p = 0.07).

As depicted in Table 5, none of the complications were significantly affected by the underlying comorbidities or the APACHE scores.

Table 5. Patient Characteristics Stratified by Complications

Key: BAL: Bronchoalveolar lavage

       MAP: Mean Arterial Pressure

Complications were not significantly associated with the amount of oxygen required (FiO2) and the mode of ventilation which the patients were on prior to the procedure. Similarly, neither the mean arterial pressure before the procedure or coagulopathy influenced the rate of complications. Hospital mortality was not different in the group with or without complications.

Figure 1 and Table 6 show the BAL cell differential.

Figure 1. BAL differential in culture with normal respiratory flora (0), bacteria (1), Viral (2), Fungal (3) and Co-infection (4). Each bar represents the differential in percentage.

Key: BAL: Bronchoalveolar lavage

          BAL N: Neutrophil count in BAL (in percentage)

          BAL L: Lymphocyte count in BAL (in percentage)

          BAL M: Macrophages count in BAL (in percentage)

          BAL E: Eosinophils count in BAL (in percentage)

Table 6. Bronchoalveolar Lavage Differential

Patients found to have bacterial pneumonia or mixed viral and bacterial infection had significantly higher neutrophil counts (mean BAL neutrophil count 82% for bacterial infection, and 80% for co-infections) than other patients (p=0.001) (Figure 2).

Figure 2. Neutrophil predominance in bacterial pneumonia. KEY: BAL-N: Bronchoalveolar lavage, neutrophil differential (in percentage).

These patients also had a higher APACHE II score (p=0.02). Hospital mortality was higher among those with BAL positive for bacteria (p= 0.012). Mortality was also significantly higher among patients with underlying malignancy (p= 0.002).

Discussion

In our study of 120 ICU bronchoscopies, we found a complication rate of 18%. No deaths were observed in this study. Hypoxia was the most common adverse event in our study, occurring in 9 procedures (7.5%) as has been noticed in the previous studies. Introduction of a bronchoscope through an endotracheal (ET) tube is known to cause airway obstruction resulting in increasing intra-tracheal pressures and variation in respiratory physiology (6). Almost all the patients who were mechanically ventilated had a size 7.5 - 8.5 ET tube or had tracheostomy in place. As in prior studies, BAL performed for evaluation of pneumonia and atelectasis were the two most common indications of the procedure (72% and 15.8% respectively) in our study (1-7). Even though bronchoscopy has not shown to be routinely superior to chest physiotherapy, certain subset of patient population may benefit from it (3,8,9). Improvement in oxygenation has been shown to occur in certain earlier studies (10,11).

Hypotension is also a known complication occurring during bronchoscopy. Our study had 7 events (5.8%) of hypotension needing vasopressor or fluid infusion. This was likely related to the sedation. Hypertension was observed in one case and bradycardia requiring treatment was seen in one. Cardiovascular abnormalities associated with bronchoscopy is generally related to the sympathetic surge happening during the procedure and the hypoxia (12-14). Per earlier studies, the complication rate of transbronchial biopsies in mechanically ventilated patients range between 0-15% (15,16,17). But it is relatively safe in comparison to open lung biopsy.

With the advent of newer technology, there has been an increase in the number of other bronchoscopic interventional pulmonary (IP) procedures, including endobronchial ablative therapies such as APC and cryotherapy. Endobronchial lesions occupying more than 50% of the airway lumen can alter the airway physiology and result in hypoxia, ventilation perfusion mismatch and hence respiratory failure. Use of ablative therapies can potentially reverse this (18). APC has been an useful tool to remove endobronchial lesions and relieve obstruction. It has been shown to be efficient and relatively safe in outpatient setting, but APC on mechanically ventilated patients has not been very well studied (19). APC in mechanically ventilated patient requires decrease in the FiO2 to less than or equal to 40%. Complications related to IP procedures performed specifically in patients requiring mechanical ventilation are difficult to assess  from the available literature (20). However, given the complexity of these cases and underlying illness, usually the complications are minor. In our study, interventional bronchoscopy procedures like APC, cryotherapy was to relieve airway obstruction which was the cause of mechanical ventilation. In our study, APC case was associated with hemorrhage. The balloon dilatation and stenting which was performed for a case of tracheal stenosis arising from malignancy. This was not associated with any complications related to the procedure in our study. Further study is needed to refine our understanding of the risks of advanced bronchoscopic techniques in ICU patients.

Procedures like EBUS are usually not done in critically ill patients. There are no studies which have looked into the use of and complications of performing EBUS in critically ill patients. Bhaskar et al. (21) report the use of esophageal access for mediastinal sampling through EBUS in ICU patients for the reason of causing hypoxia and changes in airway physiology with the EBUS scope in airway. Our study had one patient who had an EBUS for lung mass and this was not associated with any complications.

Subgroup analysis in our study showed the presence of neutrophilic predominance with neutrophil count of >80% in the BAL differential in patients diagnosed with bacterial infections and co-infections compared to those with viral/ fungal or mixed flora (p=0.001). This was similar to results from earlier studies (22,23). Neutrophilic pleocytosis in BAL fluid is frequently found in patients with pneumonia. As the neutrophil count is higher in bacterial pneumonia, it can indicate towards a differential of bacterial pneumonia even prior to the final microbiology results. Hence BAL differential may be complimentary to final culture results and maybe helpful to initiate or discontinue antibiotics in critically ill patients. Mortality among critically ill patients with bacterial pneumonia was higher compared to others (p=0.012). These patients tend to be sicker with higher APACHE II scores.

The weaknesses of the study includes the fact that it was retrospective chart review. The total number is small, and the number of the IP procedures performed is even smaller. Hence it is important that more studies should be conducted looking into the safety and complications of IP procedures in critically ill patients.

Conclusion

Our study looked into the fiberoptic bronchoscopy with BAL and inspection as well as other therapeutic procedures done in the critically ill patients. It indicates that even in critically ill patients, bronchoscopy with inspection and BAL is safe. Other interventional pulmonary procedures may have more complications. Even though the number of IP procedures performed in the study is low, the evidence of slightly more number of complications with these procedures indicates the need for caution before attempting them in the critically ill patients.

References

1. Barrett CR Jr. Flexible fiberoptic bronchoscopy in the critically ill patient. Methodology and indications. Chest. 1978;73(5 Suppl):746-9. [CrossRef] [PubMed]
2. Hertz MI, Woodward ME, Gross CR, Swart M, Marcy TW, Bitterman PB. Safety of bronchoalveolar lavage in the critically ill, mechanically ventilated patient. Crit Care Med. 1991;19(12):1526-32. [CrossRef] [PubMed]
3. Olopade CO, Prakash UB. Bronchoscopy in the critical-care unit. Mayo Clin Proc. 1989;64(10):1255-63. [CrossRef] [PubMed]
4. Steinberg KP, Mitchell DR, Maunder RJ, Milberg JA, Whitcomb ME, Hudson LD. Safety of bronchoalveolar lavage in patients with adult respiratory distress syndrome. Am Rev Respir Dis. 1993;148(3):556-61. [CrossRef] [PubMed]
5. Prebil SE, Andrews J, Cribbs SK, Martin GS, Esper A. Safety of research bronchoscopy in critically ill patients. J Crit Care. 2014;29(6):961-4. [CrossRef] [PubMed]
6. Guerreiro da Cunha Fragoso E, Gonçalves JM. Role of fiberoptic bronchoscopy in intensive care unit: current practice. J Bronchology Interv Pulmonol. 2011;18(1):69-83. [CrossRef] [PubMed]
7. Raoof S, Mehrishi S, Prakash UB. Role of bronchoscopy in modern medical intensive care unit. Clin Chest Med. 2001;22(2):241-61, vii. [CrossRef] [PubMed]
8. Kreider ME, Lipson DA. Bronchoscopy for atelectasis in the ICU: a case report and review of the literature. Chest. 2003;124(1):344-50. [CrossRef] [PubMed]
9. Marini JJ, Pierson DJ, Hudson LD. Acute lobar atelectasis: a prospective comparison of fiberoptic bronchoscopy and respiratory therapy. Am Rev Respir Dis. 1979;119(6):971-8. [PubMed]
10. Snow N, Lucas AE. Bronchoscopy in the critically ill surgical patient. Am Surg. 1984;50(8):441-5. [PubMed]
11. Stevens RP, Lillington GA, Parsons GH. Fiberoptic bronchoscopy in the intensive care unit. Heart Lung. 1981;10(6):1037-45. [PubMed]
12. Katz AS, Michelson EL, Stawicki J, Holford FD. Cardiac arrhythmias. Frequency during fiberoptic bronchoscopy and correlation with hypoxemia. Arch Intern Med. 1981;141(5):603-6. [CrossRef] [PubMed]
13. Lindholm CE, Ollman B, Snyder JV, Millen EG, Grenvik A. Cardiorespiratory effects of flexible fiberoptic bronchoscopy in critically ill patients. Chest. 1978;74(4):362-8. [CrossRef] [PubMed]
14. Trouillet JL, Guiguet M, Gibert C, Fagon JY, Dreyfuss D, Blanchet F, Chastre J. Fiberoptic bronchoscopy in ventilated patients. Evaluation of cardiopulmonary risk under midazolam sedation. Chest. 1990;97(4):927-33. [CrossRef] [PubMed]
15. Bulpa PA, Dive AM, Mertens L, Delos MA, Jamart J, Evrard PA, Gonzalez MR, Installé EJ. Combined bronchoalveolar lavage and transbronchial lung biopsy: safety and yield in ventilated patients. Eur Respir J. 2003;21(3):489-94. [CrossRef] [PubMed]
16. O'Brien JD, Ettinger NA, Shevlin D, Kollef MH. Safety and yield of transbronchial biopsy in mechanically ventilated patients. Crit Care Med. 1997;25(3):440-6. [CrossRef] [PubMed]
17. Casal RF, Ost DE, Eapen GA. Flexible bronchoscopy. Clin Chest Med. 2013;34(3):341-52. [CrossRef] [PubMed]
18. Seaman JC, Musani AI. Endobronchial ablative therapies. Clin Chest Med. 2013;34(3):417-25. [CrossRef] [PubMed]
19. Morice RC, Ece T, Ece F, Keus L. Endobronchial argon plasma coagulation for treatment of hemoptysis and neoplastic airway obstruction. Chest. 2001;119(3):781-7. [CrossRef] [PubMed]
20. Boyd M, Rubio E. The utility of interventional pulmonary procedures in liberating patients with malignancy-associated central airway obstruction from mechanical ventilation. Lung. 2012;190(5):471-6. [CrossRef] [PubMed]
21. Bhaskar N, Shweihat YR, Bartter T. The intubated patient with mediastinal disease--a role for esophageal access using the endobronchial ultrasound bronchoscope. J Intensive Care Med. 2014;29(1):43-6. [CrossRef] [PubMed]
22. Stolz D, Stulz A, Müller B, Gratwohl A, Tamm M. BAL neutrophils, serum procalcitonin, and C-reactive protein to predict bacterial infection in the immunocompromised host. Chest. 2007;132(2):504-14. [CrossRef] [PubMed]
23. Choi SH, Hong SB, Hong HL, Kim SH, Huh JW, Sung H, Lee SO, Kim MN, Jeong JY, Lim CM, Kim YS, Woo JH, Koh Y. Usefulness of cellular analysis of bronchoalveolar lavage fluid for predicting the etiology of pneumonia in critically ill patients. PLoS One. 2014;9(5):e97346. [CrossRef] [PubMed]

Cite as: Ganesh A, Singh N, Carr GE. Safety and complications of bronchoscopy in an adult intensive care unit. Southwest J Pulm Crit Care. 2015;11(4):156-66. doi: http://dx.doi.org/10.13175/swjpcc106-15 PDF

October 2015 Pulmonary Case of the Month: I've Heard of Katy Perry

Kathryn E. Williams, MB

Maxwell L. Smith, MD

Philip J. Lyng, MD

Laszlo T. Vaszar, MD

 

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 45-year-old man with a history of dyslipidemia and a family history of early coronary artery disease (CAD) underwent coronary artery calcium scoring CT. He was a non-smoker and asymptomatic.

Past Medical History

In addition to his hyperlipidemia he has a history of obesity and impaired fasting glucose.

Physical Examination

His physical examination was unremarkable.

Radiography

The thoracic CT was interpreted as a low risk for CAD but there were incidental findings (Figure 1).

Figure 1. Panels A-C: Representative views from the thoracic CT scan in lung windows. Lower panel: video of thoracic CT in lung windows.

What incidental finding is not shown on thoracic CT scan. (Click on the correct answer to proceed to the second of six panels).

1. Honeycombing
2. Multiple small pulmonary nodules
3. Patchy ground glass opacities
4. Slightly enlarged mediastinal lymph nodes

Cite as: Williams KE, Smith ML, Lyng PJ, Vaszar LT. October 2015 pulmonary case of the month: I've heard of Katy Perry. Southwest J Pulm Crit Care. 2015;11(4):126-35. doi: http://dx.doi.org/10.13175/swjpcc123-15 PDF

Pulmonary Hantavirus Syndrome: Case Report and Brief Review

Charles J. VanHook, MD

Britt Warner, PA

Angela Taylor, MD

Longmont United Hospital

Longmont, Colorado

A 31-year-old white man presented to the emergency department complaining of fever, headache, mild confusion, and muscle aches. Approximately three days earlier he had developed non-quantified fever and diffuse muscle aches and pains. He was employed as a feedlot worker. He had visited an urgent care center one day earlier and had been advised to increase his oral fluid intake and to use non-steroidal anti-inflammatory agents as needed. Upon arrival to the emergency department he was found to have a temperature of 103.6º Fahrenheit, blood pressure of 125/72 mm Hg, respiratory rate of 40 breaths per minute, and room-air oxygen saturation of 84% by pulse oximetry. Auscultation of the chest disclosed diffuse rales. Heart sounds were rapid and regular. Abdominal exam was benign. There was no skin rash. Central nervous exam demonstrated agitation and confusion, but was otherwise non-focal. Laboratory examination revealed a white blood count of 11.7 K/uL, hemoglobin of 21.5 g/DL, hematocrit of 66.8%, platelet count of 73 K/uL, partial thromboplastin time of 36 seconds, lactic acid of 2.4 mm/L, and procalcitonin of 43 ng/mL. Chest radiograph disclosed extensive bilateral infiltrates (Figure 1).

Figure 1. Chest x-ray showing bilateral infiltrates

The patient precipitously declined, with severe respiratory distress, and was emergently intubated. Despite aggressive measures, including mechanical ventilation with an FIO2 of 1.0 and PEEP of 18 cm H2O, vigorous intravenous intravenous fluid resuscitation with normal saline, and pressor support with intravenous norepinephrine and vasopressin, the patient developed refractory hypoxemia. This was followed by a bradycardic arrest and death 2 hours after presentation. Serology sent at the time of admission later returned as IgM positive for hantavirus, with subsequent testing positive for Sin Nombre IgM.

Hantaviruses are RNA viruses of the family Bunyaviridae that are transmitted to humans by contact with the saliva, urine, or feces of infected rodents, which serve as persistently infected hosts (1). Patients who work in proximity to rodents, such as animal trappers, farmers, and forestry workers are at highest risk for infection. In the Western Hemisphere, there are approximately 200 cases per year of Hantavirus Pulmonary Syndrome (HPS), which was first identified in the Four Corners area of the Southwestern United States in 1993 (2). In the United States, HPS is most commonly caused by the Sin Nombre subfamily of hantavirus. A two-week incubation period precedes a 3-6 day prodromal period during which fever and myalgia are prominent features. The cardiopulmonary phase of HPS follows, with the development of acute non-cardiogenic pulmonary edema and multi-organ dysfunction. Typical laboratory abnormalities are leukocytosis and thrombocytopenia. Elevations in hematocrit and partial thromboplastin time are strong predictors of mortality, which approaches 40%. Definitive diagnosis depends on the serologic identification of IgM antibody to hantavirus using ELISA technology.  Immunochromatographic technology may allow for same day diagnosis (3). Treatment is supportive, and varies with the severity of disease. It may include volume resuscitation, ventilatory support, and renal replacement therapy. There is no established anti-viral therapy for Hantavirus infection, although ribavirin is often used in Asia. Corticosteroids have also been used sporadically with some success, but their use remains controversial (3).

