Treatment of Coccidioidomycosis-associated Eosinophilic Pneumonia with Corticosteroids

Joshua Malo, MD

Yuval Raz, MD 

Linda Snyder, MD

Kenneth Knox, MD

University of Arizona Medical Center

Department of Medicine

Section of Pulmonary, Allergy, Critical Care, and Sleep Medicine

Tucson, AZ 85724

Abstract

Pulmonary coccidioidomycosis is a common cause of community-acquired pneumonia in endemic areas of the southwestern United States. The clinical spectrum of this disease ranges from an asymptomatic presentation to severe disease with ARDS and hypoxemic respiratory failure. Despite evidence supporting the use of corticosteroids for severe pulmonary disease in other fungal infections, there is currently no established role for this therapy in coccidioidomycosis infections. Peripheral eosinophilia is a common feature of coccidioidomycosis; however, pulmonary eosinophilia is rarely reported. In the setting of pulmonary eosinophilia of other etiologies, corticosteroid therapy has been demonstrated to have a role in reducing the inflammatory response and leading to a more rapid resolution of hypoxemic respiratory failure. We report a case of a patient with primary pulmonary coccidioidomycosis complicated by severe pulmonary eosinophilia that demonstrated rapid improvement after the initiation of corticosteroid therapy.

Case Report

A 71-year-old man presented to the emergency room in Tucson, Arizona with a one-week history of fever, cough, and malaise. The patient’s symptoms began while returning from a trip to northern California. A chest radiograph ordered by the primary care physician demonstrated a right upper lobe consolidation (Figure 1) and azithromycin was prescribed. Fevers persisted along with worsening cough over the next three days, and the patient presented for further evaluation.

Figure 1. Admission radiograph demonstrating right upper lobe airspace disease

Medical history was remarkable for viral cardiomyopathy requiring placement of an ICD after an episode of sudden cardiac death in 2006. An episode of S. bovis bacteremia occurred 4 months prior to the current presentation and was treated with a course of cefazolin. There is no known personal or family history of atopic disease. There is no history of tobacco use or significant occupational exposures. The patient had been living in Arizona during the preceding year and had no other recent travel history, dust, or environmental exposures.

On physical exam, temperature was 38.8°C and pulse oximetry saturation was 90 percent on room air. The patient was in moderate respiratory distress with rales auscultated in the right upper lung zone. Subsequent laboratory examination revealed a PaO2 of 69 mmHg on 4 liters-per-minute of oxygen via nasal cannula. A metabolic panel showed elevated transaminases and his initial leukocyte count was 11.8 x 10³/mL with differential including 5% eosinophils.

The patient was admitted to the medical ward and treated with vancomycin, cefepime, and moxifloxacin for pneumonia caused by a potentially resistant organism. Fluconazole was started on the third hospital day for empiric treatment of primary pulmonary coccidioidomycosis. A CT angiogram of the chest showed bilateral multilobar pneumonia (Figure 2).

Figure 2. CT angiogram of the chest demonstrating multilobar consolidation of the right lung

The patient deteriorated and required intubation for severe hypoxemia two days later. A bronchoalveolar lavage revealed Coccidioides spherules on cytological examination. Liposomal amphotericin B was initiated, which led to the development of oliguric renal failure necessitating hemodialysis. Initial Coccidioides serology was negative, however sputum and BAL cultures demonstrated C. immitis. Despite antifungal therapy his pulmonary status worsened with progressive bilateral pulmonary infiltrates and worsening hypoxemic respiratory failure (Figure 3).

Figure 3. CXR demonstrating progressive bilateral alveolar opacities consistent with ARDS.

In addition, he had a steadily increasing peripheral eosinophilia reaching a maximum of 40 percent with a leukocyte count of 14.8 x 10³/mL despite the absence of any signs of disseminated coccidioidomycosis. A repeat BAL again showed Coccidioides spherules and eosinophils of 40 and 56 percent from the right middle lobe and lingula, respectively. Methylprednisolone 40mg IV three times daily was started with a decline in blood eosinophils to one percent within 24 hours. Chest radiographs and A-a gradient rapidly improved over the next 3 days leading to successful extubation. The patient was transitioned to oral fluconazole and prednisone and discharged from the hospital in good condition two weeks later.

At the follow-up six weeks after initial presentation, he remains on fluconazole and prednisone 15mg daily with no signs of disseminated coccidioidomycosis and is continuing a gradual reduction of prednisone dosage.

Discussion

Coccidioidomycosis is caused by either of 2 species of the dimorphic fungus Coccidioides. Endemic regions are present in North and South America, with the majority of cases within the United States arising in Arizona and California. Although peripheral eosinophilia is a commonly reported finding (1), pulmonary eosinophilia has rarely been described.

