Diagnostic Challenges of Acute Eosinophilic Pneumonia Post Naltrexone Injection Presenting During The COVID-19 Pandemic

Michelle Breuer

Abdulmonam Ali, MD

SSM Health

Mount Vernon, IL USA

Introduction

Acute eosinophilic pneumonia (AEP) is a rare respiratory illness that may present with nonspecific symptoms ranging in severity from cough and dyspnea to potentially fatal acute respiratory distress syndrome. Although the exact etiology of AEP is unknown, it is thought to be a hypersensitivity reaction that can be idiopathic or caused by various infections, inhalation exposures, and medications (1).  Here we present a rare case of AEP secondary to injectable naltrexone.

Case Presentation

A 45-year-old Caucasian male with a history of alcohol use disorder presented to the emergency room with a 3-day history of progressively worsening dyspnea and dry cough. The patient was a lifelong non-smoker with an unremarkable past medical history aside from alcohol abuse and obesity (BMI 41.64 kg/m²). He denied fever or chills, orthopnea, chest pain, or symptoms suggestive of paroxysmal nocturnal dyspnea. He also denied any recent sick contacts, including exposure to COVID-19. Relevant history includes alcohol cessation 1 month before presentation. After 2 weeks of cessation, he received his first injection of naltrexone (Vivitrol®) as part of alcohol relapse prevention. Physical exam was notable for an initial SpO₂ of 69% on room air, sinus tachycardia at a rate of 121 bpm, and obesity. Chest examination exhibited decreased air entry with bilateral fine crackles on auscultation. No skin rashes or peripheral edema were appreciated, and the remaining physical exam was within normal limits. The patient was started on supplemental oxygen (6 liters/minute nasal cannula to maintain SpO2 above 90%).

Workup was performed and chest x-ray showed diffuse bilateral pulmonary infiltrates (Figure 1), hence, the patient was started on empiric antibiotic and steroid therapy.

Figure 1. Chest X-ray showing bilateral ground-glass opacities.

SARS-CoV-2 PCR testing was performed twice due to high clinical suspicion of COVID-19 infection (the patient was seen during the Coronavirus pandemic). Both SARS-CoV-2 tests were negative as well as the rest of the respiratory viral panel. CBC was significant for leukocytosis with an absolute peripheral eosinophil count of 0.49 x 10⁹ cells/L. Bloodwork also revealed mildly elevated troponin, d-dimer, and LDH. However, electrocardiogram showed no significant ST changes and Computerized Tomography (CT) angiography chest showed no evidence of pulmonary embolism but confirmed the chest x-ray findings of diffuse bilateral ground-glass opacities with anterolateral subpleural parenchymal sparing (Figure 2).

Figure 2. CTA chest (axial view, lung window) showing diffuse ground-glass opacities.

An echocardiogram showed an ejection fraction of 60% and normal left ventricular diastolic function. Moderate right ventricular (RV) dilation with reduced systolic function was reported and the peak RV pressure was estimated at 39 mmHg. Extensive blood testing for connective tissue disease was negative for ANCA, CCP, ANA, and cryoglobulins. Immunoglobulin E (IgE) level was within normal limits at 14KU/L (reference range < 214 KU/L).  Infectious disease serology was negative for mycoplasma, strongyloides, coccidioides, and aspergillus. HIV and hepatitis screening were also negative. Bronchoscopy with bronchoalveolar lavage (BAL) was performed and was significant for 27% eosinophils, 42% lymphocytes, 25% monocytes, 6% neutrophils (Figure 3).

Figure 3. Bronchoalveolar lavage (BAL) showing increased numbers of eosinophils.

BAL culture remained negative including mycobacterial and fungal cultures. BAL testing for Pneumocystis Jirovecii was negative as well. BAL cytology showed benign bronchial epithelial cells and inflammatory cells. No parasites were seen in BAL and fungal staining was negative.

