Pulmonary

The Southwest Journal of Pulmonary and Critical Care publishes articles broadly related to pulmonary medicine including thoracic surgery, transplantation, airways disease, pediatric pulmonology, anesthesiolgy, pharmacology, nursing and more. Manuscripts may be either basic or clinical original investigations or review articles. Potential authors of review articles are encouraged to contact the editors before submission, however, unsolicited review articles will be considered.

Rick Robbins, M.D. 9/1/16 Rick Robbins, M.D. 9/1/16

September 2016 Pulmonary Case of the Month

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

Pulmonary Case of the Month CME Information

Members of the Arizona, New Mexico, Colorado and California Thoracic Societies and the Mayo Clinic are able to receive 0.25 AMA PRA Category 1 Credits™ for each case they complete. Completion of an evaluation form is required to receive credit and a link is provided on the last panel of the activity.

0.25 AMA PRA Category 1 Credit(s)™

Estimated time to complete this activity: 0.25 hours

Lead Author(s): Lewis J. Wesselius, MD. All Faculty, CME Planning Committee Members, and the CME Office Reviewers have disclosed that they do not have any relevant financial relationships with commercial interests that would constitute a conflict of interest concerning this CME activity.

Learning Objectives:
As a result of this activity I will be better able to:

Correctly interpret and identify clinical practices supported by the highest quality available evidence.
Will be better able to establsh the optimal evaluation leading to a correct diagnosis for patients with pulmonary, critical care and sleep disorders.
Will improve the translation of the most current clinical information into the delivery of high quality care for patients.
Will integrate new treatment options in discussing available treatment alternatives for patients with pulmonary, critical care and sleep related disorders.

Learning Format: Case-based, interactive online course, including mandatory assessment questions (number of questions varies by case). Please also read the Technical Requirements.

CME Sponsor: University of Arizona College of Medicine at Banner University Medical Center Tucson

Current Approval Period: January 1, 2015-December 31, 2016

Financial Support Received: None

History of Present Illness

The patient is a 52 year-old woman with prior renal transplant in 1998 due to complications of pre-eclampsia. She had a recent decline in renal function leading to re-transplant on June 23 of this year. She was admitted to the hospital on July 8th with ventricular tachycardia. Treatment with amiodarone was begun with no further ventriuclar tachycardia. She is also taking usual anti-rejection medications.

Past Medical History, Social History and Family History

Other than the renal transplantation she has no other significant past medical history and has never smoked. Family history is noncontributory.

Physical Examination

Physical examination was unremarkable other than the surgical wounds associated with her renal transplants.

Radiography

Her chest x-ray is shown in Figure 1.

Figure 1. Admission chest radiograph.

What should be done at this time? (Click on the correct answer to proceed to the second of four panels)

Cite as: Wesselius LJ. September 2016 pulmonary case of the month. Southwest J Pulm Crit Care. 2016;13(3):101-7. doi: http://dx.doi.org/10.13175/swjpcc086-16 PDF

Rick Robbins, M.D. 7/1/16 Rick Robbins, M.D. 7/1/16

July 2016 Pulmonary Case of the Month

Kashif Yaqub, MD

Robert Viggiano, MD

Imran S. Malik, MD

Zayn A. Mian

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

Pulmonary Case of the Month CME Information

0.25 AMA PRA Category 1 Credit(s)™

Estimated time to complete this activity: 0.25 hours

Lead Author(s): Kashif Yaqub, MD. All Faculty, CME Planning Committee Members, and the CME Office Reviewers have disclosed that they do not have any relevant financial relationships with commercial interests that would constitute a conflict of interest concerning this CME activity.

Learning Objectives:
As a result of this activity I will be better able to:

Correctly interpret and identify clinical practices supported by the highest quality available evidence.
Will be better able to establsh the optimal evaluation leading to a correct diagnosis for patients with pulmonary, critical care and sleep disorders.
Will improve the translation of the most current clinical information into the delivery of high quality care for patients.
Will integrate new treatment options in discussing available treatment alternatives for patients with pulmonary, critical care and sleep related disorders.

Learning Format: Case-based, interactive online course, including mandatory assessment questions (number of questions varies by case). Please also read the Technical Requirements.

CME Sponsor: University of Arizona College of Medicine at Banner University Medical Center Tucson

Current Approval Period: January 1, 2015-December 31, 2016

Financial Support Received: None

History of Present Illness

A 53 year-old woman presented to the emergency department with dyspnea over 3 weeks. There was no cough, wheezing or other complaints.