Acute eosinophilic pneumonias may be idiopathic or a secondary inflammatory response to various infections or environmental exposures. In regions where endemic fungal infections are common, differentiating between eosinophilic pneumonias of idiopathic versus infectious etiology is vital in order to avoid inappropriate therapy and its adverse consequences. A review of the literature concerning pulmonary coccidioidomycosis and concurrent pulmonary eosinophilia demonstrates only 9 prior case reports. Corticosteroid therapy was used for treatment of the pulmonary eosinophilia in only 3 of these cases, 2 of which resulted in death from disseminated coccidioidal infection (1-3). One case ended in spontaneous resolution of disease without antifungals or corticosteroids leading the authors to suggest a conservative approach with corticosteroids due to the risk for dissemination (4).

In our case, there was progressive clinical deterioration despite ten days of treatment with appropriate antifungal regimen, leading to our decision to treat with corticosteroids. The immediate decrease in peripheral eosinophilia in conjunction with the rapid clinical improvement leads us to the conclusion that corticosteroids were beneficial in the resolution of his acute respiratory failure. The clinical response observed is similar to that expected in idiopathic acute eosinophilic pneumonia which supports the notion that the eosinophilic response, as opposed to the primary infection, was primarily responsible for our patient’s severe hypoxemia.

There remains a risk for disseminated disease. In the cases cited in which patients died of dissemination, antifungal therapy preceding corticosteroid therapy was not described. Due to the risk of underlying pulmonary coccidioidomycosis in endemic regions, corticosteroid therapy for eosinophilic pneumonia should only be considered in the setting of severe hypoxemic respiratory failure and once adequate antifungal therapy has been initiated.

According to recent guidelines there is no role for corticosteroid therapy in the treatment of coccidioidomycosis due to a lack of convincing data for efficacy and safety (5). There is precedent for treating severe pulmonary disease caused by other fungal infections, such as histoplasmosis and blastomycosis, with corticosteroids. We suggest that there is a role for the use of corticosteroid therapy in the setting of progressive respiratory failure due to coccidioidomycosis with associated pulmonary eosinophilia that has failed conventional antifungal therapy.

References

1. Echols RM, Palmer DL, Long GW. Tissue eosinophilia in human coccidioidomycosis. Rev Infect Dis 1982;4:656–664.
2. Lombard CM, Tazelaar HD, Krasne DL. Pulmonary eosinophilia in coccidioidal infections. Chest 1987;5:734–736
3. Swartz J, Stoller JK. Acute Eosinophilic Pneumonia Complicating Coccidioides immitis Pneumonia: A Case Report and Literature Review. Respiration 2009;77:102–106
4. Whitlock WL, Dietrich RA, Tenholder MF. Acute eosinophilic pneumonia (letter). N Engl J Med 1990;322:635
5. Limper AH, Knox KS, Sarosi GA, et al. Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96–128

The authors report no conflicts of interest

Address correspondence to:     Joshua Malo, MD

                                             University of Arizona Medical Center

                                             Department of Medicine    

                                             Section of Pulmonary, Allergy, Critical

                                             Care and Sleep Medicine

                                             Tucson, AZ 85724

                                             E-mail: jmalo@deptofmed.arizona.edu

Reference as: Malo J, Raz Y, Snyder L, Knox K. Treatment of coccidioidomycosis-associated eosinophilic pneumonia with corticosteroids. Southwest J Pulm Crit Care 2012;4:61-66. (Click here for a PDF version of the manuscript) 

Sympathetic Empyema Arising from Streptococcus anginosus Splenic Abscess

Emad Wissa, MD

Robert A. Raschke, M.D.

Manoj Mathew, MD, FCCP, MCCM 

Good Samaritan Regional Medical Center

1111 E. McDowell Road

Phoenix, AZ 85006

Abstract

We report a 52 year old male with a history splenic infarction, abdominal pain and shortness of breath. CT scanning revealed a splenic abcess and empyema. Cultures from both sites grew Streptococcus anginosus. These resolved with drainage and antibiotics. Physicians should consider Streptococcus species when confronted with a patient with splenic infarction.

Introduction

Sympathetic Empyema Thoracis or sympathetic empyema is a rare entity. The mechanism by which this occurs is via penetration by a subdiaphragmatic abscess into the pleural space. Most reported cases have occurred in the right hemithorax secondary to the presence of a liver abscess or ascites. Splenic abscess are rare and are often seen in the setting of embolic endocarditis, infections from Salmonella or other bacterial invade the infarcted spleen (1,2). To our knowledge, this is the first reported case of sympathetic empyema likely secondary to a Streptococcus splenic abscess.

Case Report

A 52 year old male presented with a 2 day history of shortness of breath and 2 a month history of left upper quadrant pain. His medical history included hepatitis C, drug abuse and splenic infarction. On examination his breathing was labored. His chest X-ray was remarkable for a left lower lobe opacification (Figure 1).

Figure 1. Chest x-ray showing left lower lobe opacification.

He was endotracheally intubated and started on broad spectrum antibiotics. A computed tomography (CT) of the chest and abdomen demonstrated a moderate left side pleural effusion, compressive atelectasis, a small amount of ascites and a splenic abscess (Figure 2).

