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.

Relationship between the Veterans Healthcare Administration Hospital Performance Measures and Outcomes

Richard A. Robbins, M.D.¹

Richard Gerkin, M.D.²

Clement U. Singarajah, M.D.¹

¹Phoenix Pulmonary and Critical Care Medicine Research and Education Foundation and ²Banner Good Samaritan Medical Center, Phoenix, AZ

Reference as: Robbins RA, Gerkin R, Singarajah CU. Relationship between the Veterans Healthcare Administration hospital performance measures and outcomes. Southwest J Pulm Crit Care 2011;3:92-133. (Click here for PDF version of manuscript)

Abstract

Health care organizations have been using performance measures to compare hospitals. However, it is unclear if compliance with these performance measures results in better healthcare outcomes. We examined compliance with acute myocardial infarction, congestive heart failure, pneumonia and surgical process of care measures with traditional outcome measures including mortality rates, morbidity rates, length of stay and readmission rates using the Veterans Healthcare Administration Quality and Safety report. Disappointingly, increased compliance with the performance measures was not correlated with better outcomes with the single exception of improved mortality with higher rates of compliance with echocardiography. We also evaluated the hospital level of care and found that higher levels of complexity of care correlated with the acute myocardial infarction performance measure, but not with the congestive heart failure, pneumonia, or surgical process of care performance measures.  However, level of complexity of care strongly correlated with all cause mortality (p<0.001), surgical mortality (p=0.037) and surgical morbidity (p=0.01). These data demonstrate that compliance with the performance measures are not correlated with improved healthcare outcomes, and suggest that if measures are used to compare hospitals, different measures need to be developed.

Introduction

The Joint Commission recently released “Improving America’s Hospitals: The Joint Commission’s Annual Report on Quality and Safety 2011 (1).  In this report the results of hospital compliance with the Joint Commission’s performance measures are listed. The Joint Commission announced not only is compliance improving but identified 405 hospitals as their “Top Performers on Key Quality Measures Program”. In a letter at the beginning of the report Mark Chassin, President of the Joint Commission, said “This program is designed to be an incentive for better performance on accountability measures and to support organizations in their quest to do better”.

However, there have been several criticisms of the report. First, many hospitals which were recognized as top hospitals by US News & World Report, HealthGrades Top 50 Hospitals, or Thomson Reuters Top Cardiovascular Hospitals were not included (2). Small community hospitals were overrepresented and large academic medical centers were underrepresented in the report. Chassin commented that this should be "a wake-up call to larger hospitals to put more resources into these programs…”. This is surprising since teaching hospitals, which are usually large, urban hospitals, have previously been reported to have lower risk-adjusted mortality rates and lengths of stay (3). Second, it has been pointed out that many of the performance measures are not or only weakly associated with traditional outcomes such as mortality (4-7). Therefore, we compared the compliance with the Joint Commission performance measures compared to mortality rates, morbidity rates, length of stay and readmissions using the Nation’s largest healthcare system, the Department of Veterans Affairs. The results demonstrate that compliance with performance measures are not correlated with improved outcomes.

Methods

The study was approved by the Western IRB.

Process Performance Measures. We evaluated hospital performance based on publicly available data from the 2010 VHA Facility Quality and Safety Report (9). These measures evaluate quality of care for acute myocardial infarction, congestive heart failure, pneumonia and surgical care improvement program (SCIP) during fiscal year 2009. For each of the measures, a hospital’s performance is calculated as the proportion of patients who received the indicated care out of all the patients who were eligible for the indicated care. The quality indicators are based on, and in most cases identical to those used for the Joint Commission’s Hospital Compare (acute myocardial infarction-Appendix 1; congestive heart failure-Appendix 2; pneumonia-Appendix 3, surgical quality-Appendix 4). Data were also available for each component of the congestive heart failure quality measure (see Appendix 2) which was evaluated independently.

Disease specific mortality. Hospital-specific, risk-standardized rates of mortality within 30 days of discharge are reported for patients hospitalized with a principal diagnosis of heart attack, heart failure, and pneumonia. For each condition, the risk-standardized (also known as "adjusted" or "risk-adjusted") hospital mortality rate are calculated using mathematical models that use administrative data to adjust for differences in patient characteristics that affect expected mortality rates (10).

Surgical morbidity and mortality. VA’s Surgical Quality Improvement Program (VASQIP) monitors major surgical procedures performed at VHA facilities and tracks risk adjusted surgical complications (morbidity) and mortality rates. Patient data are collected at each facility by a specially trained nurse and entered into the VA’s electronic health record: detailed preoperative patient characteristics including chart-abstracted medical conditions, functional status, recent laboratory tests, information about the surgical procedure performed, and 30-day outcomes data.

The VASQIP program analyzes these patient data using mathematical models to predict an individual patient’s expected outcome based on the patient’s preoperative characteristics and the type and nature of the surgical procedure. Overall patient outcomes for major surgical procedures are expressed by comparing observed rates of mortality and morbidity to the expected rates for those patients undergoing the procedure as observed-to-expected (O/E) ratios. For example, if, based on patient characteristics, a facility expected 5 deaths following major surgery, but only 4 patients died, the O/E ratio would be reported as 0.8.

Medical Surgical Length of Stay (LOS). These data are the VA hospital average length of stay for patients who were discharged from acute medicine or surgery bed sections. It does not include patients discharged from observation beds or discharged from other areas of the hospital such as mental health.

Readmission rates. A readmission was defined as a patient who has had a recent hospital stay and needs to re-enter the hospital again within 30 days. These rates are not adjusted for patient characteristics that affected expected admission rates, so comparisons among hospitals should be interpreted with caution.

CHF readmissions were reported separately. CHF readmission is defined by patients who had an initial hospitalization for CHF and were readmitted at least once to acute care in the hospital within 30 days following discharge for CHF.