Although Hantavirus remains a rare disease, prodromal symptoms in a patient with associated epidemiologic risk factors should heighten clinical suspicion.

References

1. Lednicky JA. Hantavirus: A short review. Arch Pathol Lab Med. 2003;127:30-35. [PubMed]
2. Duchin JS, Koster FT, Peters CJ, Simpson GL, Tempest B, Zaki S, Ksiazek TG, Rollin PE, Nichol S, Umland E, Moolenaar RL, Reef SE, Nolte KB, Gallaher MM, Butler JC, Breiman RF. Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease. N England J Med 1994;330:949-55 [CrossRef] [PubMed]
3. Bi Z, Formenty P, Roth C Hantavirus infection: A review and global update. J Infect Developing Countries. 2008;2(1):3-23. [CrossRef] [PubMed]

Cite as: VanHook CJ, Warner B, Taylor A. Pulmonary hantavirus syndrome: case report and brief review. Southwest J Pulm Crit Care. 2015;11(3):121-3. doi: http://dx.doi.org/10.13175/swjpcc122-15 PDF

September 2015 Pulmonary Case of the Month: Holy Smoke

Samir Sultan, DO

David M. Baratz, MD

Banner University Medical Center Phoenix

Phoenix, AZ

History of Present Illness

A 43-year-old woman presents to the office for second opinion of her dyspnea. She has very mild dyspnea with exertion which she notices when she cannot keep up with people going up stairs. She also has a "smoker’s cough".

Past Medical History, Family History, Social History

Her past medical history, family history and social history are unremarkable other than she smokes 1 ppd for the past 20 years and had a "collapsed lung" about 15 years ago.

Physical Examination

Her physical examination was unremarkable except for a small scar on her right chest.

Radiography 

A chest x-ray (Figure 1) was performed. 

 

Figure 1. PA (Panel A) and lateral (panel B) chest radiography.

Which of the following are true regarding the chest x-ray? (Click on the correct answer to proceed to the second of five panels)

1. The chest -ray shows a widened mediastinum
2. The chest x-ray is normal
3. The chest x-ray shows a diffuse reticulonodular infiltrate
4. The chest x-ray shows bilateral hilar adenopathy
5. The chest x-ray shows small bilateral pleural effusions

Cite as: Sultan S, Baratz DM. September 2015 puilmonary case of the month: holy smoke. Southwest J Pulm Crit Care. 2015;11(3):90-6. doi: http://dx.doi.org/10.13175/swjpcc112-15 PDF

August 2015 Pulmonary Case of the Month: Holy Sheep

Jennifer M. Hall, DO

David M. Baratz, MD

Banner University Medical Center Phoenix

Phoenix, AZ

History of Present Illness

A 42-year-old woman presented to the emergency department with chest pain and dyspnea. The onset of symptoms was acute, initially endorsing left-sided sharp chest pain which then progressed with dyspnea. Chest radiograph was read as normal. Laboratory evaluation was notable for an elevated D-Dimer which prompted a thoracic CT scan to be obtained.

Past Medical History, Family History, Social History

• She had well-controlled rheumatoid arthritis (on no medical therapy) and was diagnosed with emphysema by her PCP two years earlier.
• Her mother died from pulmonary embolism secondary to underlying lung cancer.
• She quit smoking 2 years ago with a total of 20-pack-years.

Physical Examination

Patient was in mild distress with heart rate of 105, respiratory rate of 22, but otherwise stable, SpO2 was 95% while breathing ambient air. She had diminished breath sounds in both bases, but otherwise her chest was clear to auscultation. The remainder of the exam was unremarkable.

Radiography 

A chest x-ray (Figure 1) and a thoracic CT scan (Figure 2) were performed.

Figure 1. Initial PA of the chest.

Figure 2. Thoracic CT scan in lung windows. Panels A-F: representative static images. Lower panel: video.

A chest tube was placed for the left-sided pneumothorax.

What is the next step in management? (Click on the correct answer to proceed to the second of five panels)

1. Bronchoscopy
2. Consider pleurodesis
3. Observation with repeat CT in 3 months
4. Open lung biopsy
5. 1 and 3
6. 2 and 4

Reference as: Hall JM, Baratz DM. August 2015 pulmonary case of the month: holy sheep. Southwest J Pulm Crit Care. 2015;11(2):53-8. doi: http://dx.doi.org/10.13175/swjpcc103-15 PDF

Reducing Readmissions after a COPD Exacerbation: A Brief Review

Richard A. Robbins, MD¹

Lewis J. Wesselius, MD²

¹The Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ

²Mayo Clinic Arizona

Scottsdale, AZ

Abstract

CMS' Hospital Readmissions Reduction Program (HRRP) was extended to chronic obstructive pulmonary disease (COPD) exacerbations in October 2014. HRRP penalizes hospitals if admissions for COPD exacerbations exceed a higher than expected all-cause 30-day readmission rate. Recently, a review of 191,698 Medicare readmissions after a COPD exacerbation reported that COPD explained only 27.6% of all readmissions. Patients were more likely to be readmitted if they were discharged home without home care, dually enrolled in Medicare and Medicaid, and had more comorbidities (p<0.001 compared to patients not readmitted). Data on interventions is limited but recently a study of bundled interventions of smoking cessation counseling, screening for gastroesophageal reflux disease and depression or anxiety, standardized inhaler education, and a 48-h postdischarge telephone call did not result in a lower readmission rate. We conclude that there is limited evidence available on readmission risk factors, reasons for readmission and interventions that might reduce readmissions. In the absence of defined, validated interventions it seems likely that CMS's HRRP will be unsuccessful in reducing hospital readmissions after a COPD exacerbation.

Introduction 

To address rising costs and quality concerns, the Hospital Readmissions Reduction Program (HRRP) was enacted, targeting inpatient discharges in the Medicare fee-for-service population for congestive heart failure (CHF), acute myocardial infarction (AMI), and pneumonia in 2012. HRRP was extended to chronic obstructive pulmonary disease (COPD) exacerbations in October 2014.

Correlation of Readmissions with Outcomes

There were about 800,000 hospitalizations for COPD exacerbations annually, with about 20% of patients needing to be rehospitalized within 30 days of discharge (2,3). The cost of readmissions is about $325 million for the U.S. Centers for Medicare and Medicaid Services (CMS) (4). Therefore, it is hardly surprising that CMS is attempting to reduce COPD readmission to reduce costs. The implication is that care was incomplete or sloppy on the first admission, and that better care might reduce readmissions.

However, a number of concerns have been raised questioning the wisdom of the HRRP. Hospitals with better mortality rates for heart attacks, heart failure and pneumonia had significantly greater penalties for readmission rates (5). If this correlation is found to be true with randomized trials, then CMS is financially encouraging hospitals to perform an action with potential patient harm and suggest that CMS continues to rely on surrogate markers that have little or no correlation with patient-centered outcomes. Until this question is resolved, we cannot recommend programs that discourage hospital readmissions.

Differences between COPD Exacerbations and CHF, AMI and Pneumonia Methodology

Several aspects of COPD exacerbations differentiate it from other conditions included in HRRP. AMI, CHF, pneumonia and COPD exacerbations are all defined by discharge ICD-9 codes. Examination of ICD-9 coding against physician chart review found profound underestimation of COPD exacerbations, with sensitivities ranging from 12% to 25% and positive predictive values as low as 81.5% (6). In contrast, coding data to identify pneumonia and AMI have a sensitivity and positive predictive value of over 95% (7,8). Therefore, there is a high probability of misclassification of COPD exacerbations used to calculate the readmissions penalty.

COPD exacerbations are clinically defined while AMI and CHF are defined by biomarkers (plasma troponin, B-type natriuretic peptide) and pneumonia is defined by not only a compatible clinical situation but by consolidation on chest radiography. Because COPD symptoms overlap with many other diseases, biomarker and radiograph evidence can make accurate diagnosis difficult. Furthermore, this uncertainty in diagnosis may provide an opportunity for hospitals to game the system by excluding sicker patients who present with COPD from the readmission measure (9).

COPD may also require prolonged times for recovery as opposed to AMI, CHF, and pneumonia patients who seem to require shorter recovery times. One quarter of patients with a COPD exacerbation had not returned to preexacerbation peak expiratory flow rate by day 35 (10).

There is also a suggestion of a frequent exacerbation phenotype of COPD independent of disease severity (11). The single best predictor of exacerbations was a history of exacerbations, although a history of gastroesophageal reflux (GERD) was also associated with increased exacerbations. A hospital with higher numbers of patients with the frequent exacerbation phenotype or with GERD would be expected to have a higher readmission rate but would be penalized under CMS' HRRP.

Causes for Readmission after a COPD Exacerbation

Most patients readmitted after a COPD exacerbation are not readmitted for COPD. Shah et al. (9) recently examined nearly 200,000 COPD exacerbation hospital readmissions in the Medicare population. Only 27.6% were classified as being readmitted for COPD. There were a variety of readmission diagnosis with respiratory failure, pneumonia, CHF, asthma, septicemia, cardiac dysrhythmias, fluid and electrolyte disorders, intestinal infection, and non-specific chest pain and other accounting for the rest. This data is consistent with previous studies by Jencks et al. (12) who found 36.2% of exacerbation patients were readmitted for COPD. Not surprisingly, the sickest patients (as defined by the Charlson sum) are more likely to be readmitted (9). This would also be consistent with causes of readmission being diverse rather than limited to COPD.

Importantly, two observations were made which may have major implications for care after COPD exacerbations (9). First, patients dually enrolled in Medicare and Medicaid had higher readmission rates. These patients tend to be poorer and seek care at "safety net" hospitals. A penalty for readmissions would be largest at these hospitals which may most in need of financial help. Second, patients discharged home without home care were more likely to be readmitted. This will likely influence more discharges to either an extended care facility or with home care which may actually increase costs rather than result in the cost savings that CMS hopes to collect.

Interventions that Reduce COPD Readmissions

Jennings et al. (13) used a "bundle" for patients with COPD exacerbations in hopes of reducing readmissions and emergency department visits. The bundle consisted of smoking cessation counseling, screening for gastroesophageal reflux disease and depression or anxiety, standardized inhaler education, and a 48 hour postdischarge telephone call. It is easy to criticize these interventions. A single session of smoking cessation counseling is usually inadequate (14). Although gastroesophageal reflux disease has been associated with COPD, there is only a single trial with lansoprazole demonstrating a reduction in COPD exacerbations (15). To our knowledge there is no data on screening for depression or anxiety, standardized inhaler education and a single phone call in preventing COPD readmissions. Not surprisingly, the bundle did not work. However, it underscores that interventions to prevent COPD readmissions are unknown. Until these are defined, it seems unlikely that any program will be successful in reducing COPD readmissions.

Potential COPD Readmission Reduction Strategies

Discharge and Follow-Up

Discharge to an extended care facility or with home care reduces readmissions (9). Approximately one third of readmissions after hospitalization for COPD occur within 7 days of discharge and 60% occur within 15 days (9). Therefore, even close outpatient followup within 2 weeks of discharge from the hospital, may not prevent a majority of readmissions. However, we would recommend that close follow-up of patients be liberal which seems likely to have some impact on readmissions. Follow-up telephone calls may be reasonable but probably need to be more than a single call at 48 hours (13). We offer some additional suggestions below that have not been subjected to randomized trials, but seem reasonable based on the current state of knowledge.

Pharmacologic Therapy

1. Bronchodilators. Many of the therapies that treat COPD exacerbations have been tested to determine if chronic use might prevent exacerbations. The best evidence is for the long-acting bronchodilators. Two large randomized controlled trials have confirmed that a combination of a long-acting beta agonist (salmeterol) with an inhaled corticosteroid (fluticasone) or a long-acting anticholinergic (tiotropium) reduce exacerbations (16,17). Given that only about one-third of readmissions are due to COPD, the impact, if any, with addition of long-acting bronchodilators after a COPD exacerbation would likely be small. The newer long-acting beta agonists and anticholinergics would also be expected to reduce exacerbations and might prevent readmissions.
2. Inhaled corticosteroids. Addition of inhaled corticosteroids to long-acting bronchodilators in COPD remains controversial. A meta-analysis by Spencer et al. (18) recommended regular inhaled corticosteroid therapy as an adjunct in patients experiencing frequent exacerbations. However, the data supporting this recommendation is unclear. It is also unclear if their addition would prevent readmissions.
3. Antibiotics. Continuous or intermittent treatment with some antibiotics, particularly macrolides, reduces exacerbations. Treatment with azithromycin for one year lowered exacerbations by 27% (19). Although the mechanism(s) accounting for the reduction in exacerbations is unknown, current concepts suggest the reduction is likely secondary to the macrolides’ anti-inflammatory properties. However, concern has been raised about a very small, but significant, increase in QT prolongation and cardiovascular deaths with azithromycin (20). In addition, the recent trial with azithromycin raised the concern of hearing loss which occurred in 25% of patients treated with azithromycin compared to 20% of control (19). An alternative to the macrolides may be tetracyclines such as doxycycline, which also possess anti-inflammatory properties but do not lengthen QT intervals nor cause hearing loss (21). Similar to the long-acting bronchodilators, antibiotics might reduce readmissions, but since most readmissions are not due to COPD, the effect would likely be small.
4. Medication Compliance. Poor compliance with inhaled therapies has been implicated as a factor contributing to COPD exacerbations (22). The role of COPD medication noncompliance has not been specifically assessed in hospital readmissions, although it seems likely to be a contributing factor. Socioeconomic factors influence medication compliance and could lead to greater readmission rates in hospitals caring for patients with limited financial and social resources. Poor compliance with COPD medications as well as medications for comorbid conditions may both be important as most readmissions are not due to COPD.

Conclusions

Prevention of COPD readmissions after a COPD exacerbation represents a challenge with no straight-forward strategies to reduce readmissions other than discharge to an extended care facility or home with home health. Readmissions come from heterogeneous causes but most are not due to COPD suggesting that comprehensive care for disorders other than just COPD is likely important.