Figure 2. Coronal CT of chest and upper abdomen.

A chest tube was placed into the left hemithorax, and a pigtail catheter was placed into the splenic abscess. Cultures from both sites yielded Streptococcus anginosus. The empyema was treated with antibiotics, and chest tube fibrinolytic therapy with tissue plasminogen activator (TPA) and dornase alpha. Blood cultures were sterile and echocardiogram revealed no vegetations. The patient was extubated on hospital day 4. The left pleural empyema responded well to fibrinolytic therapy with chest tube removal on day 10. The splenic abscess required long term drainage with pigtail remaining in place for 3 weeks before the abscess resolved. The patient was discharged home on hospital day 24 on amoxicillin.

Discussion

Sympathetic empyema is an infection in the pleural space caused by translocation of a bacterial infection from the liver, ascitic fluid or from a splenic abscess. This patient had a known history of splenic infarction predisposing him to bacterial invasion and splenic abscess formation. The absence of cough, sputum production, and lobar consolidation argues against an empyema arising from and underlying pneumonia, although we can not exclude that possibility. Our review of the medical literature demonstrates no known cases of sympathetic empyema from Streptococcus anginosus. Physicians should also consider this organism in a patient with a splenic abscess.

References

1. Buscaglia A. Empyema due to splenic abscess with Salmonella newport. JAMA1978;240:1990.
2. Tornos M.P, Mayor G, Nadal A, Soler A. Empyema and splenic abscess in infective endocarditis. Int J Cardio 1984;6:746-8.

Reference as: Wissa E, Raschke RA, Mathew M. Sympathetic empyema arising from streptococcus anginosus splenic abscess. Southwest J Pulm Crit Care 2012;4:48-50. (Click here for a PDF version of the case presentation)

February 2012 Pulmonary Case of the Month

Lewis J. Wesselius, MD

Associate Editor Pulmonary

History of Present Illness

A 49 year old female was seen for fever and shortness of breath in December 2011. She has a history of right infiltrating ductal breast cancer diagnosed in 2001 at age 38. Treatment included mastectomy with negative lymph nodes, followed by 4 courses of doxarubicin and cytoxan. She did well until March 2010 when erythema was noted over her right chest.  Biopsy showed adenocarcinoma consistent with  breast carcinoma. The biopsy was “triple negative”, i.e., negative for estrogen receptors, progesterone receptors and Her2. PET scan demonstrated multiple positive lymph nodes in the mediastinum, supraclavicular area and bone metastases. She received radiation to her chest wall and chemotherapy most recently gemcitabine, carboplatin and iniparib. In October 2011 brain metastases were noted and she was started on stereotactic brain radiation and dexamethasone.

Past Medical, Family and Social Histories

• She had a prothrombin mutation noted and was begun prophylactically on warfarin in 2010.
• There was a family history of breast carcinoma.
• She was a non-smoker with no unusual exposures.
• Current medications include omeprazole, metoprolol, and warfarin.

Physical Examination

She was receiving oxygen at 3 L/min by nasal cannula. Temperature was to 37.9°C. She had bilateral crackles on chest auscultation, most prominent at bases. Physical Examination was otherwise noncontributory.

Initial Laboratory Evaluation

• Hemoglobin/Hematocrit 11.8 g/dL/33.9%
• White blood count 5.1 X10⁹/L
• Platelets 64 X 10⁹/L
• INR 1.58 

Chest CT scan

Chest CT scan is in figure 1.

Figure 1. Selected images from the admission CT scan. The CT scan was interpreted as showing diffuse groundglass opacities and scattered centrilobular nodules. 

Which of the following diagnosis are consistent with the patient’s presentation and CT scan?

1. Pulmonary edema
2. Bacterial pneumonia
3. Fungal pneumonia
4. Drug reaction
5. All of the above

Reference as: Wesselius LJ. February 2012 pulmonary case of the month. Southwest J Pulm Crit Care 2012;4:42-7.

(Click here for a PDF version of the case presentation)

(Click here for a Powerpoint slide presentation of the case)

Spirometry Use in Patients Prescribed Albuterol

Kevin Park, M.D.

Che' S. Ornelas, M.D.

Richard A. Robbins, M.D.

Phoenix VA Medical Center, Banner Good Samaritan VA Medical Center and the Phoenix Pulmonary and Critical Care Medicine and Research Foundation, Phoenix, AZ

Address correspondence to:     Richard A. Robbins, M.D.

                                             502 E. Vermont Drive

                                             Gilbert, AZ 85295

                                             E-mail: rickrobbins@cox.net

Conflict of Interest Statement: None of the authors have conflicts of interest pertinent to the subject matter of this manuscript. 

Abstract

Background:  Previous studies have shown that spirometry is obtained in only about a third of patients with chronic obstructive pulmonary disease (COPD) in primary care practice. This study evaluated spirometry use in persons prescribed an albuterol inhaler in the primary care clinics at a Veterans Administration (VA) hospital.