Hospital level of care. For descriptive purposes, hospitals were grouped into levels of care. These are classified into 4 levels: highly complex (level 1); complex (level 2); moderate (level 3), and basic (level 4). In general, level 1 facilities and some level 2 facilities represent large urban, academic teaching medical centers.

Correlation with Outcomes. Pearson’s correlation coefficient was used to assess the correlation of compliance with the performance measures and outcomes. Significance was defined as p<0.05. For comparisons among hospital levels, ANOVA or Kruskall-Wallis testing was done, as appropriate.

Results

Disease specific and all cause mortality rates compared to performance measures. Hospital-specific, risk-standardized rates of mortality within 30 days of discharge for patients hospitalized with a principal diagnosis of heart attack, heart failure, and pneumonia were compared to performance measure compliance. There was no correlation (Table 1, p>0.05 all conditions) but with an increased incidence of pneumonia actually weakly correlating with higher compliance with the pneumonia performance measures (Table 1, p=0.0411). Furthermore, there was no correlation between all cause mortality and the average of the three compliance measures (Table 1, p>0.05). Because each table is large, only the correlation coefficients are presented in the text. The table data on which the correlations are based are given at the end of the manuscript. (N=the number of hospitals. NA=not available).

Table 1. Disease Specific Mortality Correlated with Performance Measure Compliance

Correlation Coefficients	r value	N	p value
Acute Myocardial Infarction Mortality and AMI Performance Measure	0.0266	103	0.7897
Congestive Heart Failure Mortality and CHF Performance Measure	0.0992	123	0.2752
Pneumonia Mortality and Pneumonia Performance Measure	0.1844	123	0.0411
All Cause Mortality vs. Average of Performance Measures	0.1118	122	0.2202

Each component of the congestive heart failure performance measure was evaluated individually. Performance of echocardiography correlated with improved mortality (Table 2, p=0.0496) but there was no correlation with use of a angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) at discharge, discharge instructions, nor smoking cessation advice (Table 2, p>0.05 all comparisons).

Table 2. Heart Failure Mortality Correlated with Compliance to Individual Heart Failure Performance Measures

Correlation Coefficients	r value	N	p
ACEI or ARB	-0.1007	112	0.2908
Smoking Cessation	0.0651	112	0.4953
Discharge Instructions	0.1411	111	0.1396
Echocardiography	-0.1860	112	0.0496

Surgical mortality and morbidity rates compared to surgical performance measures. There was no correlation between compliance with the surgical care improvement program (SCIP) and surgical mortality or morbidity (Table 3, p>0.05 both comparisons).

Table 3. Surgical Care Improvement Program (SCIP) Compliance Correlated with Observed/Expected (O/E) Morbidity/Mortality

Correlation Coefficients	r value	N	p value
O/E Mortality	0.0943	99	0.3530
O/E Morbidity	0.0031	99	0.9757

Length of Stay. None of the performance measures correlated with medical-surgical length of stay (Table 4, p>0.05 all comparisons).

Table 4. Length of Stay (LOS) Correlated with Performance Measure Compliance

Correlation Coefficients	r value	N	p value
LOS compared to AMI	0.1047	103	0.2926
LOS compared to CHF	-0.0178	123	0.8451
LOS compared to Pneumonia	-0.1679	123	0.0634
LOS compared to SCIP	-0.0404	106	0.6809
LOS compared to Average	0.0028	123	0.9755

Readmission rates. There was no correlation between all cause readmission rates and the acute myocardial infarction, congestive heart failure, pneumonia or surgical performance measures (Table 5, p>0.05 all comparisons). There was no correlation between heart failure readmission rate and the heart failure performance measure (data not shown, r=0.1525, p=0.0921).

Table 5. Readmission Rate Correlated with Performance Measure Compliance

Correlation Coefficients
	r value	N	p
AMI	0.1688	103	0.0883
CHF	0.1505	123	0.0966
Pneumonia	0.0581	123	0.5233
Average	0.1281	122	0.1597

Hospital level of care. Acute myocardial infarction performance measures inversely correlated with the hospital level of care, i.e., the higher the hospital complexity level, the better the compliance (Table 6, p=0.004). However, there was no correlation between congestive heart failure, pneumonia, surgical care improvement program or the average of the measures and the hospital level of care (Table 6).

Table 6. Hospital Level Correlated with Performance Measure Compliance

ANOVA	N	p
Acute Myocardial Infarction (AMI)	103	0.004
Congestive Heart Failure (CHF)	120	0.782
Community Acquired Pneumonia	120	0.296
Surgical Care Improvement Program (SCIP)	106	0.801
Average of Process of Care Measures	120	0.285

There was no correlation between the level of hospital care and the acute myocardial infarction, congestive heart failure, nor pneumonia mortality (Table 7, p>0.05 all comparisons). However, there was a strong correlation between all cause morality (p<0.001) and a correlation between surgical Observed/Expected mortality (Table 7, p=0.037) and surgical Observed/Expected morbidity (p=0.010).

Table 7. Hospital Level Correlated with Mortality and Surgical Morbidity

ANOVA	N	p
Acute Myocardial Infarction (AMI) Mortality	103	0.835
Congestive Heart Failure (CHF) Mortality	120	0.493
Pneumonia Mortality	120	0.547
All Cause Mortality	106	<0.001
Surgical O/E Mortality	99	0.037
Surgical O/E Morbidity	99	0.010

Discussion

These data from the Nation’s largest healthcare system demonstrate that increasing compliance of the performance measures prescribed by the Joint Commission does not affect disease specific mortality, all cause mortality, surgical mortality, surgical morbidity, length of stay or readmissions with the single exception of improved mortality correlating with increased compliance with performance of echocardiography. In contrast to the Joint Commission’s list of top hospitals which found smaller and rural hospitals to be overrepresented, we found that only the acute myocardial infarction performance measure correlated with a higher level of hospital care which represents mostly large, urban hospitals. We did find that all cause mortality and surgical morbidity highly correlated with the level of care. This would appear to differ from the Joint Commission’s list of top hospitals which tended to be small and rural, since VA hospitals with higher levels of care largely represent large urban, academic teaching medical centers.