Past Medical History, Social History and Family History

She has no significant past medical history. She was a nonsmoker. Family history was unremarkable.

Physical Examination

Decreased breath sounds over the left lower chest but otherwise unremarkable.

Laboratory Evaluation

Elevated white blood cell count with a left shift
Na+ 130 mEq/L
10-20 RBCs on urinalysis

Radiographic Evaluation

A CT angiogram of the chest was performed for possible pulmonary embolus (Figure 1).

Figure 1. Representative images from the thoracic CT in lung windows (A) and soft tissue windows (B).

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

Cite as: Yaqub K, Viggiano R, Malik IS, Mian AZ. July 2016 pulmonary case of the month. Southwest J Pulm Crit Care. 2016;13(1):1-8. doi: http://dx.doi.org/10.13175/swjpcc051-16 PDF

Rick Robbins, M.D. 4/1/16 Rick Robbins, M.D. 4/1/16

April 2016 Pulmonary Case of the Month

Lewis J. Wesselius, MD

Rodrigo Cartin-Ceba, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

Pulmonary Case of the Month CME Information

0.25 AMA PRA Category 1 Credit(s)™

Estimated time to complete this activity: 0.25 hours

Lead Author(s): Lewis J. Wesselius, MD. All Faculty, CME Planning Committee Members, and the CME Office Reviewers have disclosed that they do not have any relevant financial relationships with commercial interests that would constitute a conflict of interest concerning this CME activity.

Learning Objectives:
As a result of this activity I will be better able to:

Correctly interpret and identify clinical practices supported by the highest quality available evidence.
Will be better able to establsh the optimal evaluation leading to a correct diagnosis for patients with pulmonary, critical care and sleep disorders.
Will improve the translation of the most current clinical information into the delivery of high quality care for patients.
Will integrate new treatment options in discussing available treatment alternatives for patients with pulmonary, critical care and sleep related disorders.

Learning Format: Case-based, interactive online course, including mandatory assessment questions (number of questions varies by case). Please also read the Technical Requirements.

CME Sponsor: University of Arizona College of Medicine at Banner University Medical Center Tucson

Current Approval Period: January 1, 2015-December 31, 2016

Financial Support Received: None

History of Present Illness

The patient is a 75-year-old woman who presented with a chest mass incidentally found on chest x-ray. She was asymptomatic

Past Medical History, Social History and Family History

She has no significant past medical history and has never smoked. Family history is noncontributory.

Physical Examination

Physical examination was unremarkable.

Radiography

A thoracic CT scan was performed (Figure 1).

Figure 1. Representative thoracic CT scan in soft tissue windows showing a mass (arrow).

Which of the following are possible causes of the mass? (Click on the correct answer to proceed to the second of four panels)

Cite as: Wesselius LJ, Cartin-Ceba R. April 2016 pulmonary case of the month. Southwest J Pulm Crit Care. 2016 Apr;12(4):126-9. doi: http://dx.doi.org/10.13175/swjpcc032-16 PDF

Rick Robbins, M.D. 3/31/16 Rick Robbins, M.D. 3/31/16

Pulmonary Embolism and Pulmonary Hypertension in the Setting of Negative Computed Tomography

Peter V. Bui, MD

Sapna Bhatia, MD

Dona J. Upson, MD, MA

Department of Internal Medicine

Division of Pulmonary, Critical Care, and Sleep Medicine

The University of New Mexico and Raymond G. Murphy VA Medical Center

Albuquerque, NM

Abstract

Introduction: Chronic pulmonary hypertension (PH) can display acute elevations in pulmonary arterial pressure (PAP) in the setting of hypoxemia, pulmonary embolism (PE), and possibly sepsis.

Case Description: A 68-year-old man with chronic obstructive pulmonary disease, heart failure, recent tobacco cessation, and recent 2-vessel coronary artery bypass grafting (CABG) presented with one to two weeks of respiratory symptoms and syncope on the day of admission. He was found to have a urinary tract infection and Escherichia coli bacteremia. Transthoracic echocardiography found a systolic PAP of 100-105 mmHg, increased from a mean PAP of 32 mmHg before CABG. PE was not seen on computed tomography angiography (CTA). Ventilation-perfusion scan two days later found evidence of subsegmental PE. PAP prior to discharge was 30-35 mmHg plus right atrial pressure.