Methods: One hundred ninety-seven patients prescribed albuterol were reviewed for age, education level of the primary care practioners, other respiratory medications and diagnosis.

Results: The average age was 63.2 years (SD, 11.5), and 93% of patients were male. Obtaining spirometry was not age or sex-dependent but became more frequent with the use of tiotropium (72.2%), long-acting beta agonists (71.8%), ipratropium (69.4%)  or inhaled corticosteroids (63.5%) compared to albuterol alone (39.4%, p=0.0007). Eighty of the patients had a diagnosis of COPD (40.6%), 40 a diagnosis of asthma (20.3%), 23 other respiratory diagnoses (11.7%) but 54 (27.4%) had no respiratory diagnosis. Patients diagnosed with COPD were more likely to have spirometry performed (71.2%) than patients diagnosed with asthma (35%), other respiratory diagnosis (34.7%) or no respiratory diagnosis (40.7%) (p=0.00068).

Conclusions: The above data demonstrate that spirometry is more frequently used in patients with COPD than previously reported and increases when additional medications are added to albuterol.

Introduction

Spirometry is recommended for the diagnosis of most adult respiratory disease including chronic obstructive pulmonary disease (COPD) and asthma (1-5). However, previous publications have revealed that in patients with COPD spirometry is performed in only about a third of the patients (6-10). Based on this data, we initiated a quality improvement project to examine compliance with spirometry guidelines in primary care.

Most previous investigations have examined patients’ diagnosis of COPD or asthma and examined the percentage of patients who had spirometry. However, the diagnosis of COPD or asthma is frequently incorrect (11-13). Furthermore, these projects may likely both under- and over-diagnose COPD in patients with no symptoms (14). Since albuterol is recommended as initial treatment for both diseases (1-4), we examined recent prescriptions for albuterol at a single VA medical center. Our rationale was that this should eliminate asymptomatic patients or patients with very mild disease. We found that in patients prescribed albuterol who also had a diagnosis of COPD that spirometry was performed over double (72%) of previous reports.

Methods

This project was approved by the institutional review board of the Carl T. Hayden VA Hospital. Using VA records we identified 200 patients seen in primary care who were prescribed an albuterol inhaler and had a primary care visit between November 1-5, 2010 or November 8-12, 2010. The electronic records were reviewed for each patient. Demographic data (age, sex); education level of provider (MD or DO, nurse practioners); diagnosis (COPD, asthma, other respiratory diagnosis or no diagnosis); other respiratory medications, and the presence of spirometry were recorded. When spirometry was available for COPD patients, spirometric values of FEV1/FVC% or FEV1% predicted were recorded and used to classify COPD severity based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria (1,15).

Statistical Analysis

Comparisons between the groups with and without spirometry were made with χ2 tests for categoric variables and t tests for continuous variables. The association between having spirometry performed and patient characteristics was evaluated in unadjusted models.

Results

Chart review

Two hundred charts were examined, but 3 patients were excluded, one because they had not been prescribed albuterol and two because of incomplete data. The remaining 197 patients were evaluated.

Demographics

Age was 63+11 years and 7% of the patients were female. Age and sex were not significantly different between those who had spirometry and those who did not (data not shown, p>0.05 both comparisons).

Education Level of Provider

There were 16 MD or DO physician primary care providers and 8 nurse practioners. The physicians saw 136 patients and the nurse practioners 61. Spirometry was present on 73 of the patients seen by physicians (53.7%) and 29 of the patients seen by nurse practioners (47.5%, p=0.45).

Other Respiratory Medications

Numbers of patients with other respiratory medications are shown in Table 1. Many patients were on multiple medications. Patients on albuterol alone were significantly less likely to have spirometry than those on other medications (p=0.0007). Only two patients were receiving theophylline and one oral prednisone.

Table 1. Spirometry and other respiratory medications prescribed

LABA=Long-acting beta agonist

ICS=Inhaled corticosteroid

*p=0.0007 compared to other medications

Diagnosis

COPD was diagnosed in 80 patients (40.6%), asthma in 40 patients (20.3%), other respiratory diagnosis in 23 patients (11.7%) but no respiratory diagnosis was recorded in 54 patients (27.4%). Other respiratory diagnosis included 10 patients with tobacco dependence, 3 with dyspnea, 2 with lung carcinoma, and 2 with obstructive sleep apnea and one each with allergies, cannabis dependence, sinusitis, coin lesion, pulmonary embolus and respiratory disorder not otherwise specified. Patients with COPD were significantly more likely to have spirometry performed than other diagnosis (Table 2).

Table 2. Spirometry and respiratory diagnosis

*p=0.00068 compared to other diagnosis

Of the 57 patients with COPD and spirometry, 5 had very severe disease (FEV1 <30% predicted), 16 had severe disease (30% < FEV1< 50% predicted), 34 had moderate disease (50% < FEV1 < 80% predicted) and 2 had mild disease (FEV1>80% predicted) by GOLD criteria. Six of the 18 COPD patients without spirometry were receiving albuterol alone compared to 11 of the 57 of the COPD patients with spirometry (p=0.5519).