References

1. Centers for Medicare and Medicaid Services. Readmissions reduction program. Available at: http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/AcuteInpatientPPS/Readmissions-Reduction-Program.html (accessed 6/4/15).
2. Wier LM, Elixhauser A, Pfuntner A, Au DH. . Overview of hospitalizations among patients with COPD, 2008: Statistical Brief #106. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs [Internet]. Rockville, MD: Agency for Health Care Policy and Research (US); 2006–2011 Feb. Available from: http://www.hcup-us.ahrq.gov/reports/statbriefs/sb106.pdf (accessed 5/4/15)
3. Elixhauser A, Au DH, Podulka J. . Readmissions for chronic obstructive pulmonary disease, 2008: Statistical Brief #121. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs [Internet]. Rockville, MD: Agency for Health Care Policy and Research (US); 2006–2011 Sep. Available from: http://www.hcup-us.ahrq.gov/reports/statbriefs/sb121.pdf (accessed 6/4/15).
4. Medicare Payment Advisory Commission (MEDPAC). Report to the Congress: promoting greater efficiency in Medicare, 2007.
5. Robbins RA, Gerkin RD. Comparisons between Medicare mortality, morbidity, readmission and complications. Southwest J Pulm Crit Care. 2013;6(6):278-86.
6. Stein BD, Bautista A, Schumock GT, Lee TA, Charbeneau JT, Lauderdale DS, Naureckas ET, Meltzer DO, Krishnan JA. The validity of International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for identifying patients hospitalized for COPD exacerbations. Chest. 2012;141(1):87-93. [CrossRef] [PubMed]
7. Skull SA, Andrews RM, Byrnes GB, et al. ICD-10 codes are a valid tool for identification of pneumonia in hospitalized patients aged ≥ 65 years. Epidemiol Infect. 2008;136(2):232-40. [CrossRef] [PubMed]
8. Kiyota Y, Schneeweiss S, Glynn RJ, Cannuscio CC, Avorn J, Solomon DH. Accuracy of Medicare claims-based diagnosis of acute myocardial infarction: estimating positive predictive value on the basis of review of hospital records. Am Heart J. 2004;148(1):99-104. [CrossRef] [PubMed]
9. Shah T, Churpek MM, Coca Perraillon M, Konetzka RT. Understanding why patients with COPD get readmitted: a large national study to delineate the medicare population for the readmissions penalty expansion. Chest. 2015;147(5):1219-26. [CrossRef] [PubMed]
10. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161(5):1608-13. [CrossRef] [PubMed]
11. Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, Miller B, Lomas DA, Agusti A, Macnee W, Calverley P, Rennard S, Wouters EF, Wedzicha JA; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128-38. [CrossRef] [PubMed]
12. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service program. N Engl J Med. 2009;360(14):1418-28. [CrossRef] [PubMed]
13. Jennings JH, Thavarajah K, Mendez MP, Eichenhorn M, Kvale P, Yessayan L. Predischarge bundle for patients with acute exacerbations of COPD to reduce readmissions and ed visits: a randomized controlled trial. Chest. 2015;147(5):1227-34. [CrossRef] [PubMed]
14. Rigotti NA, Munafo MR, Stead LF. Smoking cessation interventions for hospitalized smokers: A systematic review. Arch Intern Med. 2008;168:1950-60. [CrossRef] [PubMed]
15. Sasaki T, Nakayama K, Yasuda H, Yoshida M, Asamura T, Ohrui T, Arai H, Araya J, Kuwano K, Yamaya M. A randomized, single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patients. J Am Geriatr Soc. 2009;57(8):1453-7. [CrossRef] [PubMed]
16. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775-89. [CrossRef] [PubMed]
17. Tashkin DP, Celli B, Senn S, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543-54. [CrossRef] [PubMed]
18. Spencer S, Karner C, Cates CJ, Evans DJ. Inhaled corticosteroids versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011 Dec 7;(12):CD007033. [PubMed]
19. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, Make B, Marchetti N, Martinez FJ, Madinger NE, McEvoy C, Niewoehner DE, Porsasz J, Price CS, Reilly J, Scanlon PD, Sciurba FC, Scharf SM, Washko GR, Woodruff PG, Anthonisen NR; COPD Clinical Research Network. COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011; 365:689-98. [CrossRef] [PubMed]
20. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366:1881-90. [CrossRef] [PubMed]
21. Rempe S, Hayden JM, Robbins RA, Hoyt JC. Tetracyclines and pulmonary inflammation. Endocr Metab Immune Disord Drug Targets. 2007;7:232-6. [CrossRef] [PubMed]
22. Ismaila A, Corriveau D, Vaillancort J, Parsons D, Dalal A, Su Z, Sampalis JS. Impact of adherence to treatment with tiotropium and fluticasone propionate/salmeterol in chronic obstructive pulmonary disease patients. Curr Med Res Opin. 30(7);1427-36, 2014. [CrossRef] [PubMed] 

Reference as: Robbins RA, Wesselius LJ. Reducing readmissions after a COPD exacerbation: a brief review. Southwest J Pulm Crit Care. 2015;11(1):19-24. doi: http://dx.doi.org/10.13175/swjpcc089-15 PDF

July 2015 Pulmonary Case of the Month: A Crazy Case

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 23-year-old woman presented in 2008 at outside institution with dyspnea and diffuse pulmonary infiltrates. She required intubation. After a surgical lung biopsy, she was transferred to the Mayo Clinic Hospital for further care.

Past Medical History

She has had a history of progressive dyspnea for several months, otherwise negative 

Physical Examination

Vital signs are stable. SpO2 94% on FiO2 of 0.4. She is intubated and there is a chest tube in her right chest. Otherwise the physical examination is unremarkable.

Radiography

A thoracic CT scan was performed (Figure 1).

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

Which of the following are present on the thoracic CT scan? (click on the correct answer to proceed to the second of five panels)

1. Diffuse ground-glass opacities
2. Interlobular septal thickening and intralobular reticular thickening
3. Right-sided pneumothorax
4. 1 and 3
5. All of the above

Reference as: Wesselius LJ. July 2015 pulmonary case of the month: a crazy case. Southwest J Pulm Crit Care. 2015;11(1):3-10. doi: http://dx.doi.org/10.13175/swjpcc079-15 PDF

June 2015 Pulmonary Case of the Month: Collapse of the Left Upper Lobe

G. Zacharia Reagle DO

Andreas Escobar-Naranjo MD

Department of Internal Medicine

Division of Pulmonary and Critical Care

UCSF Fresno

Fresno, CA

History of Present Illness

A 65 year-old woman who recently quit smoking presented to the ER for the third time in the preceding month with dyspnea and cough. She reported some subjective fevers and cough productive of white sputum as well as a seven kilogram unintentional weight loss in the prior four to eight weeks. She had been diagnosed with COPD in the past and on both prior ER visits was treated with oral steroids and antibiotics. She would feel some relief with the steroids but once the course was over she would quickly experience a return of her symptoms. On the third ER presentation she was admitted to the hospital.

Past Medical History:

• Asthma
• HTN
• Hypothyroidism

Past Surgical History:

• C-section x 2
• TAH and BTL
• Appendectomy
• Tonsillectomy

Medications:

• Levothyroxine 0.15mg daily
• Budesonide 40/formoterol 4.5 twice daily
• Tiotropium 18 mcg daily
• Fluoxetine 20mg daily
• Hydroxyzine 50mg three times daily
• Hydrochlorothiazide 50/triamterene 75 daily
• As needed albuterol

Allergies: No Known Drug Allergies

Social History:

A lifelong Californian, she was divorced with two healthy adult children. She is a United States Air Force veteran who served as a broadcaster from 1974-78 including a deployment to Asia. After leaving the service she worked as a Registered Nurse in burn, rehab and home health nursing. A former tobacco smoker with 35+ pack years of tobacco exposure – she quit smoking one month prior to the current admission. She is currently homeless, living in a homeless veteran’s shelter. She is a recovering alcoholic and cannabis addict.

Physical Exam:

General: Alert, mild respiratory distress, mildly anxious.

Vitals: BP: 134/80 HR: 104 RR: 18, SpO2 93% on room air T: 98.4ºF

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

Lungs: equal chest expansion, scattered bilateral wheezes with decreased airflow on the left

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

Abdomen soft, Non-tender, good bowel sounds.

Extremities No edema, nor clubbing.

Neurological: She was alert and oriented with a Glasgow Coma Score of 15, no focal defects noted.

Skin: No rashes noted.

Laboratory:

CBC: WBC 6.9 X 10⁹ cells/L, hemoglobin13.4 g/dL, hematocrit 39.4, platelet count 329 X 10⁹ cells/L

Chemistries: Na+ 139 mEq/L, K+ 3.5 mEq/L Cl- 106 mEq/L, CO2 26 mEq/L  BUN 8 mg/dL, creatinine 0.6 mg/dL, glucose 149 mg/dL, magnesium 2.0 mg/dL, phosphate 3.4 mg/dL

Mycoplasma IgM: (-)

S. pneumoniae urinary antigen: (-)

Legionella urinary antigen: (-)

Blood Cultures: (-)

Imaging:

On admission a chest CT was preformed (Figure 1).

Figure 1. Representative images from the thoracic CT scan showing central and upper zone predominate bronchiectasis, and total collapse of the left upper lobe. There also was some emphysema noted.

Which of the following causes of bronchiectasis should be considered in this case? (Click on the correct answer to proceed to the second of six panels)

1. Allergic bronchopulmonary aspergillosis
2. Autoimmune diseases including rheumatoid arthritis and Sjogren’s syndrome
3. Congenital pulmonary conditions including cystic fibrosis and primary ciliary dyskinesia
4. Immunoglobulin deficiency
5. All of the above are possible causes of bronchiectasis

Reference as: Reagle GZ, Escobar-Naranjo A. June 2015 pulmonary case of the month: collapse of the left upper lobe. Southwest J Pulm Crit Care. 2015;10(6):315-22. doi: http://dx.doi.org/10.13175/swjpcc072-15 PDF 

Lung Herniation: An Unusual Cause of Chest Pain

Max L. Cohen MD PhD

Sumugdha Rayamajhi MD

Jonathan S. Kurche MD PhD

Carolyn H. Welsh MD

Denver VA Medical Center

University of Colorado Denver

Denver, CO

Abstract

We report a morbidly obese 72-year-old man admitted with acute right-sided chest pain and hypoxemia following bouts of vigorous coughing. This case illustrates the need to consider unusual etiologies of a common clinical presentation.

Case Presentation

History of Present Illness

A 72-year-old morbidly obese male presented with a feeling of tearing chest pain radiating to the right flank following repeated bouts of vigorous coughing. He was unable to take in a deep breath or lie flat and developed an abdominal bruise shortly after the tearing pain. He denied fever, dizziness or change in his baseline clear phlegm.

His medical history included GOLD I chronic obstructive pulmonary disease for which he used daily inhaled budesonide/formoterol, as-needed inhaled albuterol/ipratropium, and supplemental oxygen with exertion at 3 liters per minute. One year prior to admission, his FEV1/FVC ratio was 0.69 with air trapping and diffusion capacity 79% predicted. He had severe obstructive sleep apnea with an apnea hypopnea index of 52 for which he used home bi-level positive pressure at night at 25/14 cm water (IPAP/EPAP) with supplemental oxygen at 2 liters per minute. He had not recently received systemic corticosteroids; his last course was 5 months prior to admission.

Past Medical History

He had hypertension, hypothyroidism, gout, an umbilical hernia, hyperlipidemia, diverticulosis, and a peripheral neuropathy due to Agent Orange exposure.

Past surgical history included a remote uvulopalatopharyngoplasty (UPPP) for his sleep apnea. Three years previously he fell from a motor scooter and was hospitalized with four fractured left ribs.

He drank alcohol frequently until several months prior to admission.

Physical Examination

Vital signs on presentation were significant for a heart rate of 110, a respiratory rate of 22, and hypoxia with an O₂ saturation of 88% on room air. His BMI was 52 kg/m². Breath sounds were distant and diminished on the right side. He had extensive ecchymosis extending from the right flank to the periumbilicum, and a tender right chest wall in the lower mid-clavicular region. He had a large umbilical hernia that was easily reduced. His legs showed 3+ edema to the thighs.

Laboratory findings

He had a white blood cell count of 11,300/ul, a hemoglobin of 10.9 g/dL, and a platelet count of 319,000/ul. He had a normal creatinine, electrolytes, and a negative troponin. The proBNP was 449 pg/ml.

Radiography

Admission roentography and computed tomography of the chest with contrast (not shown) initially revealed hyperinflated lungs, a small loculated pleural effusion, a chest wall hematoma on the right, and no pulmonary thromboembolus.

Hospital Course

Bi-level positive pressure non-invasive ventilation (PAP) was resumed with his normal home settings of 25/14 cm water. Supplemental oxygen was administered, and a combination of opiates and NSAIDs were used for pain control. He remained hypoxic, with a persistent cough, and worsening pain. The character of the pain changed from tearing to pleuritic. Repeat computed tomography of the chest prompted by persistent pain revealed herniation of lung parenchyma through the 8^th and 9^th rib to the extrathoracic space (Figures 1).

Figure 1. Panel A: Repeat CT scan with axial reconstruction demonstrating extra-thoracic presence of lung parenchyma (arrow). Panel B: Repeat CT scan with coronal reconstruction demonstrating herniation of lung parenchyme through the 8^th-9^th intercostal space (arrow).

A palpable subcutaneous mass was not present at any point during his hospitalization. The cardiothoracic surgery service was consulted for possible intervention. Given the non-incarcerated nature of hernia and presence of multiple comorbidities, a decision was made to conservatively manage and follow with repeated thoracic imaging. His pain and hypoxemia gradually improved.

Six months after presentation, lung herniation was still visible on roentography (Figure 2) but he had minimal residual pain.

Figure 2. PA chest film 6 months after initial presentation showing persistence of herniated lung (arrow).

Due to the lack of symptoms, no surgical intervention was recommended.

Discussion

Pulmonary herniation is rare. By definition, it is the protrusion of lung tissue and pleural membranes beyond the confines of thoracic cavity, and is classified as Cervical, Thoracic, Diaphragmatic or Mediastinal depending on its anatomic location (1). Etiology-based classification divides it as congenital or acquired; while congenital hernias are typically found early in life, they can present in adults (2).  Congenital hernias are associated with costal or cartilage malformation, whereas acquired hernias involve intercostal muscle weakness, especially with conditions that cause increases in intrathoracic pressure such as coughing (3), heavy weight lifting, profound obesity, or positive-pressure ventilation (including by non-invasive methods) (1-4). Other precipitating factors can include trauma, surgery, chronic obstructive pulmonary disease, asthma, chronic steroid use, inflammatory or neoplastic process (1-5). Our patient had many of the known above-mentioned risk factors and developed spontaneous traumatic herniation, likely due to vigorous coughing that led to an intercostal muscle tear. While rare, lung herniation should be considered in a patient with risk factors and chest pain, dyspnea, or hypoxemia without a clear cause.

References

1. Detorakis E, Androulidakis E. Intercostal lung herniation--the role of imaging. J Radiol Case Rep. 2014;1(8):16–24. [CrossRef] [PubMed]
2. Weissberg D, Refaely Y. Hernia of the lung. Ann Thorac Surg. 2002;74(6):1963-6. [CrossRef] [PubMed]
3. O'Shea M, Cleasby M. Lung herniation after cough-induced rupture of intercostal muscle. N Engl J Med. 2012;366(1):74. [CrossRef] [PubMed]
4. Sulaiman A, Cottin V, De Souza Neto EP, Orsini A, Cordier JF, Gamondes JP, Tronc F. Cough-induced intercostal lung herniation requiring surgery: Report of a case. Surg Today. 2006;36(11):978–80. [CrossRef] [PubMed]
5. Cafarotti S, Matarelli E, Guerra A, Dutly A. Large intercostal pulmonary hernia secondary to limited-access aortic valve surgery: video-assisted thoracoscopic technique repair. Lung. 2013;192(2):333–4. [CrossRef] [PubMed]

Reference as: Cohen ML, Rayamajhi S, Kurche JS, Welsh CH. Lung herniation: An ususal cause of chest pain. Southwest J Pulm Crit Care. 2015;10(5):311-4. doi: http://dx.doi.org/10.13175/swjpcc060-15 PDF

Valley Fever (Coccidioidomycosis): Tutorial for Primary Care Professionals

John N. Galgiani, MD

Valley Fever Center For Excellence

The University of Arizona

Tucson, AZ

Preface

In the south and central deserts of Arizona and the central valley of California, Valley Fever should be a familiar phrase to clinicians and patients alike. It is estimated that over 50,000 persons each year, or approximately 1% of the population within the most endemic regions, seek medical care for newly acquired Valley Fever infections. Certain medical and surgical specialists practicing in these areas are particularly likely to be aware of the less frequent but more serious complications of the disease. In recent years, both the Centers for Disease Control and Prevention and the Arizona Department of Health Services have contributed significantly to our understanding of Valley Fever as a public health problem.