Conclusion: PAP can rise substantially in the acute or subacute setting, particularly when multiple disease processes are involved, and decrease to (near) baseline with proper therapy. Chronic PH may even be protective. In a complex clinical setting with multiple possible etiologies for elevated PAP, clinicians should have a high suspicion for PE despite a negative CTA.

Abbreviation List

ADHF acute decompensated heart failure

CABG coronary artery bypass grafting

COPD chronic obstructive pulmonary disease

CTA computed tomography angiography

CXR conventional chest radiograph
EF ejection fraction

HCAP healthcare-associated pneumonia

HFpEF heart failure with preserved ejection fraction

INR international normalized ratio

LV left ventricle

PAP pulmonary arterial pressure

PCWP pulmonary capillary wedge pressure

PE pulmonary embolism

PH pulmonary hypertension

RA right atrium/atrial

RV right ventricle/ventricular

RHC right heart catheterization

SaO2 arterial oxygen saturation

TTE transthoracic echocardiography

UTI urinary tract infection

VTE venous thromboembolism

VQ ventilation-perfusion

Introduction

Pulmonary hypertension (PH) is classified into five groups (1). In the United States, the incidence and prevalence of PH and each of its five groups are largely unclear. Group 2, due to left heart disease, has a prevalence as high as 83% by transthoracic echocardiography (TTE) in patients with heart failure with preserved ejection fraction (HFpEF) (2). For group 3, due to chronic lung disease, in a study measuring pulmonary arterial pressure (PAP) by right heart catheterization (RHC), the prevalence of PH among patients with chronic obstructive pulmonary disease (COPD) was 36% (3). Changes in PAP in the setting of acute or subacute pulmonary embolism (PE) are unknown. We present a patient found to have transient severely elevated PAP in the setting of a negative computed tomography angiography (CTA) and positive ventilation-perfusion (VQ) scan with distractors including HFpEF, COPD, and sepsis.

Case Presentation

A 68-year-old man with severe COPD on four liters per minute of supplemental oxygen, a 50-pack-year smoking history with cessation two months before admission, HFpEF, 3-vessel coronary artery disease, myocardial infarction involving the left circumflex artery, recent 2-vessel coronary artery bypass grafting (CABG), recurrent urinary tract infections (UTIs), chronic prostatitis, and prostatic calculi presented after a syncopal episode. One day prior to admission, he experienced fevers to 40°C and shaking chills. On the day of admission, the patient woke up struggling for breath and experienced syncope while getting out of bed. He had been having altered mental status and one week of productive cough with greenish sputum. He did not have any other respiratory, urinary, and constitutional symptoms. He presented to an outside hospital, where he was treated for presumed sepsis secondary to a UTI and started on an antibiotic. He was transferred to our facility and admitted for a UTI and possible healthcare-associated pneumonia (HCAP).

At presentation at our facility, vital signs included a temperature of 36.8°C, heart rate of 87 beats per minute, blood pressure of 124 mmHg / 69 mmHg, respiratory rate of 18 breaths per minute, and oxygen saturation of 96% on three-to-four liters per minute of supplemental oxygen. The physical examination was notable for expiratory wheezing and trace lower extremity edema. White blood cell was 13.5 K/mm³, neutrophilia of 80.4%, troponin I of 0.048 ng/mL, N-terminal pro-brain natriuretic peptide of 2800 pg/mL, and urinalysis suggestive of UTI. An arterial blood gas was deemed unnecessary for unchanged supplemental oxygen, normal mentation, and lack of respiratory distress. Electrocardiography showed normal sinus rhythm, nonspecific ST and T wave abnormalities, and previously identified signs of inferior-posterior infarction without evidence of acute right heart strain. He did not receive chemoprophylaxis for venous thromboembolism (VTE) because of possible surgical intervention.

Ten days before admission (Table 1), he made a long distance drive to see Cardiothoracic Surgery for post-CABG follow-up.

Table 1. Timeline of events surrounding the patient’s hospitalization. Computed tomography angiography (CTA). Coronary artery bypass grafting (CABG). Conventional chest radiographs (CXR). Ejection fraction (EF). International normalized ratio (INR). Pulmonary arterial pressure (PAP). Pulmonary embolism (PE). Transthoracic echocardiography (TTE). Urinary tract infection (UTI). Ventilation-perfusion (VQ).