Discussion

The objective of this study was to examine spirometry use in primary care in patients with prescribed albuterol. Overall, the presence of spirometry in patients was low, with only 51.8% of patients having spirometry performed during the analysis period. Patients diagnosed with COPD or who had additional respiratory medications prescribed in addition to albuterol were more likely to undergo spirometry. In the present study, 71.8% of patients with COPD received spirometry.  This is more than twice the percentage of previous reports where only about a third of COPD patients had spirometry performed (6-10).

Spirometry is performed in some general medicine clinics, but in our hospital spirometry is performed in the pulmonary function laboratories or in the pulmonary clinic, a situation that may differ from many health-care systems. However, a previous report from a VA hospital reported only about a third of newly diagnosed COPD patients received spirometry (7). Our study differs in several aspects which might explain at least part of the variance. First, rather than looking at a diagnosis of COPD, we examined patients who were prescribed albuterol. This includes patients with asthma and other respiratory diagnosis. Second, we included patients with long-standing COPD rather COPD recently diagnosed. Previous reports suggest that as the number of visits increases that the likelihood of spirometry also increases (10). Third, many patients are “co-managed”, that is they received health care elsewhere in addition to the VA. It is entirely possible that they may have had spirometry performed elsewhere which is not available in our medical record. However, in contrast to previous studies, chart reviews were performed on each patient. If the patient had a previous spirometry recorded in the chart from another institution this should have been noted in our study. Fourth, the VA pharmacy placed restrictions on primary care physicians prescribing long-acting bronchodilators, especially tiotropium. These patients were usually referred to our pulmonary clinic where spirometry was usually required prior to referral.

Several factors have been previously identified that are related to lower rates of spirometry. Age had been reported as the factor with the most pronounced impact on decreasing the likelihood of undergoing spirometry in a VA population (6). However, we found no influence of age on the likelihood of spirometry performance. COPD diagnosis has also been reported to have a decreased likelihood of spirometry performance (8), but in contrast, we found that COPD actually increased the likelihood of spirometry performance. The use of theophylline has also been associated with decreased levels of spirometry performance. However, only about 1% of our patients were prescribed theophylline.

There are several limitations to our study. First, it is a single site study. It is possible that our primary care physicians are more likely to order spirometry because of increased awareness or restrictions in prescribing long-acting bronchodilators or referral to a pulmonary clinic. Previous reports from the VA have demonstrated that there is a large geographic variation in the use of spirometry to diagnose COPD (8). The location of the present study was in Veterans Integrated Service Network 18 (Arizona, New Mexico and West Texas) where spirometry use (36.9%) approximated the National mean (36.7%). It is unclear whether the results from the present study can be generalized to the VA as a whole or non-VA institutions is unclear. Second, we examined patients prescribed an albuterol inhaler rather than those with a diagnosis of COPD or asthma. This likely eliminates many patients with mild or no symptoms which differs from previous studies. The US Preventive Services Task Forces has recommended against screening asymptomatic patients with spirometry (16).

The patients with no diagnosis given albuterol were a heterogenous group and the indications for the use of albuterol were often absent or unclear. Although albuterol can be empirically prescribed for asthma, cough or COPD, the indications for albuterol were absent in the majority of charts.

This study suggests that in contrast to previous reports, much of the current COPD diagnosis and management is based on spirometric evidence of airway obstruction in addition to symptoms. Although the role of spirometry in routine clinical practice remains unclear, primary care providers at our VA hospital appear to frequently use spirometry in patients with COPD.