However, despite the significant impact of these complications on regional public health and individual lives, the majority of these infections are managed by primary care clinicians either without an accurate diagnosis or with sub-optimal care.

In January 1996, the Valley Fever Center for Excellence established a hotline that physicians and others with questions about Valley Fever could call for information. From the questions received through the hotline, it became increasingly apparent that many details about the causes of and necessary responses to Valley Fever were not fully understood.

One area of particular importance was the need for timely diagnosis and proper management of the initial respiratory infection. Early diagnosis of Valley Fever by primary care professionals can improve patient care by reducing patient anxiety, unneeded diagnostic tests, and unwarranted use of antibacterial agents. Moreover, early appropriate treatment can reduce the incidence of serious complications requiring additional treatment. We hope to improve this situation with this revised edition of Valley Fever (Coccidioidomycosis) Tutorial for Primary Care Professionals.

The purposes of this monograph are two-fold. First, it is intended to be a  syllabus to accompany a medical education program on the primary care aspects of coccidioidomycosis organized by the Valley Fever Center for Excellence. Slide presentations from the CME program can be found at the  Valley Fever Center for Excellence website (www.vfce.arizona.edu). While this syllabus does not follow the presentation structure of the CME program, it covers much of the same information. 

Medical centers, health maintenance organizations, or other medical groups interested in bringing this program to their site for their clinicians can arrange to do so by contacting the Center at (520) 626-6517 or through its website at http://www.vfce.arizona.edu.

Second, this publication is designed to be a reference for the office shelf. The information it contains is not intended to be an exhaustive review of the disease. The content was selected for its relevance and usefulness to busy family practitioners, internists, emergency room personnel, and others dealing with patients in the primary care setting, especially within regions endemic for the Coccidioides species.

We hope you find this information helpful. Formatting and printing of this version of Valley Fever (Coccidioidomycosis) Tutorial for Primary Care Professionals was made possible by an unrestricted grant to the Valley Fever Center for Excellence from Nielsen BioSciences, whose support we greatly appreciate.

Overview  of Coccidioidomycosis

History

The first patient recognized with what is now known as coccidioidomycosis was an Argentinean soldier in 1893. The first North American patient was recognized by a San Francisco surgeon the following year. First thought to be a protozoan infection, its true fungal nature was determined in 1900.

Initially, the infection was considered rare and fatal, but that understanding has changed dramatically. By 1935, it had been linked to the common illness known as San Joaquin Valley Fever and by the 1940s, its existence within southern Arizona was well appreciated. In addition, it is now recognized to present in a range of severities, and most people that contract the disease are known to become immune to it after a single infection (Table 1).

Table 1. Valley Fever at a Glance

Mycology

The fungal species that cause Valley Fever are in the genus Coccidioides: C. immitis and C. posadasii. In the past, all strains were designated as C. immitis, but recent genetic analysis has shown that strains segregate into two distinct groups. Strains now designated C. immitis in most cases originate from infections contracted in California. Those designated C. posadasii are from infections contracted elsewhere. At the present time, most clinical laboratories do not determine species for new isolates. Therefore, the simple case designation Coccidioides spp. is technically accurate.

In the soil (Figure 1), Coccidioides spp. survive as mycelia, growing beneath the surface at a depth ranging from inches to a few feet.

Figure 1. The life cycle of Coccidioides spp.

Since the fungus is an obligate aerobe, oxygen content is a major factor limiting the depth that it can survive in the dirt. During rainy periods, mycelia proliferate and grow closer to the surface. When the rains cease and the ground dries, the mycelia stop elongating. Along their length, alternating cells undergo autolysis, lose their internal contents, and their walls become extremely brittle. The remaining barrel-shaped single cells (known as arthroconidia) are then easily disrupted.

The size of each arthroconidium is approximately 3-5 μm. This is small enough to both remain suspended in the air and be inhaled deep into the lungs, thereby establishing an infection. At that point, an arthroconidium transforms into a spherical shape and enlarges, frequently to as much as 75 μm in diameter. Inside the growing spherule, the cell wall invaginates to repeatedly transect the space, dividing into many scores of subcompartments, each containing viable cells, termed endospores. In active infections, a mature spherule ruptures its outer wall and releases the endospore progeny, each of which can develop into another spherule. If specimens containing spherules are cultured in a laboratory, growth reverts to the mycelial form.

Epidemiology

The endemic regions of Coccidioides spp. roughly correspond to the “lower Sonoran life zone” and are areas of low rainfall, high summer temperatures, and moderate winter temperatures. Regions that fit that description are found in the

southern deserts of Arizona (including Maricopa, Pinal, and Pima counties), the central valley and southern portions of California (including Kern, Tulare, and San Luis Obispo counties), the southern tip of Nevada, southern Utah, southern New Mexico, western Texas (especially along the Rio Grande), and the northern and Pacific coastal areas of Mexico. Recently, a pocket of Coccidioides has been identified in Washington State. Some areas have been identified in Central and South America as well (Figure 2).

Figure 2. Shaded areas indicate suspected coccidioidomycosis distribution in the Western Hemisphere.

Even within endemic regions, the distribution in the soil is not uniform, and, in fact, most acreage appears free of the fungus. Thus, while occasionally disruption of soil produces increased risk of exposure, such activity often does not. Conversely, windy conditions, which typically involve large areas of the desert, may more likely result in arthroconidia becoming airborne and distributed across urban and rural areas alike. The implication is that exposure to Coccidioides spp. is more associated with living in or visiting endemic areas per se than it is with engaging in activities associated with heavy dust exposure.

Since infection occurs after inhaling an arthroconidium that has developed in the soil, virtually all infections originate in an endemic region. Very rarely, dirt which contains arthroconidia carried from the endemic region has been the source of infection elsewhere. It’s important to note that infection resulting from respiratory exposure to an infected patient has never been reported, and patients with Valley Fever need not be isolated from others. Peak infection rates occur during the driest periods of the year. In Arizona, this is the early summer and late fall, whereas in California, it is all throughout the summer.

Spectrum of Disease

The majority of infected persons have symptoms so mild that they see no need for medical attention. Of the approximately one-third of infected persons who do suffer a clinical illness, the symptoms are primarily those suggesting community-acquired pneumonia. For most such patients, it is not possible without specific laboratory testing to distinguish Valley Fever pneumonia from that caused by other etiological agents.

Whether diagnosed or not, most infections are controlled by induction of immunity, although the associated illness may last for many weeks to many months. Approximately 5% to 10% of infections result in pulmonary sequelae, and 1% or less result in the spread of the infection outside of the lungs. This leads to destructive lesions in the skin, bones, joints, meninges, and virtually any other organ or tissue in the body to which the infection has spread. These complications produce a large amount of chronic morbidity and cause an average of fewer than 200 deaths annually in the United States (Table 2).

Table 2. Spectrum of Coccidioidomycosis

Current Therapies

Many patients with Valley Fever pneumonia require no treatment, and the illness resolves as a consequence of acquired immunity. However, in some patients, coccidioidal pneumonia is acute and very severe. In others, it produces various progressive pulmonary syndromes or leads to spread of infection to other parts of the body. Such complications dictate the need for treatment, and even so the infection may remain difficult to control.

A majority of complicated infections follow a subacute or chronic progression, and initial therapy usually involves oral administration of azole antifungals, such as fluconazole or itraconazole. Typically, treatment is continued for many months to years. When therapy is discontinued after the apparent successful control of disease, a relapse of infection occurs in approximately one-third of patients.

Therefore, some patients may need lifelong therapy to maintain control.  Chief among these are patients with deficiencies in cellular immunity or those with coccidioidal meningitis. Amphotericin B is effective only if administered parenterally, and its use is often associated with significant side effects and toxicities. Despite these drawbacks, in rapidly progressive infections, amphotericin B remains the preferred initial treatment.

The Importance of Valley Fever in Primary Care

Case Reporting

Coccidioidomycosis is a reportable disease at the national level, and reporting is required in Arizona and California where cases annually number in the thousands (Figure 3).

Figure 3. Annual number of cases of coccidioidomycosis reported in Arizona and California.

In addition, the fact that Arizona has approximately twice as many infections as California is related to the differences in the population sizes in the most intensely endemic regions of the two states (Table 3).

Table 3. Population (in millions) of Selected Counties in Regions Highly Endemic for Coccidioidomycosis.

In 2007, the Arizona Department of Health Services conducted a telephone survey of nearly 500 persons, approximately 10% of those reported being newly diagnosed with Valley Fever that year (1). From these interviews, it was found that more than half were ill for longer than six months, 75% were unable to do usual daily activities for longer than three months, and 75% of workers missed an average of one month of employment. Also found were significant delays  in diagnosis.

For example, patients waited 44 days before seeking care for their illness. Once care was sought, there was an additional average delay of five months involving three or more clinic visits before the correct diagnosis was made. The impact on the health care system was substantial since over half of patients sought their care from emergency rooms, 40% of those were hospitalized one or more nights, and 25% of the patients required 10 or more visits to clinicians to manage their illness. From Arizona hospital records, there were over 1700 admissions resulting from Valley Fever infections in 2012, costing over $100 million.

As significant as these findings are, other analyses indicate that compared with the number of reported infections, the number of undiagnosed infections is even more substantial. In one study conducted in Phoenix, only 2% to 13% of patients with community-acquired pneumonia were tested for Valley Fever (2). In contrast, when Tucson patients with a clinical diagnosis of community-acquired pneumonia were prospectively tested for Valley Fever, 29% were found to be positive (3).

These and other less direct measurements all indicate that approximately 50,000 patients annually seek medical care for Valley Fever pneumonia (4). Since most coccidioidal infections can only be diagnosed by specific laboratory testing, the lack of clinicians testing for Valley Fever could easily account for the under-reporting of illness by as much as 90%.

Undiagnosed infections are almost certainly not as serious as those that are recognized. Nonetheless, there are several very important reasons why diagnosis, especially in the primary care setting, should be pursued.

Value of Early Diagnosis

A primary reason for diagnosing early coccidioidal infections is simply that it provides patients with answers to why they are feeling so poorly. By giving an illness a specific name, it removes the patient’s fear of the unknown. Diagnosis has always been a major contribution by clinicians, and the value of diagnosis to patient satisfaction should not be underestimated.

This is especially true for older patients, where the concern exists that an undiagnosed respiratory illness may represent cancer. A myriad of physical, mental, and emotional consequences are associated with an incorrect or suspected diagnosis of cancer.

For patients of all ages, an accurate diagnosis allows for reassurance in most cases and appropriate prognostic patient education.

In addition, early diagnosis of Valley Fever reduces or eliminates the need to search for another diagnosis. The symptoms associated with Valley Fever that take weeks or even months to resolve often prompt concerned clinicians to subject their patients to diagnostic blood tests, chest X-rays, CT scans, PET scans, bronchoscopy, percutaneous fine-needle aspiration, and even thoracotomies. These procedures have attendant costs, discomfort, and potential complications, which might be avoided if coccidioidomycosis were known to have been responsible for the symptoms that patients experience.

A third benefit of diagnosing coccidioidal infections early is the reduction or elimination of empiric therapy for bacterial infection. Patients with persistent respiratory complaints often receive empiric antibiotics in an ambulatory practice.

In one study, 81% of patients with Valley Fever pneumonia received at least one course, and 31% received multiple courses of antibacterial treatment for their illness (3).

In addition to the cost of antibiotics, this strategy has the potential to cause adverse events for the patient and increase antibiotic resistance in the community. A less frequent but potentially more serious problem is the use of corticosteroids for the cutaneous or rheumatologic complaints that may accompany primary coccidioidal infection. The anti-inflammatory effects of corticosteroids may impede host defenses, and their use in patients with early coccidioidal infections may cause adverse effects.

Finally, by establishing a diagnosis of coccidioidomycosis early, complications (should they arise) may be more quickly recognized and treated. Complications of coccidioidal infection usually manifest within months of the initial infection.

For this reason, symptoms that are associated with or develop in the weeks following a new coccidioidal infection may indicate extrapulmonary spread. A more detailed evaluation of new symptoms at this stage may identify a need for treatment earlier and reduce tissue destruction and consequent morbidity (Table 4).

Table 4. The Value of Early Diagnosis

In summary, the attitude that primary care professionals take regarding early diagnosis of coccidioidal infections is critical to all further discussion about the proper management of this infection in the primary care setting. Historically, the approach in general has been passive, leaving diagnosis and treatment to only the most severely ill. Providing an accurate, early diagnosis can decrease patient anxiety and eliminate unwarranted diagnostic testing and unnecessary exposure to antibiotics. Also, it can allow for earlier identification and treatment of complications.

The Arizona Department of Health Services has recommended that physicians whose patients have endemic exposure to Valley Fever be tested for this possibility should they develop signs and symptoms of pneumonia. The Valley Fever Center for Excellence endorses that recommendation as reflected in this monograph. The following section, then, describes general strategies for primary care professionals to identify and manage this important disease.

Primary Care Management of Coccidioidomycosis

Overview

The following section outlines an approach for recognizing a new infection, assessing its impact on the patient, and subsequently managing the illness depending upon its level of complications. We have developed an acronym (COCCI) for this approach based on 5 important steps.

Spectrum of Clinical Manifestations of Valley Fever

Consider the Diagnosis

The incubation period of coccidioidal infection ranges from 7 to 21 days, after which a variety of manifestations develop. The most common symptoms are fatigue, night sweats, and pulmonary symptoms (cough, chest pain, dyspnea, and hemoptysis). Although difficult to quantify, fatigue is often the most prominent symptom. Stories like “I went to bed and didn’t wake up for 15 hours” or “I got up for breakfast and then was exhausted” are common.

When a cough is present, it frequently is not particularly productive of large amounts of sputum. Fever is present in nearly half of patients. A headache occurs in approximately one-fifth of the patients with early infection; fortunately, as a transient symptom, this does not represent meningitis. Weight loss of as much as 5% to 10% is also common with coccidioidal infections. It is apparent from this that the clinical presentation overlaps substantially with the presentation of many other types of respiratory illnesses.

Skin manifestations include a diffuse nonpruritic maculopapular eruption which has been noted to occur in 16% of males and 7% of females, especially children and young adults. It is so transient and seemingly inconsequential that it is often missed. More notable are erythema nodosum (seven to eight times more frequent in women than men) and erythema multiforme. These two rashes are not specific for coccidioidomycosis. However, when found in patients with endemic exposure to Coccidioides spp., Valley Fever is frequently responsible.

Another symptom is diffuse and migratory arthralgia, present in 22% of patients. Joints may be mildly inflamed and painful but typically do not exhibit an effusion. The triad of fever, erythema nodosum, and diffuse arthralgias has produced the synonym of “desert rheumatism” for the disease. All of these manifestations are thought to be immunologically mediated and not the consequence of viable fungal cells in either the skin or the joints.

Chest radiographs often, but not always, disclose abnormalities associated with the early infection. Pulmonary infiltrates are usually one-sided and are typically patchy and not as consolidated as seen with bacterial infections. Often there is associated ipsilateral hilar adenopathy. Peripneumonic pleural effusions may also occur as part of a primary infection. Although disease of one lung is the rule, the process can occasionally be bilateral (Table 5).

Table 5. The Clinical Manifestations of Valley Fever

Routine laboratory findings commonly do not show specific abnormalities. Peripheral blood leukocyte counts are usually normal or only slightly elevated. Eosinophilia is sometimes present and occasionally to strikingly high levels. Erythrocyte sedimentation rate and C-reactive protein are often elevated.

However, recent studies indicate that serum procalcitonin levels are usually normal, which may be a useful way to distinguish coccidioidal from bacterial pneumonia.