There are multiple possible reasons for the lack of correlation between the performance measures and outcomes. Many of the outcomes are evidence based but several are not. For example, there are no randomized, multi-center studies evaluating the efficacy of discharge instructions, smoking cessation advice and pneumococcal vaccination. Studies with discharge instructions are retrospective, observational studies and have largely not shown improved outcomes (11,12). Several meta-analyses have failed to demonstrate the efficacy of pneumococcal vaccine in adults (13-15). Advice to quit smoking without follow up support or pharmacologic intervention has not been shown to lower smoking cessation rates (16). Mandating ineffective interventions such as these would not be expected to have a positive effect on outcomes. However, this is where most of the improvement in performance measure outcome has occurred (2).

Most of the interventions are grouped or bundled. Lack of compliance with any one of the bundle is taken as noncompliance with the whole. However, if the only difference between hospitals is noncompliance with an ineffective performance measure, there would not be any expected improvement in outcomes.

Many of the strongly evidence-based outcomes have very high compliance, usually exceeding 95% (9). It is possible that small improvements of 1 or 2% in effective performance measures might have too small an impact on outcomes to be detected even in large databases such as the Veterans Administration which examined 485,774 acute medical/surgical discharges in 2009.

The performance measures appear to avoid highly technical or costly interventions and often avoid interventions which have been shown positively affect outcomes. For example, beta blockers and spironolactone have been shown to be effective in heart failure but are not included in the congestive heart failure performance measures (17,18). Furthermore, carvedilol has been shown to be superior to metoprolol in improving survival (19). Why the performance measures include use of an angiotensin converting enzyme inhibitor or angiotensin receptor blocker but not carvedilol and spironolactone is unclear.

Some of the performance measures may have caused inadvertent harm. For example, administration of antibiotics within 4 hours to patients with pneumonia was a previous performance measure. However, studies showed that this performance measurement led to administration of antibiotics in many patients who proved not to have pneumonia or another infectious disease, and a systematic review concluded that “evidence from observational studies fails to confirm decreased mortality with early administration of antibiotics in stable patients with [community acquired pneumonia]”  (20-22). The time has since been changed to 6 hours, but it is unclear if that it is any better than the initial 4 hour timing used (7).

We did not confirm the Joint Commission’s findings that the top hospitals are overrepresented by small, rural hospitals. We found no correlation between hospital level of complexity of care and performance measure compliance with the exception of acute myocardial infarction which was higher in hospitals with higher complexities of care. Although we found no correlation of the performance measures with any outcome measures, we did find a strong correlation between the hospital level of complexity of care and overall survival and surgical morbidity with the hospitals having the higher level of complexity having improved survival and decreased surgical morbidity. This would seem consistent with concept that volume of care correlates with outcomes.

It seems surprising that initiation of performance measures seem to go through such little scrutiny. In a 2005 editorial Angus and Abraham (23) addressed the issue of when there is sufficient evidence for a concept to be widely applied as a guideline or performance measure. Comparing guidelines to evaluation of novel pharmacologic therapies, they point out that promising phase II studies are insufficient for regulatory approval. Instead, one, and usually two, large multicenter phase III trials are necessary to confirm reliability. The same principle is echoed in evidence-based medicine, where grade A recommendations are based on two or more large, positive, randomized, and multicenter trials. This seems a reasonable suggestion. Perhaps what is needed is an independent Federal or private agency to review and approve performance measures, and as Angus and Abraham suggest, require at least two randomized, multicenter trials before implementation

The data presented in this manuscript do not support the usefulness of increasing compliance with the Veterans Administration’s (or the Joint Commission’s) performance measures in improving outcomes such as mortality, morbidity, length of stay or readmission rates. Until compliance with the performance measures results in improved outcomes, investment to improve these performance measures seems to be a poor utilization of resources. It suggests that oversight of regulatory agencies is needed in developing and implementing performance measures. If performance measures are to be used, new, clinically meaningful measures that correlate with outcomes need to be developed. 

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17. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med 1998;339:489-97.
18. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J for the Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-17.
19. Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Pedersen C, Scherhag A, Skene A. Carvedilol Or Metoprolol European Trial Investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003;362:7-13.
20. Kanwar M, Brar N, Khatib R, Fakih MG. Misdiagnosis of community acquired pneumonia and inappropriate utilization of antibiotics: side effects of the 4-h antibiotic administration rule. Chest 2007;131:1865-9.
21. Welker JA, Huston M, McCue JD. Antibiotic timing and errors in diagnosing pneumonia. Arch Intern Med 2008;168:351-6.
22. Yu KT, Wyer PC. Evidence-based emergency medicine/critically appraised topic. Evidence behind the 4-hour rule for initiation of antibiotic therapy in community-acquired pneumonia. Ann Emerg Med 2008;51:651-62.
23. Angus DC, Abraham E. Intensive insulin therapy in critical illness: when is the evidence enough? Am J Resp Crit Care 2005;172:1358-9

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Congenital Bronchial Atresia: A Case Report with Radiographic and Pathologic Correlation

Lewis J. Wesselius, MD1

John R. Muhm, MD2

Henry D. Tazelaar, MD3

Departments of Pulmonary Medicine1, Radiology2, and Laboratory Medicine- Pathology3, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ 85259

Reference as: Wesselius LJ, Muhm JR, Tazelaar HD. Congenital bronchial atresia: a case report with radiographic and pathologic correlation. Southwest J Pulm Crit Care 2011;3:64-9. (Click here for a PDF version)

Abstract

Bronchial atresia is a rare congenital disorder characterized by localized atresia or stenosis of a segmental bronchus.  Imaging features typically include mucus impaction in distal airways associated with regional lung hyperlucency. Pathologic features of bronchial atresia have been rarely been reported.  This case demonstrates CT features of this disorder as well as the unusual finding of increased lung uptake of 18F-fluorodeoxyglucose on PET scan.  This finding led to a surgical lung biopsy to exclude infectious or neoplastic disorders.  This case provides radiologic-pathologic correlation in a patient with congenital bronchial atresia and demonstrates that localized, mildly increased uptake on PET scan be associated bronchial atresia.