References

1. Global Strategy for the Diagnosis, Management and prevention of Chronic Obstructive Pulmonary Disease 2011. Global Initiative for Chronic Obstructive Lung Disease (GOLD) www.goldcopd.com (accessed 1/26/11).
2. Qaseem A, Wilt TJ, Weinberger SE, Hanania NA, Criner G, van der Molen T, Marciniuk DD, Denberg T, Schünemann H, Wedzicha W, MacDonald R, Shekelle P; American College of Physicians; American College of Chest Physicians; American Thoracic Society; European Respiratory Society. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med 2011;155:179-91.
3. National Committee for Quality Assurance. HEDIS 2006: health plan employer data & information set, vol 2; technical specifications. Washington, DC: National Committee for Quality Assurance, 2005; 350
4. Expert panel report 3 (EPR3): Guidelines for the Diagnosis and Management of Asthma. NHLBI. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm (accessed 12/10/11).
5. Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, Casale TB, Chanez P, Enright PL, Gibson PG, de Jongste JC, Kerstjens HA, Lazarus SC, Levy ML, O'Byrne PM, Partridge MR, Pavord ID, Sears MR, Sterk PJ, Stoloff SW, Sullivan SD, Szefler SJ, Thomas MD, Wenzel SE; American Thoracic Society/European Respiratory Society Task Force on Asthma Control and Exacerbations. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical  asthma trials and clinical practice. Am J Respir Crit Care Med 2009;180:59-99.
6. Han MK, Kim MG, Mardon R, et al. Spirometry utilization for COPD: How do we measure up? Chest 2007;132:403-09.
7. Lee TA, Bartle B, Weiss KB. Spirometry use in clinical practice following diagnosis of COPD. Chest 2006;129(6):1509-15.
8. Joo MJ, Lee TA, Weiss KB. Geographic variation of spirometry use in newly diagnosed COPD. Chest 2008;134:38-45.
9. Arne M, Lisspers K, Ställberg B, Boman G, Hedenström H, Janson C, Emtner M. How often is diagnosis of COPD confirmed with spirometry? Respir Med. 2010;104:550-6.
10. Anthonisen NR, Woodlrage K, Manfreda J. Use of spirometry and respiratory drugs in Manitobans over 35 years of age with obstructive lung diseases. Can Respir J 2005;12:69-74.
11. Marklund B, Tunsäter A, Bengtsson C. How often is the diagnosis bronchial asthma correct? Fam Pract 1999;16:112-6.
12. Tinkelman DG, Price DB, Nordyke RJ, Halbert RJ. Misdiagnosis of COPD and asthma in primary care patients 40 years of age and over. J Asthma. 2006;43:75-80.
13. Zwar NA, Marks GB, Hermiz O, Middleton S, Comino EJ, Hasan I, Vagholkar S, Wilson SF. Predictors of accuracy of diagnosis of chronic obstructive pulmonary disease in general practice. Med J Aust 2011;195:168-71.
14. Enright P. Use and abuse of office spirometry. Primary Care Respiratory Journal 2008;17: 238-242.
15. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis 1983;127:725-34.
16. US Preventive Services Task Force. Screening for Chronic Obstructive Pulmonary Disease Using Spirometry. Available at  http://www.uspreventiveservicestaskforce.org/uspstf08/copd/copdrs.htm (accessed 12/12/11).

Reference as: Park K, Ornelas CS, Robbins RA. Spirometry use in patients prescribed albuterol. Southwest J Pulm Crit Care 2011;4:25-9. (Click here for a PDF version of the manuscript)

A 39 Year Old Female with Progressive Dyspnea, Dry Cough and Hypoxia: A Case Report

Sabeen Yaqub, MD 

Michelle S. Harkins, MD

Division of Pulmonary, Critical Care and Sleep Medicine

Department of Internal Medicine.

University on New Mexico

Albuquerque, NM 87131

Emails: sabeenyaqub@gmail.com

             MHarkins@salud.unm.edu

None of the authors of the above manuscript has declared any conflict of interest, which may arise from being named as an author on the manuscript.

Reference as: Yaqub S, Harkins MS. A 39 year old female with progressive dyspnea, dry cough and hypoxia: a case report. Southwest J Pulm Crit Care 2011;3:134-40. (Click here for a PDF version of the manuscript)

 Case Presentation

A previously healthy 39 year old female presented with progressive shortness of breath on exertion, dry cough, fatigue, fevers and hypoxia for the last four months. Her symptoms worsened despite being on several courses of antibiotics. Her past medical history is significant for hypertension and diabetes and medications include metoprolol and fosinopril. There is no previous history of cigarette smoking, drugs or alcohol abuse. She denied any weight loss. She was evaluated by a pulmonologist at an outside facility before being transported to our facility. Workup included chest x-ray and CT scan which showed patchy areas of consolidation. A bronchoscopy with bronchial alveolar lavage (BAL) was also performed but she became profoundly hypoxic and was transferred to the ICU intubated.

Physical Exam

An obese female who was intubated and sedated on pressure targeted ventilation with delta P 28, rate 15, FiO2 60% peep 8. Her vitals revealed a T_max of 38.6 C and blood pressure of 146/85. There were coarse breath sounds bilaterally and mild diffuse crackles in all lung fields. No clubbing or cyanosis was noted. The rest of the exam was unremarkable with a normal abdominal, cardiac and skin exam.  There was no adenopathy.

Labs

Complete blood count, electrolytes and liver function tests were normal.  HIV testing was negative.

Radiological findings

Chest x-ray demonstrated perihilar and bibasilar opacities.

CT scan is shown below in Figure 1.

Figure 1: CT Scan - Diffuse and geographic ground glass opacities accompanied by interlobular septal thickening consistent with the classic “crazy paving” with geographic distribution.

Bronchoscopy

Bronchoscopy with bronchoalveolar lavage (BAL) was performed which revealed an opaque appearing fluid with particulate matter. An open lung biopsy was performed to confirm the suspected diagnosis.

Pathology

Open Lung Biopsy revealed normal alveolar architecture with eosinophilic staining debris within the alveolar spaces that was Periodic Acid Schiff (PAS) + (Figure 2).

Figure 2: Open Lung Biopsy: Numerous alveolar spaces filled with abundant eosinophilic material (A) which is PAS positive (B) and occasional dense globular clumps with intra-alveolar macrophages. The alveolar septae are delicate without evidence of fibrosis.