Attempts to use clinical presentation and routine laboratory results as an indicator of coccidioidal infection have been uniformly unsuccessful. In one study, several patient findings were significantly associated with coccidioidal infection, as compared to patients with other causes of acute respiratory problems (5). However, the predictive value of these abnormalities was very limited and not of practical help in identifying most infections.

Selecting Patients for Evaluation

Since the signs, symptoms, and routine laboratory abnormalities are nonspecific, virtually any patient evaluated for a variety of complaints, especially those related to the respiratory system, could arguably be evaluated for coccidioidomycosis. The more patients that are tested for Valley Fever, the more infections are likely to be diagnosed.

On the other hand, despite the prevalence of Valley Fever within the endemic patient population, many other acute illnesses also exist. Thus, by increasing provider sensitivity and the number of tests ordered to diagnose Valley Fever, the overall proportion of tests that are diagnostic will decrease.

A critical step for clinicians in a busy practice is to establish routine indications for ordering the appropriate tests. Several indications are proposed, which are selected for simplicity and application to common situations (Table 6).

Table 6. In patients who reside in or have traveled to endemic regions, consider testing for coccidioidomycosis if any of the following indications are present:

Order the Right Tests

Detection of Anticoccidioidal Antibodies in Serum: Serologic Tests

For diagnosing primary infections, serologic tests are the most commonly employed laboratory approach. Of the variety of tests available, some are highly specific for an active infection, while a few have a significant frequency of false- positive results.

Specific tests are typically selected by the director of the clinical laboratory. Factors involved in such selection include the cost and rapidity of obtaining results, the availability of tests from specific reference laboratories that provide other testing services, and the sensitivity and specificity of the tests. Moreover, tests available to a specific provider may change over time because of renegotiated contracts and other factors. This has complicated the interpretation of coccidioidal serologic testing. Because of this, the following two general principles are useful in the primary care setting:

First, in most circumstances, a positive serologic test for coccidioidal antibodies is highly presumptive of a current coccidioidal infection. Therefore, a report of a positive serologic test should always be reviewed by someone familiar with test interpretation. Second, a negative serologic test never excludes the presence  of a coccidioidal infection. For this reason, in evaluating a possible coccidioidal infection, one or even two repeated serologic tests will increase the sensitivity for diagnosis. If repeated testing over the course of two months fails to produce a serologic diagnosis, further serologic testing is likely to be unrewarding.

“A positive serologic test for coccidioidal antibodies is highly presumptive of a coccidioidal infection. Therefore, a positive serologic result should always be reviewed by someone familiar with test interpretation.”

“A negative serologic test should never exclude a coccidioidal infection. In evaluating a possible coccidioidal infection, repeated serologic tests will increase the sensitivity for diagnosis.”

Tube Precipitin (TP) Antibodies

Antibodies of this type were originally detected by the presence of a precipitin button that formed at the bottom of a test tube after overnight incubation of patient serum mixed with coccidioidal antigen. Because IgM is most adept at forming such immune precipitins and because these reactions were detected early after onset of infection, this test is now often referred to as the “IgM test.”

The antigen responsible for this reaction is a polysaccharide from the fungal cell wall. Up to 90% of patients will have TP antibodies detected at some time within the first three weeks of symptoms, and this will decline to less than 5% after seven months of the onset of a self-limited illness.

Complement Fixing (CF) Antibodies

When patient serum is mixed with coccidioidal antigen, an immune complex forms which consumes complement. This event is detected by the subsequent addition of tanned red blood cells, which normally lyse in the presence of complement but remain intact if the complement is depleted. Since IgG is the immunoglobulin class usually involved in such immune complexes, this test is often referred to as the “IgG test.”

Although this test was originally developed using various complex extracts of C. immitis, it is now known that the antigen involved in this reaction is a chitinase, a protein enzyme important in the structure of the fungal cell wall. In early coccidioidal infections, CF antibodies are detected somewhat later and for longer periods than TP antibodies. CF antibodies can be detected in other body fluids and their detection in the cerebrospinal fluid is an especially important aid to the diagnosis of coccidioidal meningitis.

Another difference between CF and TP antibodies is that CF results are expressed as titers, such as 1:4 or 1:64, indicating the greatest dilution of serum at which complement consumption is still detected. In general, higher CF titers reflect more extensive coccidioidal infection, and rising CF antibody concentrations are associated with worsening disease. Thus, serial determinations of CF antibody concentrations are of prognostic as well as diagnostic value.

Immunodiffusion Tests (IDTP, IDCF)

Antibodies that were detected by the original TP or CF tests can be detected by an alternative procedure known as the immunodiffusion (ID) tests (IDTP and IDCF, respectively). Although the conduct of the IDTP and IDCF tests is quite similar, each uses a different antigen to measure different types of antibodies.

As with the original tests, the IDTP is reported by some laboratories as the “IgM test” and the IDCF as the “IgG test” result. Both tests have been found to be at least as sensitive as their original counterparts. Moreover, immunodiffusion tests are amenable to being manufactured and distributed as commercially prepared kits, thus allowing the tests to be performed in labs not fully dedicated to a mycology specialty.

Enzyme-linked Immunoassays (EIA)

An EIA test for coccidioidal antibodies is available commercially. The test kit allows for the specific detection for IgM or IgG antibodies. However, these results are not interchangeable with IgM or IgG test results. Positive EIA results are highly sensitive for coccidioidal infection. However, false-positive results have been noted with the IgM EIA test. How frequently this occurs is not a settled issue (6-8).

Latex Tests

Latex tests for coccidioidal antibodies are also commercially available. They are attractive to clinical laboratories because of their ease of use and rapidity of obtaining a result. However, there are significant numbers of false-positive reactions, and therefore a positive latex test is not as reliable as any of the other tests described in this section.

Cultures for Coccidioides spp. 

Isolating Coccidioides spp. from sputum or another clinical specimen is definitive evidence of a coccidioidal infection. Despite this, early infections are usually not diagnosed by culture. The reasons why cultures are not routinely obtained in the ambulatory care setting are related to several factors.

First, fungal cultures are an unusual request in the ambulatory care setting. Although it would be valuable if this were to change, requesting fungal cultures on a sputum specimen currently may be disruptive to workflow. Another consideration is that patients with coccidioidal pneumonia may not be able to produce a specimen for culture. While this problem can usually be circumvented, it takes extra steps. Finally, there is a potential risk to laboratory personnel of isolating Coccidioides spp.

Laboratories handling fungal cultures should be thoroughly versed in safe- handling of such specimens and culture medium, and small outpatient laboratories may not be so equipped or trained. None of these considerations are absolute barriers to obtaining culture confirmation. Since negative serologies do not exclude the diagnosis of coccidioidomycosis, cultures may be the only way to obtain a timely diagnosis in some patients. As a general rule, the more serious the illness, the more likely fungal cultures should be considered as an essential part of the diagnostic evaluation.

Handling of Specimens

Sputum or other clinical specimens should be collected in a sterile container. This may be done in the clinic at no risk to personnel, since the infection is not transmitted from the primary specimen. Patients with scant sputum can be asked to take a specimen cup home with them and collect a specimen early in the morning (when sputum is usually more readily retrievable) and then return the cup.

Such specimens can be stored refrigerated until transfer to the medical facility. For more serious problems, other respiratory secretions (bronchoscopic aspirates) and tissue specimens (skin or bone biopsies) can be submitted for culture.

Laboratory Evaluation

Direct examination of secretions can be performed immediately or after the addition of potassium hydroxide. Although culture results are more sensitive than direct examination, identification of spherules in this way is diagnostic and very rapid. Coccidioides spp. cannot be detected by Gram staining. However, spherules can be seen with cytology stains such as are performed on bronchoscopy specimens, by hematoxylin and eosin stains of tissue sections, and with other specialized stains.

Coccidioides spp. are not particularly fastidious and grow well on most mycologic and bacteriologic media. Furthermore, growth usually develops within four to seven days of incubation. Some clinical laboratories within the coccidioidal endemic region have used these characteristics to advantage by holding all routine bacteriologic sputum cultures for a week before discarding the plates, since some patients who are thought to have bacterial pneumonia will actually yield Coccidioides spp.

When growth occurs, it is typically as a white (nonpigmented) mold. However, there are many exceptions to this general appearance, and the morphologic appearance is not reliable in determining if the fungus is or is not Coccidioides spp.

Once growth is evident on culture medium, care should be taken not to open the culture container except in an appropriate biocontainment cabinet. Cultures at this stage are infectious and can cause disease in persons exposed to them unless the cultures are properly handled. Since the morphologic appearance of Coccidioides spp. is not sufficient to determine the species, additional laboratory testing must be carried out for specific identification.

The most common way for microbiologists to perform additional testing is to detect a specific DNA sequence using a commercially available DNA probe. Smaller laboratories often refer the culture to a reference laboratory where species identification is completed.

As of December 2012, Coccidioides spp. are no longer designated select agents by the Centers for Disease Control and Prevention (CDC).

Skin Testing

Dermal hypersensitivity to coccidioidal antigens is highly specific for past coccidioidal infection, and if used in patients when they are healthy, it can index patients as to whether they are at risk of future illness due to Valley Fever.

For example, persons who demonstrate a reactive skin test are very likely to be immune for life and have little chance of future coccidioidal problems. On the other hand, for those who do not react, Valley Fever remains a possible etiology in a future illness. However, because skin test results remain positive after infection in most persons for life, it may not relate to the current illness. In addition, some of the most serious infections may be associated with selective anergy, and the skin test may not demonstrate reactivity.

Therefore, as useful as skin test results are for indexing risk in patients while healthy, important limitations exist when used as a screening procedure for recent or current infection. If Valley Fever is diagnosed by other means, skin testing may have prognostic significance, as patients with progressive infections often fail to develop dermal reactivity to coccidioidal antigens. Since the 1990s, there was no coccidioidal skin test commercially available. However, a company (Nielsen BioSciences, San Diego, CA) has redeveloped a spherule-based skin test antigen (SPHERUSOL®) and has received approval from the FDA to market it.

Results of a skin test are measured at 48 hours after the antigen is injected intradermally. Induration of greater than 5 mm is considered reactive. Erythema at the injection site is not of diagnostic value. Coccidioidal skin testing does not influence coccidioidal serology results.

Check for Risk Factors

The First Step Postdiagnosis

Once a diagnosis of coccidioidal infection is established, the next step is to review any possible risk factors that might make the patient particularly susceptible to complications. This is usually accomplished during a complete history and physical examination.

Immunosuppression

By far the most clearly demonstrable risk of complications from a coccidioidal infection is the coexistence of major immunosuppressive conditions that adversely affect cellular immunity. These would include immunosuppression to prevent rejection of organ transplants, AIDS in HIV-infected persons, and anti–tumor necrosis factor therapy for rheumatologic conditions. For example, the risk of infections extending beyond the lungs in renal transplant recipients can be as high as 75%. This risk is much greater than the risk of a similar complication in the general population.

Immunosuppressive conditions that affect humoral immunity appear to have relatively little risk for complications of coccidioidal infection. Similarly, splenectomy, hypocomplementemia, or neutrophil dysfunction syndromes are not major risk factors for this disease.

Diabetes Mellitus

Patients with diabetes appear to have an increased risk of pulmonary complications (9). While many of such patients resolve their initial infection without residual problems, a disproportionate number seem to develop symptoms related to pulmonary cavities and chronic pneumonia. There is little or no evidence that this group of patients is at increased risk for developing extrapulmonary infections.

Pregnancy

Women who contract Valley Fever during pregnancy are at particular risk of serious infection. Those at highest risk for serious infection are women diagnosed during the third trimester or immediately postpartum. Such infections may be life-threatening and should be regarded as complicated management problems.

Other Risk Factors

There are additional factors that should be considered relevant to the risk of complications from coccidioidal infection. Complications are more frequent in men than in women and in adults than in children. Life-threatening infections are more common in the elderly. Recent evidence suggests this is related in part to accumulated comorbidities in aging persons rather than age itself (10).

In addition, there appears to be an increased risk of disseminated infection among African Americans, Filipinos, and perhaps other racial groups. Racial predilection for complications is somewhat conjectural since the exact definitions of racial groups are in dispute and carefully controlled epidemiologic studies are not available. Even if racial differences exist (as most authorities believe), the increase in risk may be only four-fold above that of the population as a whole.

Check for Progressive Pulmonary Syndromes or Disseminated Disease

Assessing Complications

Even in the absence of the risk factors previously discussed, it is important to assess patients with coccidioidal infections for complications because they can also occur in patients without apparent reason.

Complications from initial coccidioidal infections are divided into those that  occur in the chest and those that involve parts of the body outside of the lungs (extrapulmonary dissemination). These two types of complications usually do not overlap. Most complications produce localized symptoms and signs of chronic or subacute inflammation. As a result, a careful review of symptoms and physical examination are usually a sufficiently sensitive initial screen.

Most complications manifest within the first year or two after the initial infection. If a new complaint develops in association with a recent coccidioidal infection, its possible relationship to the infection should be considered. For example, in general practice, low back pain is a common symptom, and mild discomfort is often managed symptomatically before extensive diagnostic studies are undertaken.

However, if this symptom were to occur in a patient within weeks or months of developing coccidioidal pneumonia, it may be useful to recommend a radionuclide scan to determine if the new symptom is due to infection in the lumbar vertebrae. This is done to detect complications early, before serious tissue destruction occurs. Similarly, persistent or progressive headaches, skin lesions, or joint effusions in the context of a recently diagnosed coccidioidal pneumonia might warrant more detailed investigation with lumbar puncture, biopsy, or aspiration, respectively.

Persistent or Slowly Resolving Pneumonia

Most pulmonary infections are subacute in nature. Without treatment, symptoms usually improve within the first month but may not completely resolve for several months. In some patients, the course of illness is even more protracted. There is no consensus regarding how protracted illness must be before it is considered as slowly resolving. However, in studies of new therapies for coccidioidomycosis, entry criteria often specify that pulmonary disease must have been present for at least three months. In clinical practice, shorter periods of illness may be more reasonable.

Pulmonary Cavitation

Cavities form in approximately 5% of patients with coccidioidal pneumonia. Half of these cavities will disappear within the first two years. Many cavities cause no symptoms. Others cause discomfort, cough, hemoptysis, and occasionally constitutional symptoms of fatigue, night sweats, and weight loss. Occasionally, a coccidioidal cavity will rupture into the pleural space. This usually has an abrupt onset and consequently leads to prompt evaluation. Given the peripheral nature of many coccidioidal cavities, this event is surprisingly uncommon.

Chronic Fibrocavitary Pneumonia

A few patients experience repeated development of pneumonia over a period of many years. Sometimes, this includes different lobes of the lung.

Diffuse Fulminant Pneumonia

In some patients, coccidioidal pneumonia is very severe, causing hypoxia and requiring respiratory support to prevent respiratory collapse. This is obviously a major complication and is handled very differently than most infections.

Extrapulmonary Dissemination

When infection spreads beyond the lungs, it usually does so within the  first several months after the initial infection and nearly always within the first two years. In this way, coccidioidal infections differ from tuberculosis, which commonly returns decades after the initial infection. An important exception to this rule is in the intervening development of major degrees of immunosuppression of the nature discussed previously. The most common sites of dissemination are skin, joints, bones, and the meninges. However, virtually any part of the body can be affected.

Initiate Management

Strategies for Uncomplicated Early Infections

Once a diagnosis of coccidioidal infection is established and a thorough evaluation for enhanced risk and evidence of complications has been accomplished, a rational management strategy can be formulated.

Patients who do not have risk factors, symptoms, or physical findings suggestive of progressive infection can be classified as having early uncomplicated infections. In general, a majority of patients will fall into this category and might be safely managed by primary care practitioners. The remainder may benefit from consultation with a specialist in infectious diseases, pulmonary diseases, neurology, or other disciplines to aid in developing a treatment plan. Management of complicated coccidioidal infections is beyond the scope of this monograph, but comprehensive treatment guidelines are available.