The constellation of the above clinical, radiological, and laboratory findings was highly suggestive of acute eosinophilic pneumonia diagnosis. The patient’s methylprednisolone dose was increased to 125mg every 8 hours. Due to high FiO2 requirements and poor pulmonary reserve, the patient remained intubated after his bronchoscopy procedure. Over the following 48 hours, FiO₂ requirements improved significantly and his repeat chest x-ray showed almost complete resolution of the pulmonary infiltrates. The patient was successfully extubated to 2 liters of oxygen via nasal cannula on the third day.  Supplemental oxygen was eventually weaned off to room air. There wasn’t significant desaturation observed with the exercise trial. He was discharged home on a gradually tapering dose of oral steroids over 6 weeks. The patient was later seen at the pulmonary clinic for a follow-up visit. He was doing well and denied any significant respiratory symptoms. A follow-up chest x-ray was within normal limits (Figure 4).

Figure 4. Chest x-ray upon follow-up.

Discussion 

Acute eosinophilic pneumonia (AEP) is defined by rapid eosinophilic infiltration of the lung tissue, resulting in impaired gas exchange. Presenting symptoms are nonspecific and may include cough, progressive dyspnea, chest pain, and fever (2). Chest imaging of patients with AEP shows diffuse bilateral parenchymal infiltrates. Diagnosis can be made in the appropriate clinical and radiological context, with BAL showing at least 25% eosinophils on the fluid differential, and with no other identifiable causes (1).

The pathogenesis of AEP is not completely understood; however, it is hypothesized to involve a hypersensitivity reaction in patients with genetic susceptibility (3,4). AEP can be associated with many identifiable causes including cigarette smoke most notably, as well as other inhalants, infections, and medications. Although antibiotics and nonsteroidal anti-inflammatory drugs are among the more common inciting medications, injectable naltrexone has been implicated in several case reports (3,5,6,7).

The clinical presentations of AEP can mimic SARS-CoV-2 pneumonia, community-acquired pneumonia, or ARDS; hence, a high index of clinical suspicion is essential to avoid delay in therapy. A confident diagnosis of AEP can usually be made without a lung biopsy in patients who meet the following criteria (8):

1) acute onset of febrile respiratory manifestations (≤ 1-month duration before consultation).

2) bilateral diffuse opacities on chest radiography.

3) hypoxemia, with PaO₂ on room air<60 mm Hg, and/or PaO₂/FiO₂≤300 mm Hg, and/or oxygen saturation on room air<90%.4) lung eosinophilia, with >25% eosinophils on BAL differential cell count (or eosinophilic pneumonia at lung biopsy).

5) absence of known causes of AEP, including drugs, infections, asthma, or atopic disease.

In our case, the patient has met most of the suggested criteria for diagnosing AEP in addition to the presence of a triggering factor (a clear temporal relationship between the development of symptoms and the recent naltrexone injection). However, we met with a few obstacles before making the diagnosis of AEP.  During these unprecedented times, any patient presenting with acute hypoxic respiratory failure, and/or ground-glass opacities (both are classic for SARS-CoV-2 pneumonia as well as AEP) must go through an additional screening process to rule out COVID-19, including contact and airborne infection isolation precautions in addition to the standard precautions and SARS-CoV-2 PCR testing.  

On the other hand, several recent reports of AEP presumably triggered by SARS-CoV-2 infection had been described (9-10), which was another factor that contributed to making the diagnosis of AEP more challenging in his case and kept COVID-19 high on the differential diagnosis list. Furthermore, our patient received steroids on the initial presentation which likely affected the accuracy of the total eosinophilic counts in the BAL.

AEP has a higher likelihood than chronic eosinophil pneumonia of presenting with more severe symptoms and has a greater potential of rapid progression to respiratory failure. One review study reported 30-80% of AEP patients required intensive care unit admission and another case review noted 20% of AEP patients required mechanical ventilation (4,11). Treatment includes supportive care, recognition and avoidance of identifiable triggers, and systemic corticosteroids. Most patients rapidly improve with prompt corticosteroid treatment and experience complete recovery (1,3). Relapse of AEP rarely occurs (4).

Numerous conditions can cause pulmonary eosinophilia that needs to be differentiated from AEP. Different classifications have been suggested, but we will list the broad categories and most common etiologies including chronic eosinophilic pneumonia, eosinophilic granulomatosis with polyangiitis (EGPA, previously known as Churg-Strauss), drug and toxin-induced eosinophilic lung disease, helminthic, and fungal infection-related eosinophilic lung diseases, idiopathic hypereosinophilic syndrome, neoplasms, interstitial lung disease, coccidioidomycosis, tuberculosis, and allergic bronchopulmonary aspergillosis.