Case Presentation

A 35-year-old woman was referred for evaluation of an abnormal thoracic CT scan.     An abnormality was noted on a routine chest radiograph 2 years previously, and thoracic CT reportedly showed an “infiltrate” in the right upper lobe.  Bronchoscopy with bronchoalveolar lavage performed 1 year previously was reportedly negative.  The patient was asymptomatic and denied any cough, fever or shortness of breath.  On physical examination the patient was afebrile and the chest examination was within normal limits.  She had a normal complete blood count and serologic studies for coccidioidomycosis were negative.  A recent chest radiograph (Figure 1) and thoracic CT (Figure 2) performed at the referring medical center demonstrated abnormalities in the right upper lobe, without clear visualization of the posterior segment right upper lobe bronchus. Repeat bronchoscopy was performed which and reportedly demonstrated a patent right upper lobe posterior segmental bronchial orifice, although limited visualization into the airway was noted.  Microbiologic studies and cytologic examination of the bronchoalveolar lavage fluid were negative.

Figure 1:   Chest radiograph performed one month prior to presentation shows small nodular opacities of indeterminate etiology in the right upper lung.

Figure 2:  Thoracic CT shows atresia of the central portion of the right upper lobe posterior segment bronchus (arrow).  In the right upper lobe posterior segment, peripheral to the atretic bronchus, numerous irregular opacities resulting from dysplastic bronchi filled with mucus are noted.  The hypoattenuating areas in the right upper lobe posterior segment represent hypoperfused secondary pulmonary lobules resulting from the obstructed, dysplastic bronchioles.

Subsequent Clinical Course

Subsequent 18F-fluorodeoxyglucose positron emission tomography (FDG- PET, Figure 3) scan performed at the outside medical center showed hypermetabolism within the right upper lobe, with a standard uptake value (SUV) of 2.9.

Figure 3: Image from Coronal FDG-PET shows areas of mild-to-moderate increased uptake (SUV 2.2) in the posteromedial aspect of the right upper lobe.

The finding of elevated FDG uptake on PET scan, as well as an increase in the extent of CT abnormalities, raised clinical concern for an undiagnosed infectious process or low-grade malignancy. The patient subsequently underwent a thoracoscopic lung biopsy at the outside institution to exclude those possibilities.

Further radiology review of the lung CT scan was concurrently requested by the referring physician and the radiographic features of bronchial atresia involving the posterior segment of the right upper lobe were noted.  There was a dysplastic bronchus supplying the posterior segment of the right upper lobe, filled with mucus, and associated with evidence of hypoperfusion of that segment.  Review of the tissue obtained at lung biopsy (Figure 4) demonstrated mucus impaction in small airways, consistent with changes secondary to bronchial atresia.  There was no evidence of active infection or a neoplastic process.

Figure 4: VATS biopsy specimen obtained from the right upper lobe.  The biopsy shows a chronic bronchiolitis (a) with lymphoid hyperplasia and germinal centers (b.center). There is also prominent bronchiolectasis (c) with mucostasis in the airway lumen and extending into the surrounding lung (d).

Discussion

Bronchial atresia is an uncommon congenital tracheobronchial abnormality first described in 1953 and is characterized by stenosis of a segmental airway (1). The abnormality generally involves a single segment, although cases with mult- isegment involvement have been reported (2).  The apical-posterior segment of the left upper lobe is most frequently involved, followed by segments within the right upper, middle and lower lobes (3,4).  This abnormality is frequently asymptomatic and is incidentally detected on chest radiography in 58% of cases (2). Patients may present, often in early adulthood, with symptoms of recurrent infections (21%), dyspnea (14%) and cough (6%). Cases associated with spontaneous pneumothorax have been reported (5).

The diagnosis of congenital bronchial atresia can generally be made from thoracic CT findings alone. Characteristic imaging findings include mucus impaction in dilated airways distal to the area of stenosis (6), typically associated with  regional pulmonary parenchymal hyperlucency due to hypoperfusion, representing mosaic perfusion, resulting from obstructed dysplastic bronchi.

Bronchoscopy can be helpful to exclude competing diagnostic considerations and to exclude infectious processes.  In some patients, segmental airway atresia or an obvious narrowing may be directly observed at bronchoscopy.  However, the area of stenosis is not always visible at bronchoscopy (7). In our patient, the bronchoscopy did not clearly identify an area of segmental narrowing, although that finding was suggested by the CT scan (Figure 2).

FDG-PET (Figure 3), performed to evaluate for a possible undiagnosed infectious or malignant process, showed increased uptake in the areas of radiographic abnormality.      However, subsequent VATS biopsy of the right upper lobe was negative for any infectious or neoplastic process.  Increased uptake pulmonary parenchymal on FDG-PET scan is commonly seen in lung neoplasms and infections, but has also been reported in non-infectious inflammatory lung conditions, including sarcoidosis and idiopathic pulmonary fibrosis (8,9).  There are prior case reports of localized pulmonary parenchymal uptake on FDG-PET scans performed in patients with benign airway disorders, including acute bronchitis and allergic bronchopulmonary aspergillosis (10,11).  The finding of increased uptake on FDG-PET scan has not previously been reported in patients with congenital bronchial atresia.  The specific reason for the localized uptake in the pulmonary parenchyma distal to the atretic bronchus in our patient is not certain. It is possible that local inflammation associated with mucostasis contributed to this finding as there was some evidence of interstitial inflammation noted on the surgical lung biopsy.