General guidelines for managing patients with uncomplicated infections are outlined in Figure 4.

Figure 4. Managing uncomplicated coccidioidomycosis.

Health Education and Recommendations to the Patient and Family

Very commonly, establishing a diagnosis will be of great help to the patient because it clearly identifies the nature of the illness and allows the health care provider the opportunity to explain what may happen in the future. A general review of how patients contract Valley Fever, the typical symptoms, the need for therapy, or the lack of the need for therapy, may be helpful to put the patient’s experience in a more general and knowledgeable context.

Patient information leaflets have been prepared to facilitate this process and are available from the Valley Fever Center for Excellence.

Explaining that the illness usually improves slowly over a period of weeks to even months will be useful in allowing patients to align their expectations with the natural history of the illness. The patient can be advised that he or she cannot transmit the infection to others and therefore poses no risk to others.

Although the prognosis is generally favorable for most patients, it is important to explain to patients some of the infrequent but possible complications, both pulmonary and extrapulmonary. Worsening respiratory symptoms should prompt reevaluation, and new focal symptoms outside of the chest should be noted and, if they persist, be brought to the attention of the treating clinician. Explaining the need for follow-up to the patient even as the infection resolves without therapy should improve adherence to follow-up care.

Frequency of Follow-Up Health Care Visits

Continued follow-up is, in fact, at the core of the management of uncomplicated coccidioidal infections. This is needed to confirm that the illness remains uncomplicated and that more specific interventions are not necessary.

In addition, residual pulmonary abnormalities may remain, which should be documented for future reference so that they are not unnecessarily reevaluated as a new problem years later. In rare instances, coccidioidal infections and lung neoplasms have coexisted, and this possibility should be considered during the follow-up period.

The interval between medical visits varies according to the severity of the symptoms and the course of infection up to the point of diagnosis. If symptoms are still worsening, follow-up visits or telephone contact might be appropriate within days to a week later, since continued worsening may prompt reevaluation and the initiation of antifungal therapy.

On the other hand, if there is clear evidence of improvement, then a return visit might be appropriate in two to four weeks. After the first two or three visits, the intervals between visits typically range from one to several months. By two years, an uncomplicated coccidioidal infection can be considered resolved.

Monitoring the Course of Infection

Several clinical and laboratory findings are helpful to assess the course of infection. Generally, systemic signs of fever, night sweats, and weight loss are the first to abate as a coccidioidal infection improves. The respiratory symptoms of chest pain, cough, and sputum production may be more protracted.

Not infrequently, fatigue and an inability to resume normal activities are some of the last symptoms to resolve. Since this is commonly a chronic process, patients may fail to see changes in these symptoms from day to day, and only when asked to compare their current state with one week or one month earlier do they become cognizant of improvements. Often, having the patient keep a journal with entries every other week is a helpful tool to document progress.

Laboratory tests can also be helpful in providing objective evidence of improvement. Erythrocyte sedimentation rate, often elevated with early coccidioidal infections, is an inexpensive measure of systemic inflammation and can be used to monitor progress. Typically, this would not be measured any more often than on a weekly basis. In addition, the CF or IDCF antibody concentration is expected to decrease as a coccidioidal infection resolves, and it is important to demonstrate this response. If these results do not normalize as expected, concern should be raised that complications may be developing and that further diagnostic studies may be in order. Repeated serologic testing should seldom be any more frequent than every two weeks and usually ranges from one to several months between tests.

A suggested plan for follow-up timing for review of systems (ROS), physical examination, coccidioidal CF tests, and chest radiographs is shown in Table 7.

Table 7. Suggested Plan for Follow-up Visits.

Chest radiographs should be repeated to demonstrate either resolution of all pulmonary abnormalities or to document what residual abnormalities persist. Early in the course of infection, the interval may be as frequent as several days until symptoms or radiographic findings demonstrate that abnormalities are stable or improving. Subsequent chest radiographs should be obtained either every several weeks or every several months. Often, two views of the chest are sufficient to monitor progress, and the increased sensitivity of CT scans is not usually needed as the patient improves.

Antifungal Therapy

For early uncomplicated coccidioidal infections, most patients can be managed without antifungal therapy. There are currently five commercially available oral antifungal drugs with activity for treating coccidioidal infections: ketoconazole, fluconazole, itraconazole, voriconazole, and posaconazole. Published reports have demonstrated activity of all of these agents in treatment of complicated coccidioidal infections, but there are no randomized trials demonstrating that any of these drugs shorten the course of early uncomplicated infections or prevent later complications. Two recent observational studies also provide no evidence for a beneficial effect in the pharmacologic treatment of early coccidioidal pneumonia (11,12).

Given this uncertainty, the decision whether to initiate antifungal drug therapy for uncomplicated coccidioidal pneumonia is highly individualized. This issue is addressed further in the Infectious Diseases Society of America (IDSA) Practice Guidelines (13). Treatment with fluconazole or itraconazole for such patients typically involves doses ranging from 200 to 400 mg per day, with treatment durations ranging from several to many months.

Treatment of complicated infections is beyond the scope of this monograph but is also addressed in the IDSA Practice Guidelines. The length of treatment for such patients ranges from one year to the entire course of the patient’s lifetime, depending upon the location of the infection and underlying risk factors.

The cost of therapy is substantial. Drug costs alone range from $2,000 to $20,000 per year, depending upon the specific drug and the daily dose prescribed.

Physical Therapy Reconditioning As an Approach to Persistent Fatigue

Not infrequently, patients who resolve all evidence of active infection continue to be disabled because of profound fatigue. For example, in a study from the University of Arizona that compared the impact of Valley Fever to mononucleosis, twice as many students with Valley Fever dropped out for a semester (14). It is very possible that this persistent symptom is a consequence of patients becoming deconditioned as a consequence of the fatigue that Valley Fever first produces.

If that is true, then referral to a physical therapist to assist the patient with a reconditioning program might be very helpful to hasten recovery. The Valley Fever Center for Excellence has initiated this practice, and the preliminary results have been encouraging.

Conclusion

Valley Fever represents a substantial public health problem, the true burden of which likely remains under-recognized. The clinical presentation of this disease is often non-specific, and increased awareness among clinicians, particularly those involved in primary care, about the disease is essential in order to ensure that patients with Valley Fever receive a timely and accurate diagnosis. Clinicians should maintain a high clinical suspicion for Valley Fever in patients who live in the endemic region or who have traveled to these areas. Although only a small proportion of patients with Valley Fever develop pulmonary complications or extrapulmonary disease, it is important to identify these complications as early as possible. For the other patients, most coccidioidal infections are uncomplicated. The five steps—Consider the diagnosis, Order the right tests, Check for risk factors, Check for complications, and Initiate management (COCCI)—are a simple way for generalists to identify those with complications and to manage uncomplicated infections without specialty referral.

References

1. Tsang CA, Anderson SM, Imholte SB, et al. Enhanced surveillance of coccidioidomycosis, Arizona, USA, 2007-2008. Emerg Infect Dis. 2010;16(11):1738-44. [CrossRef] [PubMed]
2. Chang DC, Anderson S, Wannemuehler K, et al. Testing for coccidioidomycosis among patients with community-acquired pneumonia. Emerg Infect Dis. 2008;14(7):1053-9. [CrossRef] [PubMed]
3. Valdivia L, Nix D, Wright M, et al. Coccidioidomycosis as a common cause of community- acquired pneumonia. Emerg Infect Dis. 2006;12(6):958-62. [CrossRef] [PubMed]
4. Campion JM, Gardner M, Galgiani JN. Coccidioidomycosis (Valley Fever) in older adults: an increasing problem. Ariz Geriatr Soc J. 2003;8(3):3-12.
5. Yozwiak ML, Lundergan LL, Kerrick SS, Galgiani JN. Symptoms and routine laboratory abnormalities associated with coccidioidomycosis. West J Med. 1988;149(4):419-21. [PubMed]
6. Wieden MA, Lundergan LL, Blum J, et al. Detection of coccidioidal antibodies by 33-kDa spherule antigen, Coccidioides EIA, and standard serologic tests in sera from patients evaluated for coccidioidomycosis. J Infect Dis. 1996;173(5):1273-7. [CrossRef] [PubMed]
7. Kuberski T, Herrig J, Pappagianis D. False-positive IgM serology in coccidioidomycosis. J Clin Microbiol. 2010;48(6):2047-9. [CrossRef] [PubMed]
8. Blair JE, Currier JT. Significance of isolated positive IgM serologic results by enzyme immunoassay for coccidioidomycosis. Mycopathologia. 2008;166(2):77-82. [CrossRef] [PubMed]
9. Santelli AC, Blair JE, Roust LR. Coccidioidomycosis in patients with diabetes mellitus. Am J Med. 2006;119(11):964-9. [CrossRef] [PubMed]
10. Blair JE, Mayer AP, Currier J, Files JA, Wu Q. Coccidioidomycosis in elderly persons. Clin Infect Dis. 2008;47(12):1513-8. [CrossRef] [PubMed]
11. 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] [PubMed]
12. Blair JE, Chang YH, Cheng MR, et al. Characteristics of patients with mild to moderate primary pulmonary coccidioidomycosis. Emerg Infect Dis. 2014;20(6):983-990. [CrossRef] [PubMed]
13. Galgiani JN, Ampel NM, Blair JE, et al.; Infectious Diseases Society of America. Coccidioidomycosis. Clin Infect Dis. 2005;41(9):1217-23. [CrossRef] [PubMed]
14. Kerrick SS, Lundergan LL, Galgiani JN. Coccidioidomycosis at a university health service. Am Rev Respir Dis. 1985;131(1):100-2. [PubMed]

Additional Selected References

• Ampel NM. Coccidioidomycosis in persons infected with HIV-1. Ann N Y Acad Sci. 2007;1111:336-42. [CrossRef] [PubMed]
• Bergstrom L, Yocum DE, Ampel NM, et al. Increased risk of coccidioidomycosis in patients treated with tumor necrosis factor alpha antagonists. Arthritis Rheum. 2004;50:1959-66. [CrossRef] [PubMed]
• Blair JE, Kusne S, Carey EJ, Heilman RL. The prevention of recrudescent coccidioidomycosis after solid organ transplantation. Transplantation. 2007;83:1182-1187. [CrossRef] [PubMed]
• Blair JE, Mulligan DC. Coccidioidomycosis in healthy persons evaluated for liver or kidney donation. Transpl Infect Dis. 2007;9:78-82. [CrossRef] [PubMed]
• Braddy CM, Heilman RL, Blair JE. Coccidioidomycosis after renal transplantation in an endemic area. Am J Transplant. 2006;6:340-5. [CrossRef] [PubMed]
• Comrie AC. Climate factors influencing coccidioidomycosis seasonality and outbreaks. Environ Health Perspect. 2005;113:688-92. [CrossRef] [PubMed]
• Deresinski S. Coccidioides immitis as a potential bioweapon. Semin Respir Infect. 2003;18:216-9. [PubMed]
• Flaherman VJ, Hector R, Rutherford GW. Estimating severe coccidioidomycosis in California. Emerg Infect Dis. 2007;13:1087-90. [CrossRef] [PubMed]
• Hirschmann JV. The early history of coccidioidomycosis: 1892-1945. Clin Infect Dis. 2007;44:1202-7. [CrossRef] [PubMed]
• Johnson RH, Einstein HE. Amphotericin B and coccidioidomycosis. Ann N Y Acad Sci. 2007;1111:434-41. [CrossRef] [PubMed]
• Johnson RH, Einstein HE. Coccidioidal meningitis. Clin Infect Dis. 2006;42:103-7. [CrossRef] [PubMed]
• Laniado-Laborin R. Coccidioidomycosis and other endemic mycoses in Mexico. Rev Iberoam Micol. 2007;24:249-58. [PubMed]
• Pappagianis D. Coccidioidomycosis in California state correctional institutions. Ann N Y Acad Sci. 2007;1111:103-11. [CrossRef] [PubMed]
• Saubolle MA. Laboratory aspects in the diagnosis of coccidioidomycosis. Ann N Y Acad Sci. 2007;1111:301-14. [CrossRef] [PubMed]
• Stevens DA, Clemons KV. Azole therapy of clinical and experimental coccidioidomycosis. Ann N Y Acad Sci. 2007;1111:442-54. [CrossRef] [PubMed]
• Sunenshine RH, Anderson S, Erhart L, et al. Public health surveillance for coccidioidomycosis in Arizona. Ann N Y Acad Sci. 2007;1111:96-102. [CrossRef] [PubMed] 

Reference as: Galgiani JN. Valley fever (coccidioidomycosis): turtorial for primary care physicians. Southwest J Pulm Crit Care. 2015;10(5):265-88. doi: http://dx.doi.org/10.13175/swjpcc073-15 PDF PDF in booklet form

Common Mistakes in Managing Pulmonary Coccidioidomycosis

 John N. Galgiani MD¹

Kenneth Knox MD^1,2

Craig Rundbaken DO³

John Siever MD⁴

¹Valley Fever Center for Excellence and ²Arizona Respiratory Center

University of Arizona College of Medicine, Tucson, Arizona;

³Arizona Institute of Respiratory Medicine, Sun City West, Arizona;

And

⁴Arizona Pulmonary Specialists, Phoenix, Arizona

Abstract

Coccidioidomycosis (Valley Fever) is a common disease in Arizona and certain other parts of the Southwestern United States. Despite this, there is a surprising lack of awareness, neglect in diagnosis, and inadequacy of management by many clinicians in these endemic regions.  This review discusses why early diagnosis of coccidioidal infection is valuable to patient care and offers a variety of management options that are particularly useful and others which often are of little value.

Introduction

Coccidioidomycosis (Valley Fever) should be a familiar and well-managed disease for Arizona primary care clinicians, and specialists in pulmonary medicine or infectious diseases. In many years it is the second most commonly reported infectious disease to the Arizona Department of Health Services. It also constitutes nearly a third of all community acquired pneumonias (CAP) in Phoenix and Tucson (1-3). Coccidioidal infections in Arizona are responsible for two-thirds of all infections reported in the United States (4). Despite its expected frequency, in primary care practices it is common not to consider the diagnosis or to order necessary testing. In one study from Maricopa County, serologic tests for Valley Fever were ordered in less than 20% of persons with CAP (5). Furthermore, when specialists are referred patients with newly diagnosed Valley Fever, their management strategies vary widely, frequently falling outside of treatment guidelines developed both by the American Thoracic Society and the Infectious Diseases Society of America (6, 7).

There are reasons why a gap exists between medical practices and optimal management of patients with Valley Fever. Although the Arizona Board of Medical Examiners issues approximately a thousand new licenses each year, most recipients have neither received their doctorate nor postgraduate education in Arizona. As documented by the Arizona Department of Health Services, only 12% of surveyed Arizona clinicians graduated from an Arizona medical school, only 47% received house staff training in Arizona medical centers, and only 16% had received CME training in Valley Fever within the past year (8). Moreover, a large majority of Arizonans moved to this state relatively recently, previously lived outside of the coccidioidal endemic region, and are themselves unfamiliar with the disease. Finally, since so many persons eventually resolve their illness whether or not treated with antifungal drugs, some clinicians perceive coccidioidomycosis not to be a serious public health problem and not an important diagnosis to make.