Diagnosis:  Pulmonary Alveolar Proteinosis (PAP)

Hospital Course 

She underwent a partial whole lung lavage of the right lung first and remained intubated post procedure.  She underwent a repeat lavage of the right lung four days later and then a whole lung lavage on the left one week later due to bilateral infiltrates and difficulty weaning from the ventilator. Each lavage consisted of 12 liters of warmed saline and there was progressive clearing of the cloudy material obtained by the end of the lavage.  BAL cultures were obtained which were positive for Staphlococcus aureus and Klebsiella but were negative for Nocardia, Pneumocystis, and acid fast bacilli. She was treated with antibiotics for 7 days for the bacterial infection.  She was then successfully extubated.

Discussion

PAP also known as pulmonary alveolar phospholipoproteinosis is a diffuse lung disease characterized by accumulation of amorphous PAS+ lipoproteinaceous material in the distal airspaces with little or no inflammation and preservation of the underlying lung architecture.^1-3

Three forms of PAP are recognized; congenital, secondary and acquired. Congenital form is present in neonates and results from mutations in genes for surfactants or GM-CSF receptors. The acquired form is the most common and GM-CSF antibodies contribute to macrophage dysfunction and impaired processing of surfactant. The secondary form is associated with high level dust exposure (silica, aluminium, titanium), hematologic malignancy and after allogenic bone marrow transplant for myeloid malignancy and infection (Nocardia, viral, Pneumocystis). Macrophages are overwhelmed by accumulation of surfactant rich material and they lose the ability to phagocytize.

Clinical signs and symptoms include dyspnea on exertion, cough, fatigue, weight loss and low grade fevers.  Clubbing, cyanosis and crackles on physical exam may be present. Patients with PAP have an increased risk of opportunistic infection with Nocardia, Mycobacteria, fungi and Pneumocystis due to impaired macrophage and neutrophil function. Laboratory abnormalities include polycythemia, hypergammaglobulinemia, and increased LDL. On Chest x-ray bilateral symmetrical alveolar opacities are located centrally in the mid and lower lung zones in a ‘bat wing’ distribution. CT scan reveals heterogenous distribution of ground glass opacification and septal thickening.

The diagnostic work-up should include a history and physical consistent with PAP, a CT scan, fiberoptic bronchoscopy to obtain lavage fluid and transbronchial biopsies and serum assay for Anti-GM-CSF antibodies.  To exclude the presence of concurrent infections special stains and cultures for opportunistic infection should be obtained. In one of the largest cohort studies of 248 PAP patients, diagnosis was made by High Resolution CT (HRCT) scan and BAL in 59%; HRCT, BAL and transbronchial biopsy in 34% and VATS biopsy in 7%.⁴ Characteristic findings on BAL are an opaque or milky appearance due to abundant lipoproteinaceous material, alveolar macrophages that are engorged with PAS positive material, increased SP-A levels and large acellular eosinophilic bodies. On histological specimens, the normal alveolar architecture is preserved although the alveolar septa may be thickened due to type-2 cell hyperplasia. There is little or no inflammatory cell infiltrate. The terminal bronchioles and alveoli are filled with PAS positive lipoproteinaceous material.

The treatment options vary with the severity of disease. In the cohort study, asymptomatic patients were the most likely to have a stable course and only 8% worsened during follow up. ⁴ Among symptomatic patients the proportion of stable, improved and worsening disease was 45%, 30%, and 25% respectively. Patients with longer duration are likely to have progressive disease.

Asymptomatic patients can be observed with periodic reassessment of symptoms, pulmonary function testing (PFTs) and chest x-rays (CXRs). In patients with mild symptoms (mild hypoxia on exertion, normoxia on rest) supplemental oxygen is appropriate. Patients with moderate to severe disease may elect for whole lung lavage or a trial of experimental treatment with GM-CSF or plasmapheresis. Whole lung lavage under general anesthesia via a double lumen endotracheal tube is recommended for patients who have moderate to severe disease.^5-7 Indications for lung lavage include resting PaO2 <65, A-a gradient >40, shunt fraction>10-12% and severe hypoxia or dyspnea on rest and exertion. Clinical course is variable. Thirty-forty percent of patients require one lavage while others require lung lavage at intervals of 6-12 months.

Experimental therapy with GM-CSF has been used. ^8-13 In an open trial of 25 patients, GM-CSF was given subcutaneously and 48% experienced symptomatic and radiological improvement. However the proportion of responders to whole lung lavage appears to be the largest.^11-12 Given the experimental nature of GM-CSF therapy, lung lavage as primary therapy is recommended. Lung transplant is reserved for patients who deteriorate despite whole lung lavage but recurrence in allograft has been reported.¹⁴ Treatment with rituximab and plasmapheresis have had mixed results.^15-16 Though the most recent open label trial of rituximab given in 10 PAP patients demonstrated that it is well tolerated and improved oxygenation parameters up to six months after therapy and may have decreased the need for whole lung lavage.   The exact mechanism of benefit is unclear but is likely related to clearing of the autoantibodies present in the lung.¹⁷ There is no role for glucocorticoids as therapy for PAP.  