The lung biopsy obtained in this patient showed findings consistent with bronchial atresia including mucostasis in airways. The finding of mucostasis correlates with the CT findings of mucus impaction in dilated airways.  Review of the literature indicated only one prior report of pathologic findings in patients with bronchial atresia (12). The findings in our case- respiratory bronchioles plugged with mucus- are consistent with those previously reported. Dilation of surrounding alveoli without evidence of destruction has also been previously reported, consistent with air-trapping.

Summary

Congenital bronchial atresia is an uncommon disorder that can present with a specific pattern on thoracic CT performed on asymptomatic patients or patients with respiratory symptoms of recurrent infections, dyspnea and cough. Bronchoscopy can be helpful to exclude other diagnostic considerations and may demonstrate evidence of segmental bronchial stenosis, although the area of stenosis may not be evident in all cases. Our patient presented with the unusual finding of mildly increased, localized uptake of FDG-PET scan, a finding previously unreported.  Lung biopsy confirmed pathologic features consistent with bronchial atresia, including airway dilatation and terminal bronchial mucus impaction.

References

1. Ramsey BH, Byron FX.  Mucocele, congenital bronchiectasis and bronchogenic cyst. J. Thoracic Surg 1953;26:21-30.
2. Jederlinic PJ, Sicilian L, Baigelman W, et al.  Congenital bronchial atresia – a report of 4 cases and a review of the literature.  Medicine 1986;65:73-83.
3. Meng RL, Jensik RJ, Faher LP, Matthew GP, Kittle CF.  Bronchial atresia, Ann Thoracic Surg 1978;25:184-192.
4. Muller NL, Fraser RS, Colman N, Pare P.  Developmental and hereditary lung disease.  In: Radiologic diagnosis of diseases of the chest.  Philadelphia, PA: Saunders; 2001: 125-128.
5. Berkman N, Bar-Ziv J, Breuer R.  Recurrent spontaneous pneumothorax associated with bronchial atresia.  Resp Med 1996;90:307-309.
6. Matsushima H, Takoyanagi N, Satoh M, et al.  Congenital bronchial atresia: radiologic findings in nine patients.  J Comp Assist Tomog  2002;26:860-864.
7. Ward S. Morcos SK. Congenital bronchial atresia – presentation of three cases and a pictoral review.  Clin Radiol 1999;54:144-148.
8. Brudin LH, Balind SO, Rhodes CG, et al.  Fluorine-18 deoxyglucose uptake in sarcoidosis measured with positron emission tomography.  Eur J Nucl Med 1994;21:297-305.
9. Groves Am, Win T, Screaton NJ, et al.  Idiopathic pulmonary fibrosis and diffuse parenchymal lung disease: implications from initial experience with18F-FDG PET/CT. J Nucl Med 2009;50:538-545.
10. Kicska G, Zhuang H, Alavi H.  Acute bronchitis imaged with F-18 FDG positron emission tomography.  Clin Nucl Med 2003;28:511-512.
11. Nakajima H, Sawaguchi H, Hoshi S, Nakajimo S, Tohda Y.  Intense 18F- fluorodeoxyglucose uptake due to allergic bronchopulmonary aspergillosis. Jap J. Allergology 2009;58:1426-32.
12. Gipson MG, Cummings KW, Hurth KM. Bronchial atresia  Radiographics 2002;29:1531-1535.

Pulmonary Nocardiosis and Empyema in a Patient with Metastatic Neuroendocrine Tumor

Nimesh K. Patel, DO

Linda Snyder, MD

University of Arizona, Department of Medicine. Tucson, Arizona

Reference as: Patel NK, Snyder L. Pulmonary nocardiosis and empyema in a patient with metastatic neuroendocrine tumor. Southwest J Pulm Crit Care 2011;3:28-33. (Click here for a PDF version)

Abstract

Nocardia is a ubiquitous aerobic gram-positive bacterium that can cause local or disseminated infection. Nocardiosis involves the lung in the majority of cases. Nocardiosis is often an opportunistic infection, but can also affect non-immunocompromised hosts. This case report highlights the presence of empyema due to Nocardia cyriacigeorgica infection, an unusual feature of Nocardia pulmonary involvement. 

Case Presentation

History of Present Illness: A 65 year-old male with a history of metastatic neuroendocrine tumor of the pancreas, was admitted to the hospital with a one-week history of hemoptysis, cough, and dyspnea. He was treated for presumed community acquired pneumonia with moxifloxacin two weeks prior to admission. He was receiving monthly octreotide injections for treatment of the neuroendocrine tumor. The patient had no history of corticosteroid use.  

Physical examination:

Vital signs: Temperature 99.9F, Respirations18, Blood Pressure 104/69, Pulse 96, SaO2 91% on oxygen at 2 liters per minute by nasal cannula

General: The patient was in no acute distress. He was alert and oriented to person, place and time.

HEENT: No significant abnormalities.

Chest: Dullness to percussion, mid-lower right thoracic cavity, with scattered crackles. 

Cardiovascular: regular rate, normal S1 and S2, no murmurs appreciated.  Abdomen: positive bowel sounds, soft, non-tender, non-distended, positive hepatosplenomegaly. 

Extremities: +2 pitting edema bilaterally extending to mid-thigh level

Laboratory and radiographic findings: The peripheral white blood cell count was 8, 000 cell/mm³ with a differential as follows 91% neutrophils/bands, 7% lymphocytes, 1% myelocyte, 1% reactive lymphocyte, hemoglobin was 11 g/dL and the platelet count was normal. The basic metabolic panel revealed blood urea nitrogen of 30 mg/dl and creatinine of 1.5 mg/dl. The hepatic panel was normal except for an elevated alkaline phosphatase of 530 IU/L. Coccidioides IgM and IgG serology performed by immunodiffusion were negative.