In this article, we will first address the last of these causes for the inattention to coccidioidomycosis and provide the evidence that southwestern clinicians, especially within the Arizona counties of Maricopa, Pima, and Pinal, should include Valley Fever frequently in their differential of CAP and other pulmonary syndromes. We will then highlight a number of what we believe are commonly made mistakes in diagnosis and management of coccidioidal pneumonia and its pulmonary sequelae. Admittedly, this will occasionally involve areas of personal opinion, albeit formed over many years of practice within the Phoenix and Tucson, Arizona areas. We also acknowledge the possibility that we “have it wrong” and that some management strategies that we believe are mistakes are in fact better approaches than we give them credit. The real purpose of this review is to provoke increased discussion by our colleagues within the endemic region about what constitutes best practices and what are not necessary or even counter-productive for our patients.

What is “simple,” uncomplicated early coccidioidal infection and why should clinicians be concerned about it?

Coccidioidomycosis is an infection that results after inhaling one or more spores (arthroconidia) of either Coccidioides immitis (the species usually found in California) or Coccidioides posadasii (the species usually found in Arizona and every other endemic region other than California) (9). As few as one spore is lethal to mice in experimental coccidioidomycosis (10) and likely similarly low exposures are sufficient to cause infection in humans. Based on conversion rates and prevalence rates of coccidioidal delayed-type dermal hypersensitivity in Pima County and in Bakersfield school children, respectively (11, 12), the risk of infection is estimated to be approximately 3% per year although there is year-to-year variation as a result of weather patterns (13, 14). Also, it was found in 2007 that the median time of residence within Arizona for newly diagnosed coccidioidal infections was 12 years (15) which suggests approximately a 4% annual risk. Based on older epidemiology (16, 17), it is thought that a third of infections result in clinical illness sufficient to seek medical attention. If you apply these overall estimates to the resident populations of the highly endemic counties of Arizona and California and assume that a portion is already immune because of past infection, estimated new infections would be 150,000 and medically important illness would occur in 50,000 patients each year.

A common misconception among primary care clinicians is that coccidioidomycosis, as it presents to clinicians for care, is usually a mild and inconsequential illness. That many textbooks refer to the initial illness as a “flu-like” syndrome only helps to perpetuate this idea. In fact, all the evidence indicates that those seeking medical care for a documented coccidioidal infection have a very debilitating disease. Evidence from otherwise healthy college students indicates that they are twice as likely to drop a semester of study because of Valley Fever than for mononucleosis (18). More recently, the Arizona Department of Health Services found that i) Illness lasted an average of 6 months, ii)     75% of employed persons stopped working, half missed two or more weeks, and iii) 40% were hospitalized (15). It is simply not tenable to expect that patients seeking care because of early coccidioidomycosis will not be significantly impacted and that accurate diagnose is unnecessary.

Most clinical coccidioidomycosis presents as community acquired pneumonia (CAP), not as a mild “flu-like” illness. Signs and symptoms include cough, chest pain, fever and profuse night sweating, weight loss, and commonly profound fatigue. Occasional patients have peripheral blood eosinophilia, Erythema nodosum, or Erythema multiforme, any of which should heighten suspicion for Valley Fever within its endemic areas. However, most patients do not have these findings, and the most common complaints are not at all specific to coccidioidal pneumonia. In two prospective Arizona studies, CAP in ambulatory patients was due to coccidioidal infection as frequently as 29% of the time (2, 3). In these studies and also in an earlier study (19), it was not possible to differentiate with any degree of precision which patients had coccidioidomycosis from those with other types of pneumonia without specific laboratory testing.

Despite the high probability that Arizona patients with CAP are infected with Coccidioides spp., evidence indicates that most clinicians do not try to establish this diagnosis. In one study of two separate medical groups in Maricopa County, coccidioidal testing was done for patients with CAP in only 2% and 13%, respectively (5). As a result, many patients are treated needlessly with antibacterial drugs (2, 3, 5, 20). If illness is protracted, further evaluation may be undertaken to exclude the possibility of malignancy and may include bronchoscopy, percutaneous needle aspiration, or even thoracotomy. If coccidioidal infection had been considered early in the evaluation, many such invasive procedures might be avoided as unnecessary. The frequent lack of testing of CAP patients living in or visiting endemic regions for Valley Fever is a major deficiency in routine primary care of these patients and one that can easily be rectified by simple changes in practice patterns. The Arizona Department of Health Services, the Maricopa and Pima County Medical Societies, and the Arizona Chapter of the Infectious Diseases Society of America have all endorsed testing such patients with CAP for coccidioidomycosis.

Applying a pathogenic model of coccidioidomycosis to managing Valley Fever CAP.

How does infection cause illness? In general, the pulmonary illness evolves through three or four phases. Initially, fungal proliferation starts from the inhaled arthroconidium transforming into a mature spherule followed by multiple cycles of spherule rupture, each taking several days to complete. With each spherule rupture, hundreds of endospore progeny are released into the pulmonary tissue (21). A key concept is that it is spherule rupture and not the presence of the spherule itself which triggers an acute inflammatory response (21-24). It is the acute inflammation which produces the pulmonary symptoms, fever, night sweating, and weight loss. If fungal proliferation continues unchecked, it is the ongoing inflammation that produces tissue destruction, fibrosis, and pulmonary cavitation. That inflammation and tissue destruction are the result of ongoing rupture of spherules and not caused by the mere presence of spherules is a pivotal concept. In a second phase, effective cellular adaptive immunity is stimulated by the coccidioidal infection and this inhibits spherule rupture which in turn reduces and eventually eliminates the stimulus for acute inflammation. Although a growing literature implicates Th-1 mediated mechanisms (9, 25-29), the fine details have not been fully defined. In the third, convalescent phase, whatever damage was caused by the acute inflammatory process of the first and second phases resolves either by healing or fibrosis and the symptoms caused by the inflammation abate. For many patients, there follows a fourth phase which involves protracted fatigue and inanition which can dramatically interfere with return to a normal sense of well-being. It is distinguished by an absence of symptoms of ongoing inflammation or evidence of progressive tissue damage.

How long it takes for each of these phases to evolve varies widely among different patients and produces the clinical range of illness from subclinical infections that do not lead to an office visit to infections that produce serious illness, even life-threatening pulmonary failure. However, at the time of diagnosis, assessing patients with respect to where they fall along this evolution from active fungal proliferation to convalescence can be a useful means of arriving at an individualized management program.

Role of antifungal treatment in early coccidioidal infection. Early coccidioidal pneumonia will usually resolve eventually whether treated or not, and evidence is lacking as to whether antifungal treatment is useful for patients to hasten resolution of illness or to prevent subsequent complications. Because of these uncertainties, opinions vary widely regarding whether to treat all patients on the hope that treatment is beneficial or to only treat a subset of newly diagnosed patients with risk factors for complications, with more extensive pneumonia, or with a protracted course of illness. If treatment is begun, the usual dosage would be 200 – 400 mg per day of fluconazole and continued usually for three to six months and sometimes longer than a year, even in the absence of co-existing immunosuppression, diabetes (30), or evidence of complications (3, 31).

Considering the pathogenesis of coccidioidomycosis, the potential value of early antifungal drug treatment would be to reduce or eliminate fungal growth and consequent spherule rupture. The result of treatment would therefore be to assist in the evolution of the first and second phases of illness. How it might help in speeding up convalescence, is less clear. Importantly, for phase-four patients, those with protracted fatigue with no objective evidence of ongoing inflammation or tissue destruction, there is very little reason to expect that an antifungal drug would offer any benefit since in such patients fungal proliferation has already stopped. While a variety of supportive measures including physical therapy for reconditioning may be very helpful for these patients (see below), continued antifungal drug treatment seems inappropriate and even counterproductive.

Although the exact value of antifungal treatment is an unsettled issue, there is consensus that after coccidioidomycosis is diagnosed, additional diagnostic studies in search of an etiology can be curtailed and whatever antibacterial agents have been initiated prior to the accurate diagnosis can be stopped. These are immediate and very tangible benefits of early diagnosis whether or not an antifungal is used. Additionally, as evidence of ongoing inflammation decreases, antifungal treatment that might have been started can be reassessed and in many patients discontinued.

Role of coccidioidal serology tests in management. Detecting anti-coccidioidal antibodies is a valuable means of diagnosing coccidioidal infections (32, 33). Also, when coccidioidal serologic tests were originally described and all tests were done by a single research laboratory, there was a useful relationship established between severity of extrapulmonary infections and the magnitude of complement-fixing titers (34). Unfortunately, there is currently considerable variation in the quantitative results that are obtained from different laboratories as they conduct their testing. Even serial results obtained from the same laboratory may vary because of factors unrelated to actual changes in the clinical status of the patient. In general, once the diagnosis of coccidioidomycosis is established, further coccidioidal serology tests should be restricted to titration of complement fixing antibodies either by the originally described procedure or by its surrogate, quantitative immunodiffusion (32). Even then, results and their changes over time should be only one part of the overall evaluation of the patient’s clinical status and may well be discounted if they are inconsistent with the rest of the evaluation.

Strategies for avoiding common mistakes in managing early coccidioidal infections. One very common mistake in the management of early uncomplicated coccidioidal pneumonia is to concentrate on treatment with antifungal drugs to the neglect of patient education which often is more important to the overall success of management. Patients who receive a new diagnosis of Valley Fever often have many questions and concerns about what this will mean for them. Providing a clear description of what Valley Fever is and how it needs to be managed often is very helpful in reducing anxiety. The Arizona Department of Health Services has printed material about Valley Fever that they distribute free of charge to help with patient education (available at http://www.azdhs.gov/phs/oids/epi/valley-fever/index.htm), but it is likely that additional explanations tailored to the patient’s specific situation will also be valuable.

A second common mistake is to excessively follow a patient’s pulmonary process with repeated CT scans. Whether or not a CT scan of the chest was involved with the initial evaluation of the presenting illness, it is frequently possible to continue management without this imaging once the etiology is established. Often the higher resolution of CT scans in comparison to plain views of the chest is simply unnecessary to guide subsequent management since relatively small changes in the shape of pulmonary infiltrates and hilar nodes provide little useful insight into what next steps ought to be taken. For example, if a pulmonary nodule is so small that it cannot reliably be seen on plain films, there may be no benefit to tracking its size one way or another. Avoiding unnecessary CT scans reduces both radiation exposure and cost.

A third management issue frequently mishandled by both primary care clinicians and specialists alike is the very common complaint of fatigue in patients with coccidioidal pneumonia. In the first phases of illness where there is focal evidence of ongoing inflammation, fatigue is expected and handled as part of the overall illness. However, in what we termed the “fourth phase” above, where inflammatory markers have resolved and focal ongoing damage no longer exists, patients are frequently not adequately managed. In our experience, which is very consistent with published descriptions, Valley Fever can be responsible for protracted fatigue, even after all other signs of infection have resolved. For example, in his excellent 1956 monograph, Fiese (35) writes:

“Profound fatigability and lassitude may persist for months after an otherwise uneventful recovery. Such residual symptoms are often alarming to the patient who is aware of the serious complications. It is important that the physician remember the frequency of post-infection lassitude, so that he may reassure the patient who fears that his disease is becoming disseminated.”

This has been especially striking in patients who have never before had fatigue as a significant ongoing complaint. In addition, because of the lack of normal activity, patients invariably become deconditioned and may not know how to methodically recondition, which can compound the disability, leading to frustration and sometimes reactive depression. We would encourage clinicians to provide such patients medical recommendations to employers to allow time away or reduced workloads to facilitate recuperation. In addition, a logical adjunct to help with the reconditioning would be a referral to a physical therapist to establish baseline levels of strength and endurance, set goals, and to provide a structured plan to accelerate the process. Although there does not yet exist a literature addressing the specific methods most effective in a physical therapy rehabilitation program, general reconditioning strategies would be most appropriate.

A fourth management mistake involves an overly aggressive handling of effusions that sometimes occur with early coccidioidal infection. Parapneumonic effusions associated with coccidioidal pneumonia are frequent if looked for carefully (36). However, on occasion they are not small and may be noted in patients prior to diagnosing the pulmonary process as coccidioidomycosis. As it turns out, coccidioidal parapneumonic effusions are generally self-limited and do not normally need aggressive drainage or decortication (37) as would often be employed for bacterial pleural infections. As a result, without early diagnosis of the coccidioidal etiology, it is very likely that unnecessary procedures would be instituted. This is especially true in pediatric patients where early video assisted thoracic surgery (VATS) is increasingly used for bacterial empyemas (38).

The consequences of coccidioidal pneumonia: Their management and mismanagement.

Nodules. Approximately 5% of coccidioidal pulmonary infections leave a nodule, visible by plain radiographs, in the region of the infiltrate. Undoubtedly, this number is even higher with CT scans. Often coccidioidal nodules are asymptomatic and their appearance is indistinguishable from cancer, including increased metabolic activity on PET/CT scan (39, 40). One benefit of early diagnosis of coccidioidal pneumonia is that when the acute pneumonia evolves into a residual nodule, the etiology of the lesion is known and no further evaluation is necessary. In that regard, asking the patient about a past diagnosis of coccidioidal pneumonia and associated X-rays may establish that the nodule is benign.  However, the antecedent acute pneumonia is often not identified and the nodule is detected as an incidental finding. In such cases, the most important issue is to determine if the lesion is malignant and the approach to this should be the same whether coccidioidomycosis is or is not in the differential. Once it is determined that the asymptomatic nodule is due to coccidioidal infection, a common mistake is to initiate antifungal therapy. Treatment at this stage has no effect since its stability indicates that there is no fungal proliferation for an antifungal to inhibit. Periodic evaluation with plain radiographic views of the chest is reasonable but, as with the surveillance of acute coccidioidal pneumonia, in most cases follow-up with CT scans is unnecessary.

Fibrocavitary chronic coccidioidal pneumonia. Another occasional consequence of coccidioidal pneumonia is the development of a cavity, sometimes with surrounding fibrosis. Much of the time cavities are single, often very peripheral near the pleural surface, with little or no surrounding infiltrate (so called “thin-walled” cavity), and asymptomatic. Others have more surrounding infiltrate or an air-fluid level within the cavity, can over time involve additional segments of the lung, and can produce symptoms such as pleuritic pain, cough, and hemoptysis.

A common mistake is the overtreatment of asymptomatic thin-walled cavities. While such lesions may spontaneously close or expand, there is no evidence that treatment alters such cavities. Similarly, despite their peripheral nature, very few such cavities rupture into the pleural space (see below). While surgical removal is occasionally an appropriate management strategy, most asymptomatic cavities can safely be observed with periodic plain films of the chest without surgical intervention.

Management of symptomatic, complex, or expanding cavities may involve oral azoles such as fluconazole (41) or surgical resection (42). Formulating the selection and timing of these two options is highly individualized. However, we would underscore that surgical management is often technically more challenging than might appear from an examination of the radiographic images. In experienced hands, video assisted thoracoscopic surgery (VATS) is increasingly utilized (43). However, some situations still require more extensive thoracotomy. It is highly recommended that patients be referred to thoracic surgeons who are specifically experienced in resecting coccidioidal lesions.

Ruptured coccidioidal cavity. As indicated above, it is surprising how few coccidioidal cavities rupture, resulting in a bronchopleural fistula and collapse of the lung. Their occurrence is most frequently in otherwise healthy athletic males and about half the time it is the first clinical manifestation of the coccidioidal infection (44). Because rupturing spherules are inflammatory, cavity rupture results in a pyopneumothorax with an air-fluid level rather than a simple pneumothorax as would be typical of a spontaneous pneumothorax or a ruptured pulmonary bleb. Failure to make this distinction often results in a delay in diagnosis.

Once diagnosed, it is possible that oral azole antifungal therapy with re-expansion of the lung using chest tubes may resolve the problem. However, very frequently this is not effective in closing the air-leak and surgical resection of the ruptured cavity is needed. As with surgical intervention of other coccidioidal pulmonary lesions, a surgeon familiar with managing such problems is preferred.