In addition to AEP, several conditions are associated with elevated BAL eosinophils greater than 25%.  These conditions include chronic eosinophilic pneumonia, EGPA, tropical pulmonary eosinophilia.  Other conditions causing BAL eosinophilia, but less than 25%, include connective tissue disease, drug-induced pneumonitis, fungal pneumonia, idiopathic pulmonary fibrosis, pulmonary Langerhans cell histiocytosis, sarcoidosis.

Finally, multiple medications are implicated in drug-induced AEP, however, naltrexone is still not well recognized as a potential cause.  In a recent retrospective review, naltrexone was not included in the medication list compiled (11).

Conclusion

Injectable naltrexone, a long-acting opioid antagonist, is used for the treatment of opioid and alcohol dependence. Although rare, the use of injectable naltrexone is associated with the potentially fatal side effect of AEP. Since AEP shares many clinical attributes with other causes of acute lung injury, including community-acquired pneumonia and SARS-CoV-2 pneumonia, it can be easily overlooked. Therefore, having an accurate history and an appropriate index of suspicion is important for early detection and proper management (3).

References

1. De Giacomi F, Vassallo R, Yi ES, Ryu JH. Acute Eosinophilic Pneumonia. Causes, Diagnosis, and Management. Am J Respir Crit Care Med. 2018 Mar 15;197(6):728-736. [CrossRef] [PubMed]
2. Katz U, Shoenfeld Y. Pulmonary eosinophilia. Clin Rev Allergy Immunol. 2008 Jun;34(3):367-71. [CrossRef] [PubMed]
3. Mears M, McCoy K, Qiao X. Eosinophilic Pneumonia and Extended-Release Injectable Naltrexone. Chest. 2021;160(4): A1676 [Abstract]. [CrossRef]
4. Suzuki Y, Suda T. Eosinophilic pneumonia: A review of the previous literature, causes, diagnosis, and management. Allergol Int. 2019 Oct;68(4):413-419. [CrossRef] [PubMed]
5. Horsley R, Wesselius LJ. June 2107 Pulmonary Case of the Month. Southwest J Pulm Crit Care. 2017;14(6):255-61. [CrossRef]  
6. Esposito A, Lau B. Saved by the BAL: A Case of Acute Eosinophilic Pneumonia After Methyl-Naltrexone Injection. Chest. 2019;156(4):A2210 [Abstract]. [CrossRef]
7. Korpole PR, Al-Bacha S, Hamadeh S. A Case for Biopsy: Injectable Naltrexone-Induced Acute Eosinophilic Pneumonia. Cureus. 2020 Sep 3;12(9):e10221. [CrossRef] [PubMed]
8. Philit F, Etienne-Mastroïanni B, Parrot A, Guérin C, Robert D, Cordier JF. Idiopathic acute eosinophilic pneumonia: a study of 22 patients. Am J Respir Crit Care Med. 2002 Nov 1;166(9):1235-9. [CrossRef] [PubMed]
9. Araújo M, Correia S, Lima AL, Costa M, Neves I. SARS-CoV-2 as a trigger of eosinophilic pneumonia. Pulmonology. 2022 Jan-Feb;28(1):62-64. [CrossRef] [PubMed]
10. Murao K, Saito A, Kuronuma K, Fujiya Y, Takahashi S, Chiba H. Acute eosinophilic pneumonia accompanied with COVID-19: a case report. Respirol Case Rep. 2020 Nov 16;8(9):e00683. [CrossRef] [PubMed]
11. Bartal C, Sagy I, Barski L. Drug-induced eosinophilic pneumonia: A review of 196 case reports. Medicine (Baltimore). 2018 Jan;97(4):e9688. [CrossRef] [PubMed]
12. Salahuddin M, Anjum F, Cherian SV. Pulmonary Eosinophilia. 2021 Dec 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. [PubMed]

Cite as: Breuer M, Ali A. Diagnostic Challenges of Acute Eosinophilic Pneumonia Post Naltrexone Injection Presenting During The COVID-19 Pandemic. Southwest J Pulm Crit Care Sleep. 2022;24(2):26-31. doi: https://doi.org/10.13175/swjpccs002-22 PDF 