The chest radiographs from two weeks prior to admission (Figure 1), admission (Figure 2) and admission computerized tomography of the chest (Figure 3) are shown.  

Figure 1. Chest radiograph two weeks before admission:  Right middle lobe consolidation with volume loss and small right pleural effusion

 

Figure 2.  Chest radiograph on admission: Increasing patchy opacifications involving the right upper lobe, right middle lobe, and left lower lobe, with cavity formation noted in the left lung. There is right paratracheal lymphadenopathy noted.

Figure 3: Computerized tomography of the chest showing multifocal consolidation with a necrotizing process containing central lucencies. A loculated, moderate sized right anterior pleural effusion with lucencies is compatible with an empyema.

Hospital course:

Our patient was started on broad-spectrum antimicrobial therapy and underwent chest tube drainage of the loculated effusion.  A sputum gram stain revealed 4+ weakly acid-fast branching bacilli, consistent with Nocardia. The gram stain of the pleural fluid showed 3+ polymorphonuclear cells and 3+ gram-positive, branching, weakly acid-fast bacilli, consistent with Nocardia.  The culture from sputum and pleural fluid grew Nocardia cyriacigeorgica. 

Computerized tomography of the brain showed no intracranial abnormalities. The patient was treated with high dose trimethoprim/sulfamethoxazole, two double strength tablets three times a day with monitoring of sulfamethoxazole levels. The patient clinically improved with antimicrobial treatment and drainage of the empyema. The chest tube was successfully removed and the patient’s symptoms of cough and dyspnea resolved. A chest x-ray showed resolution of the right middle lobe and left lower lobe infiltrative process.

Figure 4.  Chest radiograph post-antimicrobial treatment: Interval resolution of right middle lobe and left lower lobe infiltrative process. Post infectious inflammatory changes are noted in the right middle lobe.

Discussion

Nocardiosis is an important opportunistic infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia asteroides has been considered the most common species to cause human disease, however classification has become more complex with the use of molecular techniques. Species formerly included in the Nocardia asteroides complex are now considered distinct species.  Nocardia cyriacigeorgica is one of the more common isolates and has been noted to cause pleural disease and empyema.  Nocardia species are found in soil and can become airborne; the most common route of entry for infection is inhalation. Effective cell-mediated immunity of the host is crucial to combating infection with Nocardia species.  Two recent reviews of nocardiosis highlight important clinical features of this disease (1,2). The most common symptoms are fever, cough, pleuritic chest pain and headache. Specific risk factors for Nocardia infection are present in the majority of patients and include corticosteroid treatment and immunosuppression. Additional risk factors include malignancy and chronic lung disease. Of interest to pulmonologists, chronic obstructive pulmonary disease (COPD) was a common underlying condition, representing over 20% of patients with nocardiosis in these reports. Common chest radiographic presentations of pulmonary nocardiosis include consolidation, nodules and cavities. The diagnosis of pulmonary nocardiosis is made from sputum and bronchoalveolar lavage specimens in the majority of patients. In addition, recent reviews document that pleural effusions are present in up to 35% of patients with pulmonary nocardiosis.  In one report, when pleural fluid was sampled, Nocardia was isolated in the majority of patients. Nocardia cyriacigeorgica can cause invasive pulmonary disease and was found to be the predominant species in pulmonary nocardiosis in one review.

Summary

Nocardiosis is an important opportunistic pulmonary disease. The diagnosis should be included in the differential diagnosis of pulmonary infiltrates in immunosuppressed populations, including patients after organ transplantation, with advanced HIV infection and those receiving chronic corticosteroid therapy or chemotherapy. Radiographic findings of lung involvement are variable and include single or multiple nodules or cavities, alveolar or interstitial infiltrates, and pleural effusions. This case report highlights the unusual presentation of Nocardia cyriacigeorgica pulmonary infection with extensive cavitary parenchymal disease and concomitant empyema. 

References

1. Minero MV, et al. Nocardiosis at the Turn of the Century.  Medicine 2009;88:250-61.
2. Tomas RM, et al. Pulmonary Nocardiosis: Risk factors and outcomes. Respirology 2007;12:394-400 .
3. Latef SM, et al. Nocardia cyriacigeorgica empyema in 45-yr-old male with dual granulomatous lung disease. Chest 2008 134:c12001.
4. Schlaberg R. Nocardia cyriacigeorgica: an emerging pathogen in the United States.  Journal of Clinical Microbiology 2008;46:265-73.
5. Maraki S. Nocardia cyriacigeorgica pleural empyema in an immunocompromised patient.  Diagnostic Microbiology and Infectious Disease 2006;56:333-5.

SANDSTORM IN THE CHEST?

Manmadha Rao Talluri, M.D.

Department of General Medicine, Nizam’s Institute of Medical Sciences, Hyderabad, INDIA

Reference as: Talluri MR. Sandstorm in the chest? Southwest J Pulm Crit Care 2011;3:1-4. Click here for a PDF version

Corresponding Author:

Dr.Manmadha Rao Talluri

Associate professor

Department of General Medicine

Senior Pulmonologist

Nizams institute of Medical Sciences,

Panjagutta, Hyderabad, India

Phone – 914023489240

Mobile-919490295029

Email: manmadh2277@rediffmail.com

Abstract 

A 32 year old female presented with dry cough and progressive breathlessness of one year duration. There was no history suggestive of collagen vascular disease, lung parenchymal infection or allergic airway disease. Clinical evaluation showed basal fine inspiratory crepitations. Radiographic examination of the chest revealed a black pleura line and lung parenchymal calcification. CT scan of the chest demonstrated nodular calcification of lung parenchyma with a “crazy pavement” pattern, which is suggestive of alveolar calcification. Pulmonary function test showed a severe restrictive defect. On transbronchial lung biopsy calcific spherules suggestive of the alveolar microlithiasis were seen. Diagnosis of pulmonary alveolar microlithiasis was made and symptomatic treatment was given, as there is no specific therapy available. The case illustrates an unusual cause of shortness of breath in a young female with striking radiographic features. 