Diffuse coccidioidal pneumonia. Occasionally, the initial coccidioidal pneumonia is wide-spread, involving several areas of both lungs and requiring intensive care and ventilatory support (45). Most cases of diffuse reticulonodular coccidioidal pneumonia are the result of fungemia in a severely immunocompromised patient (46-48). In Arizona patients with untreated AIDS, with this pattern, the coccidioidal infection frequently co-existed with Pneumocystis spp. infection (49). Not appreciating this can lead to initiating steroids and pneumocystis treatment which if antifungals are not also begun will exacerbate the coccidioidal infection. Less frequently, a very similar radiographic appearance can occur in immunologically normal persons following high-inoculum infection such as can occur at archeology excavation sites (50, 51). In contrast to where fungemia is responsible, patients with high-inoculum infections do not usually have extrapulmonary infections and often respond very quickly to treatment.

New advocacy for improving the care of patients with coccidioidomycosis.

The Valley Fever Center for Excellence, established in 1996 at the University of Arizona, promotes education, research, and improved care for coccidioidomycosis. As part of its program it established in 2009 a clinical network which later was named the Valley Fever Alliance of Arizona Clinicians (VFAAC). This year, the VFAAC Board of Directors published a Valley Fever tutorial for primary care clinicians that is available on the Center’s website (https://www.vfce.arizona.edu/resources/pdf/Tutorial_for_Primary_care_Physicians.pdf) or by requesting a copy directly from the Center. The purpose of VFAAC is to link clinicians in Arizona who are interested in and experienced with coccidioidomycosis and to provide among them avenues of communication. Clinicians interested in becoming members of VFAAC can submit an application form which is reviewed and approved by the Board of Directors at one of its meetings held several times each year. Thus far VFAAC has expanded to over 125 clinicians. VFAAC membership is encouraged for any clinician licensed by the Boards of Medical Examiners, Osteopathic Examiners, Nursing, Physician Assistants, Behavior Health, Physical Therapy, or Occupational Therapy. Clinicians interested in learning more about VFAAC can contact the Valley Fever Center at vfever@email.arizona.edu.

References

1. Hector RF, Rutherford GW, Tsang CA, Erhart LM, McCotter O, Komatsu K, et al. Public health impact of coccidioidomycosis in California and Arizona. International Journal of Environmental Research and Public Health. 2011;8(4):1150-73. [CrossRef] [Pubmed]
2. Valdivia L, Nix D, Wright M, Lindberg E, Fagan T, Lieberman D, et al. Coccidioidomycosis as a common cause of community-acquired pneumonia. Emerg Infect Dis. 2006;12(6):958-62. [CrossRef] [Pubmed]
3. Kim MM, Blair JE, Carey EJ, Wu Q, Smilack JD. Coccidioidal pneumonia, Phoenix, Arizona, USA, 2000-2004. Emerg.Infect Dis. 2009;15(3):397-401. [CrossRef] [Pubmed]
4. CDC. Increase in reported coccidioidomycosis - United States, 1998-2011. MMWR Morb Mortal Wkly Rep. 2013;62:217-21.
5. [PubMed]
6. Chang DC, Anderson S, Wannemuehler K, Engelthaler DM, Erhart L, Sunenshine RH, et al. Testing for coccidioidomycosis among patients with community-acquired pneumonia. Emerg Infect Dis. 2008;14(7):1053-9. [CrossRef] [Pubmed]
7. Galgiani JN, Ampel NM, Blair JE, Catanzaro A, Johnson RH, Stevens DA, et al. Coccidioidomycosis. Clin Infect Dis. 2005;41(9):1217-23. [CrossRef] [PubMed]
8. Limper AH, Knox KS, Sarosi GA, Ampel NM, Bennett JE, Catanzaro A, et al. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011;183(1):96-128. [CrossRef] [PubMed]
9. Chen S, Erhart LM, Anderson S, Komatsu K, Park B, Chiller T, et al. Coccidioidomycosis: knowledge, attitudes, and practices among healthcare providers--Arizona, 2007. Med Mycol. 2011;49(6):649-56. [CrossRef] [PubMed]
10. Nguyen C, Barker BM, Hoover S, Nix DE, Ampel NM, Frelinger JA, et al. Recent advances in our understanding of the environmental, epidemiological, immunological, and clinical dimensions of coccidioidomycosis. Clin Microbiol Rev. 2013;26(3):505-25. [CrossRef] [PubMed]
11. Abuodeh RO, Shubitz LF, Siegel E, Snyder S, Peng T, Orsborn KI, et al. Resistance to Coccidioides immitis in mice after immunization with recombinant protein or DNA vaccine of a proline-rich antigen. Infect Immun. 1999;67(6):2935-40. [PubMed]
12. Dodge RR, Lebowitz MD, Barbee RA, Burrows B. Estimates of C. immitis infection by skin test reactivity in an endemic community. Am J Public Health. 1985;75:863-5. [CrossRef] [PubMed]
13. Larwood TR. Coccidioidin skin testing in Kern County, California: Decrease in infection rate over 58 years. Clinical Infectious Diseases. 2000;30(3):612-3. [CrossRef] [PubMed]
14. Tamerius JD, Comrie AC. Coccidioidomycosis incidence in Arizona predicted by seasonal precipitation. PLoS.One. 2011;6(6):e21009. [CrossRef] [PubMed]
15. Brown H, Comrie A, Tamerious J, Khan M, Tabor J, Galgiani J. 2014. Climate, wind storms, and the risk of valley fever (coccidioidomycosis). In The Influence of Global Environmental Change on Infectious Disease Dynamics. Washington (DC). Institute of Medicine & National Academies Press. pp. 266-282. Available at: http://www.iom.edu/Reports/2014/The-Influence-of-Global-Environmental-Change-on-Infectious-Disease-Dynamics.aspx
16. 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]
17. Smith CE. Coccidioidomycosis. In: Coates JB, Hoff EC, eds. Communicable Diseases transmitted chiefly through respiratory and alimentary tracts. Washington, DC: Office of the Surgeon General, Medical Department, US Army; 1958:285-316.
18. 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]
19. Kerrick SS, Lundergan LL, Galgiani JN. Coccidioidomycosis at a university health service. Am Rev Respir Dis. 1985;131:100-2. [PubMed]
20. Yozwiak ML, Lundergan LL, Kerrick SS, Galgiani JN. Symptoms and routine laboratory abnormalities associated with coccidioidomycosis. West J Med. 1988;149:419-21. [PubMed]
21. Blair JE, Chang YH, Cheng MR, Vaszar LT, Vikram HR, Orenstein R, et al. Characteristics of patients with mild to moderate primary pulmonary coccidioidomycosis. Emerg Infect Dis. 2014;20(6):983-90. [CrossRef] [PubMed]
22. Shubitz LF, Dial SM, Perrill R, Casement R, Galgiani JN. Vaccine-induced cellular immune responses differ from innate responses in susceptible and resistant strains of mice infected with Coccidioides posadasii. Infect Immun. 2008;76(12):5553-64. [CrossRef] [PubMed]
23. Huntington RW. Pathology of coccidioidomycosis. In: Stevens DA, ed. Coccidioidomycosis. A text. New York: Plenum Medical Book Co.; 1980:113-32. [CrossRef]
24. Echols RM, Palmer DL, Long GW. Tissue eosinophilia in human coccidioidomycosis. Rev Infect Dis. 1982;4:656-64. [CrossRef] [PubMed]
25. Cole GT, Xue JM, Okeke CN, Tarcha EJ, Basrur V, Schaller RA, et al. A vaccine against coccidioidomycosis is justified and attainable. Med Mycol. 2004;42(3):189-216. [CrossRef] [PubMed]
26. 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]
27. Vinh DC, Schwartz B, Hsu AP, Miranda DJ, Valdez PA, Fink D, et al. Interleukin-12 receptor beta1 deficiency predisposing to disseminated Coccidioidomycosis. Clin Infect Dis. 2011;52(4):e99-e102. [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-e5. [CrossRef] [PubMed]
29. Ampel NM, Hector RF. Measuring cellular immunity in coccidioidomycosis: the time is now. Mycopathologia. 2010;169(6):425-6. [CrossRef] [PubMed]
30. Santelli AC, Blair JE, Roust LR. Coccidioidomycosis in patients with diabetes mellitus. Am J Med. 2006;119(11):964-9. [CrossRef] [PubMed]
31. 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] [PubMed]
32. Pappagianis D, Zimmer BL. Serology of coccidioidomycosis. Clin Microbiol Rev. 1990;3:247-68. [PubMed]
33. Saubolle MA, McKellar PP, Sussland D. Epidemiologic, clinical, and diagnostic aspects of coccidioidomycosis. J Clin Microbiol. 2007;45(1):26-30. [CrossRef] [PubMed]
34. Smith CE, Saito MT, Simons SA. Pattern of 39,500 serologic tests in coccidioidomycosis. JAMA. 1956;160:546-52. [CrossRef] [PubMed]
35. Fiese MJ. Coccidioidomycosis. Springfield: Charles C Thomas; 1958.
36. Birsner JW. The roentgen aspects of five hundred cases of pulmonary coccidioidomycosis. Am J Roentgenol Rad Ther. 1954;72:556-73. [PubMed]
37. Lonky SA, Catanzaro A, Moser KM, Einstein H. Acute coccidioidal pleural effusion. Am Rev Respir Dis. 1976;114:681-8. [PubMed]
38. Galgiani JN. Elements of Style in Managing Coccidioidomycosis. Clin Infect Dis. 2013;56(11):1586-8. [CrossRef] [PubMed]
39. Nguyen BD. F-18 FDG PET/CT imaging of disseminated coccidioidomycosis. Clin Nucl Med. 2006;31(9):568-71. [CrossRef] [PubMed]
40. Reyes N, Onadeko OO, Luraschi-Monjagatta Mdel C, Knox KS, Rennels MA, Walsh TK, et al. Positron emission tomography in the evaluation of pulmonary nodules among patients living in a coccidioidal endemic region. Lung. 2014;192(4):589-93. [CrossRef] [PubMed]
41. 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]
42. Jaroszewski DE, Halabi WJ, Blair JE, Coakley BJ, Wong RK, Parish JM, et al. Surgery for pulmonary coccidioidomycosis: a 10-year experience. Ann Thorac Surg. 2009;88(6):1765-72. [CrossRef] [PubMed]
43. Ashfaq A, Vikram HR, Blair JE, Jaroszewski DE. Video-assisted thoracoscopic surgery for patients with pulmonary coccidioidomycosis. J Thorac Cardiovasc Surg. 2014;148(4):1217-23. [CrossRef] [PubMed]
44. Cunningham RT, Einstein H. Coccidioidal pulmonary cavities with rupture. J Thorac Cardiovasc Surg. 1982;84:172-7. [PubMed]
45. 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]
46. Bronnimann DA, Adam RD, Galgiani JN, Habib MP, Petersen EA, Porter B, et al. Coccidioidomycosis in the acquired immunodeficiency syndrome. Ann.Intern.Med. 1987;106:372-9. [CrossRef] [PubMed]
47. 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]
48. Ampel NM, Ryan KJ, Carry PJ, Wieden MA, Schifman RB. Fungemia due to Coccidioides immitis. An analysis of 16 episodes in 15 patients and a review of the literature. Medicine (Baltimore). 1986;65:312-21. [CrossRef] [PubMed]
49. 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(6):384-91. [CrossRef] [PubMed]
50. 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]
51. Larsen RA, Jacobson JA, Morris AH, Benowitz BA. Acute respiratory failure caused by primary pulmonary coccidioidomycosis. Two case reports and a review of the literature. American Review of Respiratory Disease. 1985;131(5):797-9. [PubMed]

Reference as: Galgiani JN, Knox K, Rundbaken C, Siever J. Common mistakes in managing pulmonary coccidioidomycosis. Southwest J Pulm Crit Care. 2015;10(5):238-49. doi: http://dx.doi.org/10.13175/swjpcc054-15 PDF

Editor's Note: For accompanying editorial see "Eliminating Mistakes in Managing Coccidioidomycosis" by Tim Kuberski.

May 2015 Pulmonary Case of the Month: Pneumonia with a Rash

Richard A. Robbins, MD

Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ

History of Present Illness

A 77-year-old man underwent a thoracic CT scan  for follow up of a known thoracic aneurysm.  However, he had been feeling tired for about a week with a cough, night sweats and fever. He had no shortness of breath, wheezing or known history of lung disease.

Past Medical History, Social History and Family History

He has a history of hypertension and a known thoracic aortic aneurysm. There was a  surgical repair of his right clavicle after a motor vehicle accident. He is single and has lived in Arizona for over 50 years. He just returned from a trip to California where he visited Disneyland. He does not smoke. Family history is noncontributory.    

Current Medications

• Dutasteride
• Levothyroxine
• Atorvastatin

Physical Examination

His physical examination was reported as unremarkable. SpO2 was 95% on room air.

Radiography

Figure 1. Representative images from his thoracic CT scan showing a left lower lobe consolidation (red arrows). Panel A: coronal projection in lung windows. Panel B: axial view in lung windows.

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

1. Begin empiric antibiotics
2. Bronchoscopy with bronchoalveolar lavage
3. Sputum Gram stain and culture
4. 1 and 3
5. All of the above

Reference as: Robbins RA. May 2015 pulmonary case of the month: pneumonia with a rash. Southwest J Pulm Crit Care. 2015;10(5):203-7. doi: http://dx.doi.org/10.13175/swjpcc044-15 PDF 

April 2015 Pulmonary Case of the Month: Get Down

Michael Pham, MD

Karen Swanson, DO

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 59 year old woman was admitted with hypercapnic respiratory failure and an altered mental state. She had progressive “breathing issues” for the last year and was  increasingly error prone with decreased mental acuity at the end of her work shift for the last 6 months. She was on oxygen at 2 L by nasal cannula at home and has had several admissions over the last 3 months for hypercapnic respiratory failure.

Past Medical History

Obstructive sleep apnea with continuous positive airway pressure (CPAP) intolerance, type 2 diabetes mellitus, and fibromyalgia. She is a life-long nonsmoker.

Physical Examination

Vital signs: T 36.9º C, P 116 beats/min, R 42 breaths/min, BP 134/80 mm Hg, SpO2 93% on room air.

General: She appeared very short of breath.

Neck: No jugular venous distention.

Lungs: Clear anteriorly.

Heart: RR with a tachycardia. 

Abdomen: no organomegaly or masses.

Neurologic:

• +3-to-4 of 5 strength upper and lower extremities
• Difficulty holding upright posture
• Decreased sensation in lower extremities
• R > L lower extremity gastrocnemial fasciculations
• Hand asterixis/tremor bilaterally
• Decreased DTRs diffusely

Laboratory

ABG's: pH 7.3 / CO₂ 82 / pO₂ 77. Following 4 hours CPAP: pH 7.4 / CO₂ 68 / pO₂ 80

Basic metabolic panel: Na⁺ 138 | Cl^- 86 | Creatinine 0.4

                                         K⁺ 4.8 | TCO₂ 44 | BUN 13

                                         Ca⁺⁺ 4.9 / PO₄^- 4.1 / Mg⁺⁺ 1.9

Complete blood count: WBC 11.9 cells/mm³, Hemoglobin 10.8 g/dL

Liver function tests, ammonia and lactate were all normal.

Radiography

Admission chest x-ray is shown in Figure 1.

Figure 1. Admission chest x-ray.

Which of the following is/are true regarding the chest x-ray? (Click on the correct answer to proceed to the second of four panels)

1. Elevated right hemidiaphragm
2. Right pleural effusion
3. Volume loss in the right hemithorax
4. 1 and 3
5. All of the above

Reference as: Pham M, Swanson K. April 2015 pulmonary case of the month: get down. Southwest J Pulm Crit Care. 2015;10(4):152-8. doi: http://dx.doi.org/10.13175/swjpcc040-15 PDF