March 2021 Pulmonary Case of the Month: Transfer for ECMO Evaluation

Nicholas G. Blackstone, MD

April Olson, MD

Angela Gibbs, MD

Bhupinder Natt, MD

Janet Campion, MD

University of Arizona College of Medicine – Tucson

Tucson, AZ USA

History of present illness

A 31-year-old male fire fighter with a history of recurrent “atypical pneumonia”, environmental and drug allergies, nasal polyps, asthma, and Crohns disease (not on immunosuppressants) was transferred from an outside hospital for management of acute hypoxic respiratory failure with peripheral eosinophilia. Prior to admission he reported a 2-week history of worsening dyspnea, productive cough and wheezing, prompting an urgent care visit where he was prescribed amoxicillin-clavulanate for suspected community acquired pneumonia. Despite multiple days on this medication, his symptoms significantly worsened until he was unable to lie flat without coughing or wheezing. He was ultimately admitted to an outside hospital where his labs were notable for a leukocytosis to 22,000 and peripheral eosinophilia with an absolute eosinophil count of 9700 cells/microL. His blood cultures and urine cultures were negative, and a radiograph of the chest demonstrated bilateral nodular infiltrates. With these imaging findings combined with the peripheral eosinophilia there was a concern for Coccidioidomycosis infection and he was subsequentially started on empirical fluconazole in addition to ceftriaxone and azithromycin. Bronchoalveolar lavage (BAL) was performed revealing 80% eosinophils, 14% polymorphic nuclear cells (PMNs), 4% monocytes and 2% lymphocytes, no pathogens were identified. The patient’s clinical status continued to decline despite antimicrobial therapy, and he was intubated for refractory hypoxia. At this point, the patient was transferred to our hospital for further care.

What is the most likely diagnosis in this patient? (Click on the correct answer to be directed to the second of four pages.)

1. Acute asthma exacerbation
2. Bacterial pneumonia
3. Coccidioidomycosis pneumonia
4. Eosinophilic pneumonia
5. Rocky Mountain Spotted Fever

Cite as: Blackstone NG, Olson A, Gibbs A, Natt B, Campion J. March 2021 Pulmonary Case of the Month: Transfer for ECMO Evaluation. Southwest J Pulm Crit Care. 2021;22(3):69-75. doi: https://doi.org/10.13175/swjpcc069-20 PDF

July 2018 Pulmonary Case of the Month

Anjuli M. Brighton, MB, BCh, BAO

Mayo Clinic Arizona

Scottsdale, AZ USA

Pulmonary Case of the Month CME Information

Completion of an evaluation form is required to receive credit and a link is provided on the last page of the activity. 

0.25 AMA PRA Category 1 Credit(s)™

Estimated time to complete this activity: 0.25 hours

Lead Author(s): Anjuli M. Brighton, MB. 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 completing this activity, participants will be better able to:

1. Interpret and identify clinical practices supported by the highest quality available evidence.
2. Establish the optimal evaluation leading to a correct diagnosis for patients with pulmonary, critical care and sleep disorders.
3. Translate the most current clinical information into the delivery of high quality care for patients.
4. Integrate new treatment options 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, 2017-December 31, 2018

Financial Support Received: None

History of Present Illness

An 81-year-old gentleman was admitted for syncope. He had felt unwell for one month. His recent illness started with the “flu”. He had lingering productive cough, low volume hemoptysis and felt very fatigued. After a coughing episode he apparently lost consciousness and was taken to the emergency department.

Past Medical History, Social History and Family History

He has a past medical history of hypertension, glaucoma, diverticulosis and COPD. He was taking only antihypertensives including a diuretic. He has a 30 pack-year history of smoking but quit 10 years ago.

Physical Examination

• Normotensive
• Tachypneic
• SpO2 96% on 2L NC
• Afebrile
• Diffuse wheezing, diminished at L base
• Irregularly irregular heart rate

Which of the following are indicated at this time? (Click on the correct answer to be directed to the second of six pages)

1. Chest x-ray
2. Complete blood count (CBC)
3. Electrocardiogram (EKG)
4. 1 and 3
5. All of the above

Cite as: Brighton AM. July 2018 pulmonary case of the month. Southwest J Pulm Crit Care. 2018;17(1):1-6. doi: https://doi.org/10.13175/swjpcc073-18 PDF 

June 2017 Pulmonary Case of the Month

Robert Horsley, MD

Lewis J. Wesselius, MD 

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 61-year-old woman presented to the emergency department for 3 days of fevers up to 102º F, malaise, and progressive shortness of breath. Her symptoms started immediately after he last naltrexone injection for alcohol use disorder.