Case Summary

History and Physical Examination: A 32 year old woman presented with dry cough and progressive exertional shortness of breath of one year duration. There was no history of bronchial asthma, varicella, rheumatic heart disease, recurrent respiratory tract infections, tuberculosis, occupational dust exposure or connective tissue disease. Furthermore there was no family history of similar complaints but family members were unavailable for screening. Clinical examination showed normal vital signs, facial puffiness with acne and no clubbing. Upper respiratory tract examination was normal. Fine end inspiratory crepitations were heard on lung auscultation. No rhonchi or wheezing was heard. The remainder of the physical examination was normal.

Laboratory Evaluation: Complete blood count, urine examination and renal function tests were within normal limits. Calcium and phosphate were normal. A parathyroid hormone level was not performed. Immunological evaluation showed an antinuclear antibody (ANA) of 1:1 and a rheumatoid factor 42 IU/ml (normal < 30 IU/ml). DsDNA, Anti SS-a, SS-b and U1 RNP were all negative.

Radiography: Radiograph of the chest shown multiple high-density pulmonary nodules in both the lung fields involving all zones with increased density noted in the bases, with a sand storm appearance and a black pleura line (Figure 1).

Figure 1 Radiograph of the chest shows multiple high density pulmonary nodules in both lungs involving all zones with increased density in base as compared to apex, with sand storm appearance and bilateral black pleural lines indicated by the white arrows.

CT scan of the chest is shown in Figure 2.

Figure 2. CT scan cross-sectional imaging showing multiple calcific densities in both lungs with thickening and increased density along the fissure and along the mediastinal margin. A black pleural line is noted.

Additional Studies: Pulmonary function test demonstrated a severe restrictive defect. Ultrasound abdomen was normal with no evidence of nephrocalcinosis. Two dimensional echocardiography was normal. Transbronchial biopsy of the lung showed calciphic spherules, which is the hall mark of the pulmonary alveolar microlithiasis (Figure 3).

Figure 3. Transbronchial biopsy showing intra-alveolar calcific spherules (H & E, X 200). Insert shows higher magnification of calcific spherules (H&E, X400).

Genetic studies and level of surfactant A and D were not measured.

Clinical Course: The patient was continued on corticosteroids and theophyllines empirically added for dyspnea. Bisphosphonates or chelating agents were not used. She was advised to undergo lung transplantation; which could not be done due to financial constraints. The patient gradually worsened over 2 years and succumbed due to respiratory failure. Permission for an autopsy was not granted.

Discussion

Pulmonary alveolar microlithiasis is a rare disease of unknown etiology, characterized by wide spread laminated clacipherites in alveolar spaces. Other causes of diffuse lung calcification include following tuberculosis, varicella, silicosis, and the metastatic calcification seen with hypercalcemia or renal disease (1).

Pulmonary alveolar microlithiasis is usually sporadic, but an autosomal recessive form has been described in Mediterranean countries (1). The disease is characterized by paucity of symptoms despite wide spread involvement of the lung. Usually presenting in the third or fourth decade of life with cough and dyspnea, pulmonary alveolar microlithiasis usually is a progressive disease with an insidious clinical course resulting in respiratory failure (1,2).

Calcium metabolism has been reported as normal in pulmonary alveolar microlithiasis. Changes in the alveolar membrane secretions resulting in greater alkalinity have been hypothesized to play a major role in the pathogenesis of the disease. The change in alkalinity promotes the intra alveolar precipitation of calcium phosphates. Mutations in the SLC34A2 gene in type II pneumocytes that encodes type IIb sodium phosphate co-transporter have been reported (3). Serum surfactant protein A&D are markedly elevated, which can be useful to monitor the disease activity and progression (4).

Radiograph of the chest is characterized by the presence of a “sand storm” appearance and a black line along the pleura. CT scan usually shows bilateral lung parenchymal nodular calcifications and a “crazy paving” pattern, which is not specific for the diagnosis of pulmonary alveolar microlithiasis (5). Crazy paving has a variety of other causes some of which follow: infectious (Pneumocystis), neoplastic (mucinous bronchoalveolar carcinoma), idiopathic (pulmonary alveolar proteinosis, nonspecific interstitial pneumonitis), inhalational (lipoid pneumonia), and sanguineous disorders (pulmonary hemorrhage syndromes). 

Unfortunately, no established treatment is available.  Management with corticosteroids, chelating agents, bisphopshonates and bronchoalveolar lavage have all been disappointing. The only viable option for these patients is the bilateral lung transplantation (1).

Conclusion

Pulmonary alveolar microlithiasis is a rare disorder, which should always be considered in the differential diagnosis of calcific micronodular pulmonary lesions.

References

1. Tachibana T, Hagiwara K, Johkoh T. Pulmonary alveolar microlithiasis: review and management. Curr Opin Pulm Med 2009;15:486-490.

2. Castellana G, Gentile M, Castellana R, Fiorente P, Lamorgese V. Pulmonary alveolar microlithiasis: clinical features, evolution of the phenotype, and review of the literature. Am J Med Genet 2002;111:220-224.

3. Huqun, Izumi S, Miyazawa H, Ishii K, Uchiyama B, Ishida T, et al. Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis. Am. J. Respir. Crit. Care Med  2007;175:263-268.