He had an increased oxygen requirement from three-to-four to four-to-five liters per minute, bilateral lower extremity edema, and supratherapeutic international normalized ratio (INR) of 4.4 on warfarin for postoperative atrial fibrillation, that had since resolved. TTE showed a normal sized left ventricle (LV), LV ejection fraction of 50-55%, inferolateral wall akinesis, basal inferior wall akinesis, mildly dilated right ventricle (RV), mildly reduced RV systolic function, mildly dilated right atrium (RA), PAP of 70-80 mmHg, and right atrial pressure of 10-15 mmHg. The patient refused hospitalization. Furosemide and metolazone were increased, and warfarin discontinued. His INR was 1.4 four days before admission.

Outpatient medications included amiodarone, simvastatin 10 mg, aspirin 81 mg, metoprolol 25 mg three times a day, and furosemide 80-100 mg daily. Six weeks prior to admission, RHC found RA pressure of 12 mmHg, RV pressure of 45/15 mmHg, PAP of 45/25 mmHg with a mean pressure of 32 mmHg, pulmonary capillary wedge pressure (PCWP) of 15 mmHg, cardiac output of 7.98 L/min, cardiac index of 3.55 L/min/m², SaO2 97%, mixed venous saturation of 71%, pulmonary vascular resistance of 2.1 dynes-sec-cm^-5, and system vascular resistance of 782 dynes-sec-cm^-5.

At presentation, his respiratory symptoms were attributed to pneumonia and not acute decompensated heart failure (ADHF) or COPD. Initial antibiotics for HCAP and UTI coverage were cefepime and vancomycin. Conventional chest radiographs (CXRs) (Figure 1) on hospital day 0 and the CTA a few days later were not suggestive of pneumonia.

Figure 1. Conventional radiography of the chest showing no acute cardiopulmonary findings but enlarged pulmonary arteries.

An influenza viral panel was negative. Outside blood cultures grew Escherichia coli, while blood, urine, and sputum cultures from our facility were negative. CXRs over the following week were unchanged.

Because of the elevated PAP found prior to admission, Pulmonology was consulted for pulmonary hypertension. TTE on hospital day 3 found a normal RV size, mildly reduced RV systolic function, mildly dilated RA, systolic PAP of 100-105 mmHg, and RA pressure of <5 mmHg. His Wells score for PE was 3.0 to 4.5, suggesting moderate risk (4). The CTA did not identify a PE. In view of a high suspicion for PE, Pulmonology reviewed the CTA with a chest radiologist, who noted that the images were of suboptimal thickness. A VQ scan (Figure 2) was ordered on hospital day 5 and showed multiple bilateral VQ defects consistent with a high probability for PE.

Figure 2. Ventilation-perfusion scan on hospital day 5 showing multiple bilateral ventilation-perfusion defects. The study was consistent with a high probability for pulmonary embolism.

Ultrasound Doppler studies of the lower extremities on hospital day 6 were normal. Repeat TTE on hospital day 5 found a normal sized LV, LV EF of 45-50%, basal inferior wall akinesis, inferolateral wall akinesis, mildly dilated RV, mildly reduced RV systolic function, normal RA size, and PAP of 30-35 mmHg plus RA pressure. The patient was discharged on anticoagulation and antibiotics.

Discussion

We describe a patient who developed transiently elevated PAP in the setting of sepsis secondary to UTI and E. coli bacteremia, acute or subacute PE, HFpEF, and COPD. At baseline, he likely had PH from COPD and HFpEF out of proportion to PCWP. The increased PAP to 70-80 mmHg 1.5 weeks prior to admission was thought to be due to the hypervolemia observed by outpatient Cardiothoracic Surgery. Recent CABG, long-distance travel, and infection predisposed him to VTE. PE may have caused the dyspnea and syncope experienced on the day of admission. The negative CTA and systolic PAP of 100-105 mmHg on TTE on hospital day 3 may have reflected movement of PE downstream to the subsegmental or smaller arteries and thus inability to be seen on CTA, especially given the suboptimal thickness of the images. Volume status and vascular changes in the setting of recent hypervolemia, possibly due to HF or PH, and concurrent infection may have contributed to this elevated PAP. In light of the presentation of unexplained dyspnea and syncope, Wells score of 3.0 to 4.5, and elevated PAP, suspicion for PE was high. The high pretest probability of PE precipitated obtaining a VQ scan on hospital day 5. The scan supported the presence of bilateral PE, likely in the subsegmental or smaller arteries. PAP of 30-35 mmHg on subsequent TTE suggested resolution of PE.