Follow up in our patient

The patient was followed in clinic after discharge. She continued to complain of an increased cough productive of clear mucus. She denied any changes in activity level or shortness of breath. PFTs were slightly worse than before. CT chest was concerning for increased bilateral densities.  She had a GM-CSF antibody titer of 1:6400 which confirms acquired PAP (a 1:400 titer is considered abnormal).

She was given a 3 month trial of inhaled GM-CSF and seen in clinic after 3 months with repeat PFTs and CT chest. She denied any changes in symptoms. PFTs also were unchanged from those done 3 months prior.  However, CT chest did look slightly worse with increased markings in the upper lobes.

She continued inhaled GM-CSF for another 3 months and sputum cultures for AFB, Nocardia and other pathogens were negative. After consulting with National Jewish Physicians, she was started on Mycophenolate mofetil orally advanced to the maximum dose of 3 gm/day. She has done well with improvement in her cough, lung function, six minute walk tests and CT scans and has not needed further whole lung lavage.  There are currently no reports of using this drug in this condition and thus it warrants further study for proof of benefit. Our patient has done well thus far, but there is also a case report of Mycophenolate actually causing PAP when used as an immunosuppressant in a patient with Wegener’s Granulomatosis so caution when using this is advised.¹⁸

References

1. Shah, PL, Hansell, D, Lawson, PR, et al. Pulmonary alveolar proteinosis: Clinical aspects and current concepts on pathogenesis. Thorax 2000; 55:67.

2. Kariman, K, Kylstra, JA, Spock, A. Pulmonary alveolar proteinosis: Prospective clinical experience in 23 patients for 15 years. Lung 1984; 162:223.

3. Milleron, BJ, Costabel, U, Teschler, H, et al. Bronchoalveolar lavage cell data in alveolar proteinosis. Am Rev Respir Dis 1991; 144:1330.

4. Inoue, Y, Trapnell, BC, Tazawa, R, et al. Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan. Am J Respir Crit Care Med 2008; 177:752.

5. Claypool, WD, Rogers, RM, Matuschak, GM. Update on the clinical diagnosis, management, and pathogenesis of pulmonary alveolar proteinosis (phospholipidosis). Chest 1984; 85:550.

6. Larson, RK, Gordinier, R. Pulmonary alveolar proteinosis. report of six cases, review of the literature, and formulation of a new theory. Ann Intern Med 1965; 62:292.

7. Beccaria, M, Luisetti, M, Rodi, G, et al. Long-term durable benefit after whole lung lavage in pulmonary alveolar proteinosis. Eur Respir J 2004; 23:526.

8. Seymour, JF, Dunn, AR, Vincent, JM, et al. Efficacy of granulocyte-macrophage colony-stimulating factor in acquired alveolar proteinosis [letter]. N Engl J Med 1996; 335:1924.

9. Barraclough, RM, Gillies, AJ. Pulmonary alveolar proteinosis: a complete response to GM-CSF therapy. Thorax 2001; 56:664.

10. De Vega, MG, Sanchez-Palencia, A, Ramirez, A, et al. GM-CSF therapy in pulmonary alveolar proteinosis. Thorax 2002; 57:837.

11. Kavuru, MS, Sullivan, EJ, Piccin, R, et al. Exogenous granulocyte-macrophage colony-stimulating factor administration for pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2000; 161:1143.

12. Venkateshiah, SB, Yan, TD, Bonfield, TL, et al. An open-label trial of granulocyte macrophage colony stimulating factor therapy for moderate symptomatic pulmonary alveolar proteinosis. Chest 2006; 130:227.

13. Seymour, JF, Doyle, IR, Nakata, K, et al. Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in patients with idiopathic alveolar proteinosis. Thorax 2003; 58:252.

14. Parker, LA, Novotny, DB. Recurrent alveolar proteinosis following double lung transplantation. Chest 1997; 111:1457.

15. Kavuru, MS, Bonfield, TL, Thomassen, MJ. Plasmapheresis, GM-CSF, and alveolar proteinosis. Am J Respir Crit Care Med 2003; 167:1036.

16. Borie, R, Debray, MP, Laine, C, et al. Rituximab therapy in autoimmune pulmonary alveolar proteinosis. Eur Respir J 2009; 33:1503.

17.  Kavuru MS, Malur A, Marshall I, Barna BP, Meziane M, Huizar I, Dalrymple H, Karnekar R, Thomassen MJ. An Open-Label Trial of Rituximab Therapy in Pulmonary Alveolar Proteinosis. Eur Respir J. Published on April 8, 2011 as doi: 10.1183/09031936.00197710.

18. Shah S, Phan N, Goyal G, Sharma G. Pulmonary Alveolar Proteinosis in a 67-Year-Old Woman with Wegener’s Granulomatosis. J Gen Intern Med. 2010; 25:1105.