Past Medical History, Social History and Family History

• Alcohol use disorder
• Treated with monthly naltrexone injections, received 3 doses total, and gabapentin
• No other previous medical issues
• Nonsmoker

Physical Examination

• Vital signs: Pulse 100, BP 108/90, respiratory rate 34, SpO2 93% 10L non-rebreathing mask
• Cyanotic on room air
• Lungs clear

Radiography

A portable chest x-ray was performed in the emergency department (Figure 1).

Figure 1. AP chest radiograph taken in the emergency department.

A thoracic CT scan was performed (Figure 2).

Figure 2. Representative images from thoracic CT in lung windows.

Laboratory

• CBC showed a white blood cell count of 12,000 cells/mcL.
• The differential showed a left shift.
• Lactate was 5.2 mmol/L

Which of the following is (are) true? (Click on the correct answer to proceed to the second of five pages)

1. A lactate level of 5.2 can be a normal finding in a critically ill patient
2. Her symptoms are likely an allergic reaction to naltrexone
3. The most likely diagnosis is an atypical pneumonia
4. 1 and 3
5. All of the above

Cite as: Horsley R, Wesselius LJ. June 2107 pulmonary case of the month. Southwest J Pulm Crit Care. 2017;14(6):255-61. doi: https://doi.org/10.13175/swjpcc063-17 PDF

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

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

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

PMH, FH, SH

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

Physical Examination

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

Spirometry

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

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

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

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

August 2012 Pulmonary Case of the Month

All Eosinophilia Is Not Asthma

Lewis J. Wesselius, MD

Departments of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 73 year old man was seen with a one month history of shortness of breath. He dated this to an emergency room visit for an arm injury for which he had a DPT vaccination. Previously, he had been able to swim regularly, but he is now unable to swim due to worsening dyspnea. He also had some cough that was nonproductive.

PMH, SH and FH

He has a past medical history of coronary artery disease with prior stenting of his right and left anterior descending artery in 2010. He also has a history of hypertension, dysplipidemia, a carotid endarterectomy and a single seizure after a corneal transplant.

His present medications include:

• Atorvastatin
• Lisinopril
• Metoprolol
• Warfarin

He has a minimal smoking history and denied use of alcohol, drugs or unusual exposures. 

Physical Examination

His vitals signs were normal and he was afebrile but he was receiving supplemental oxygen at 3 lpm.

Chest examination revealed bilateral crackles but no wheezes.

Cardiovascular examination showed a regular rhythm with a Grade 2/6 systolic ejection murmur.

He had no clubbing or edema.

The remainder of the physical examination was either normal or noncontributory.

Chest X-ray

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

 Figure 1. Admission chest x-ray showing the PA (Panel A) and lateral (Panel B).

Which of the following are possible causes of the patient’s clinical picture?

1. Coccidioidomycosis (Valley Fever)
2. Allergic reaction to the DPT vaccination
3. Pulmonary edema
4. A + C
5. All of the above

Reference as: Wesselius LJ. August 2012 pulmonary case of the month: all eosinophilia is not asthma. Southwest J Pulm Crit Care 2012;5:58-64. (Click here for a PDF version of the case presentation)

A 61 Year Old Immunosuppressed Man With A Symptomatic Pulmonary Infiltrate

Carmen Luraschi-Monjagatta¹

Amber Noon¹

Neil Ampel¹

Suzette Chavez¹

Mitch Goldman²

Kenneth S  Knox¹

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

Indiana University School of Medicine, Indianapolis, IN²

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

Abstract

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

Case Presentation

History of Present Illness

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

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

Physical examination

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

Laboratory findings

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

 

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

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

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

Hospital course

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

Discussion

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

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

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

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

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

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

Summary

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

References

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

Corresponding author:

Kenneth S Knox, M.D.

Associate Professor of Medicine, University of Arizona

Southern Arizona VA Health Care System

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

Tucson, AZ 85723

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

Acknowledgment:

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

Author Contributions:

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

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

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

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

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

Abbreviations:

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