CTA is the most common study to diagnose acute PE. A number of early studies found CTA to be at least as equivalent in sensitivity and specificity to VQ scan (5-10). Studies using data from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II found the sensitivity and specificity of CTA to be 83% and 96%, respectively, and of VQ scan to be 77.4%. and 97.7%, respectively (11, 12). However, CTA miss up to 20% to 36% of PE in subsegmental and smaller arteries (13-15). A meta-analysis of Wells criteria found sensitivity and specificity of 0.84 and 0.58, respectively, for a cutoff score of less than 2 and 0.60 and 0.80, respectively, for a cutoff score of 4 or less (16).

The degree to which HFpEF, COPD exacerbation, acute or subacute PE, and sepsis affect PAP has had limited investigation. In patients with ADHF, Aronson et al. (17) found PH in 42.6% and pulmonary arterial systolic pressures as high as 70 to 80 mmHg. Sibbald et al. (18) found that 57% of septic patients developed PH and had increases in mean PAP (27 ± 7 mmHg in septic patients found to have PH versus 15 ± 3 mmHg in septic patients found not to have PH, p < 0.01). In patients with chronic bronchitis who went into acute respiratory failure, Abraham et al. (19) found transient increases in mean PAP of approximately 15-20 mmHg (mean PAP 52.2 mmHg at admission and 36.5 mmHg prior to discharge).

The mechanism of PH can be mechanistically complex or intuitively simple. PH involves changes in nitric oxide, endothelin, thromboxane, and prostacyclin pathways, among other possible cellular and biological pathways of pulmonary endothelial dysfunction (20-25). Proinflammatory signals such as during infection affect these pathways (26). Other mechanisms include vascular congestion in HF, physical obstruction from PE, and vasoconstriction in hypoxemia leading to elevated PAP and subsequent PH (27-31). In our patient, there was likely a combination of several mechanisms contributing to his elevated PAP and PH.

Our patient may have been able to tolerate such an acute rise in pulmonary hypertension because of the effects of chronic pulmonary hypertension, although the pathophysiologic mechanisms have not been fully elucidated. Vonk-Noordegraaf et al. (32) described adaptive and maladaptive remodeling in pulmonary hypertension. In adaptive remodeling, the RV size is normal to moderately dilated; the RV mass/volume ratio is higher than normal, as seen in concentric remodeling; and the RVEF is normal to mildly decreased. For our patient, multiple TTE suggested adaptive remodeling, although our cardiologists did not comment on concentric remodeling.

We present the case of a patient with multiple comorbidities including HFpEF and COPD that likely caused the baseline PH seen on previous RHC and the subsequent development of severely increased PAP in the setting of sepsis and acute or subacute PE. His underlying chronic PH may have been protective given that he did not develop acute right HF from the sudden increase in PAP, and survived. The transient elevation in PAP in our patient reiterates that many disease processes can affect PAP, whether directly or indirectly, through simple or complex mechanisms. A CTA to evaluate possible PE should be verified to have the proper technique. A high suspicion for PE in the setting of acute PH despite a negative CTA warrants further investigation.

Acknowledgements

Dr. Loren Ketai of the Department of Radiology of The University of New Mexico reviewed the images of the computed tomography angiography and ventilation-perfusion scans.

Cecilia Kieu assisted in the preparation of the figures for this manuscript.

References

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Cite as: Bui PV, Bhatia S, Upson DJ. Pulmonary embolism and pulmonary hypertension in the setting of negative computed tomography. Southwest J Pulm Crit Care. 2016 Mar;12(3):116-25. doi: http://dx.doi.org/10.13175/swjpcc016-16 PDF

Rick Robbins, M.D. 3/1/16 Rick Robbins, M.D. 3/1/16

March 2016 Pulmonary Case of the Month

Ramachandra R. Sista, MD

Maxwell L. Smith, MD

Lewis J. Wesselius, MD

Departments of Pulmonary Medicine and Pathology

Mayo Clinic Arizona

Scottsdale, AZ

Pulmonary Case of the Month CME Information

0.25 AMA PRA Category 1 Credit(s)™

Estimated time to complete this activity: 0.25 hours

Lead Author(s): Ramachandra R. Sista, MD. All Faculty, CME Planning Committee Members, and the CME Office Reviewers have disclosed that they do not have any relevant financial relationships with commercial interests that would constitute a conflict of interest concerning this CME activity.

Learning Objectives:
As a result of this activity I will be better able to:

Correctly interpret and identify clinical practices supported by the highest quality available evidence.
Will be better able to establsh the optimal evaluation leading to a correct diagnosis for patients with pulmonary, critical care and sleep disorders.
Will improve the translation of the most current clinical information into the delivery of high quality care for patients.
Will integrate new treatment options in discussing available treatment alternatives for patients with pulmonary, critical care and sleep related disorders.

Learning Format: Case-based, interactive online course, including mandatory assessment questions (number of questions varies by case). Please also read the Technical Requirements.

CME Sponsor: University of Arizona College of Medicine at Banner University Medical Center Tucson

Current Approval Period: January 1, 2015-December 31, 2016

Financial Support Received: None

History of Present Illness

A 74-year-old man was referred for a recently identified right pleural effusion and dyspnea on exertion.

Past Medical History, Family History and Social History

He has a history of anemia, hypertension, and prostate cancer with a prostatectomy in 2015. He is a life-long nonsmoker and has no occupational exposures. Family history is noncontributory.

Physical Examination

He had diminished breath sounds at the right lung base and a palpable spleen. Otherwise the physical examination was unremarkable.

Laboratory

CBC: hemoglobin 8.5 g/dL, white blood count 7.7 X 109 cells/L, platelets 357 X 109 cells/L.

Radiography

A chest X-ray showed a right pleural effusion. Representative images from the CT scan are shown in Figure 1.

Figure 1. Representative images from the CT scan.

Which of the following is the most likely diagnosis? (Click on the correct answer to proceed to the second of five panels)

Cite as: Sista RR, Smith ML, Wesselius LJ. March 2016 pulmonary case of the month. Southwest J Pulm Crit Care. 2016;12(3):74-80. doi: http://dx.doi.org/10.13175/swjpcc020-16 PDF

Rick Robbins, M.D. 12/29/15 Rick Robbins, M.D. 12/29/15

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

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]
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]
Simmons BP, Aber RC. Mycoplasma pneumoniae pneumonia. Symptoms mimicking pulmonary embolism with infarction. JAMA. 1979;241(12):1268-9. [CrossRef] [PubMed]
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]
Ascer E, Marques M, Gidlund M. M pneumonia infection, pulmonary thromboembolism and antiphospholipid antibodies. BMJ Case Rep. 2011;2011. [CrossRef] [PubMed]
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]
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]
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]
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]
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]
Bakshi M, Khemani C, Vishwanathan V, Anand RK. Mycoplasma pneumonia with antiphospholipid antibodies and a cardiac thrombus. Lupus 2006;15:105–6. [CrossRef] [PubMed]
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]
Joo CU, Kim JS, Han YM. Mycoplasma pneumoniae induced popliteal artery thrombosis treated with urokinase. Postgrad Med J. 2001;77:723–724. [CrossRef] [PubMed]
Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet. 1999;353(9159):1167-73. [PubMed]
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]
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

Rick Robbins, M.D. 12/1/15 Rick Robbins, M.D. 12/1/15

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)

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

Rick Robbins, M.D. 9/28/15 Rick Robbins, M.D. 9/28/15

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

Lednicky JA. Hantavirus: A short review. Arch Pathol Lab Med. 2003;127:30-35. [PubMed]
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]
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

Rick Robbins, M.D. 8/1/15 Rick Robbins, M.D. 8/1/15

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)

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

Rick Robbins, M.D. 6/1/15 Rick Robbins, M.D. 6/1/15

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)

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

Rick Robbins, M.D. 5/18/15 Rick Robbins, M.D. 5/18/15

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

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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]
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Additional Selected References

Ampel NM. Coccidioidomycosis in persons infected with HIV-1. Ann N Y Acad Sci. 2007;1111:336-42. [CrossRef] [PubMed]
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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]
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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]
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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

Rick Robbins, M.D. 5/14/15 Rick Robbins, M.D. 5/14/15

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.

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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.

Rick Robbins, M.D. 4/1/15 Rick Robbins, M.D. 4/1/15

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)

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

Rick Robbins, M.D. 1/1/15 Rick Robbins, M.D. 1/1/15

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

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

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

University of New Mexico

Albuquerque, New Mexico

History of Present Illness

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

PMH, SH & FH

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

Physical Exam

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

General: His mental status was not altered.

HEENT: No papilledema was appreciated on eye exam.

Neck: JVP not appreciated.

Lungs: he had diminished breath sounds bilaterally on auscultation.

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

Abdomen: No abdominal distention or lower extremity edema appreciated.

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

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

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