4. Takahashi H, Chiba H, Shiratori M, Tachibana T, Abe S. Elevated serum surfactant protein A and D in pulmonary alveolar microlithiasis. Respirology 2006;11:330-333.

5. Gasparetto EL, Tazoniero P, Escuissato DL, Marchiori E, Frare E Silva RL, Sakamoto D. Pulmonary alveolar microlithiasis presenting with crazy-paving pattern on high resolution CT. Br J Radiol 2004;77:974-976.

This case was presented at the Great Cases session during the American Thoracic Society meeting in Denver, CO on May 15, 2011. A PowerPoint slide presentation was prepared for than session and a link to the slides is below.

Click here for a PowerPoint slide presentation

A MIDDLE-AGED MAN WITH A HISTORY OF RENAL CELL CARCINOMA

Roxanne Garciaorr

Richard A. Robbins

Phoenix VA Medical Center, Phoenix, AZ

Reference as: Garciaorr R, Robbins RA. A middle-aged man with a history of renal cell carcinoma. Southwest J Pulm Crit Care 2011;2:79-84. (Click here for PDF version)

Presented at the Arizona Thoracic Society April, 2009 in Scottsdale, AZ and the Great Cases Session at the American Thoracic Society International Conference, May, 2011 in San Diego, CA. 

Abstract

A 56 year old man was seen with a lung nodule. He had an extensive past medical history including renal cell carcinoma, congestive heart failure, obstructive sleep apnea and a 135 pack-year history of smoking. His physical examination was consistent with congestive heart failure. Sputum cultures for bacteria, fungi and tuberculosis were all negative. A CT scan revealed a spiculated, noncalcified 2.1 mass in the right lower lobe.  PET scan showed the lesion to have a standard uptake value of 1.5. The lesion was followed and after 3 months had enlarged to 6.4 cm. Biopsy was done and consistent with a lung abscess. Conservative therapy resulted in resolution only to have the lesion recur 22 months later with the patient expiring from massive hemoptysis and respiratory failure. This case illustrates the usefulness of doubling time in separating benign from malignant lung lesions.

Case Presentation

History of Present Illness.

A 56 year old man was seen in pulmonary consultation because of a right lower lobe mass discovered incidentally during a CT scan for pulmonary embolism. He was admitted to the Phoenix VA with complaints compatible with congestive heart failure. He had an extensive PMH with multiple myocardial infarctions with stent placements; resultant congestive heart failure; obesity: type 2 diabetes mellitus; obstructive sleep apnea, a 135 pack-year history of smoking; and right renal cell carcinoma found incidentally in 2006 with subsequent right nephrectomy 2 years previously.

Physical Examination

The patient was a tall, obese man who was afebrile.  Bilateral rales were noted about half way up the lung fields bilaterally and 2+ pretibial edema. The remainder of the physical examination was unremarkable.

Laboratory Findings

Urine analysis, complete blood count, and basic metabolic panel had the following abnormalities and pertinent negatives: hemoglobin 11.0 g/dl; hematocrit 31.9%; WBC 8200 cells/microl; creatinine 1.9 mg/dl; BUN 41 mg/dl; glucose 200 mg/dl. Hemoglobin A1C was 8.9% and a brain naturetic peptide was 887 pg/ml. Arterial blood gases were PaO2 82 mm Hg, PaCO2 25 mm Hg and pH 7.44 while breathing room air. Sputum cultures for bacteria, fungi and tuberculosis were negative. Serology testing for Coccidiomycosis was negative.

Radiography

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

Figure 1. Admission chest X-ray.

A representative slice of the CT scan showing the right lower lobe mass is shown in Figure 2.

Figure 2. Chest CT showing noncalcified, spiculated 2.1 cm nodule in the right lower lobe indicated by the arrow.

A PET scan was performed and the lesion had a standard uptake value of 1.5.

Subsequent Course

Multiple diagnosis including lung cancer, metastatic renal cancer, and infection were considered. The patient was reluctant to undergo biopsy but agreed to an outpatient course of doxycycline and a repeat CT scan 3 months later (Figure 3).

Figure 3. Repeat CT scan done 3 months later showing enlargement of the right lower lobe mass to 6.4 cm indicated by the arrow.

The patient was agreeable to needle biopsy (Figure 4).

Figure 4. Needle aspiration of lung mass showing an absence of malignant cells with acute inflammation compatible with a lung abcess.

Gastroenterology consultation was obtained and esophageal motility and esophogastroduodenoscopy revealed only gastritis.

The patient was followed and a repeat CT scan done 3 months later revealed shrinkage of the lesion (Figure 5).

Figure 5. CT scan done 6 months after biopsy (9 months after original CT scan). The right lower lobe lesion appears smaller at 1.2 cm.

The patient was followed and was asymptomatic until 22 months after initially seen when he presented with hemoptysis and shortness of breath. Repeat CT scan again showed a lesion in the area of the original lesion with cavitation and an air fluid level (figure 6).

Figure 6. CT scan done 22 months after original CT scan showing cavitation and an air fluid level indicated by the arrow.

Bronchoscopy with bronchoalveolar lavage was performed. Cultures for bacteria, fungi and tuberculosis were negative. He subsequently died from massive hemoptysis and respiratory failure.

Discussion

This case demonstrates the usefulness of doubling time in separating malignant from nonmalignant chest lesions. Between his first and second CT scans this patient’s lesion had enlarged from 2.1 to 6.4 cm over 102 days giving a calculated doubling time of 21 days (1). Lung cancers generally have average doubling times of about 100 days but have been reported to vary between 30 and 500 days. Doubling times of < 30 days usually indicate an infectious process. The lesion was aspirated because of its growth but no organism was identified. However, doubling time may occasionally be difficult to determine when nodules are not spherical or the borders are particularly vague such as in ground glass opacities or semi-solid lesions.

Narrowing the initial cause of this lung lesion was difficult because of the multiple potential causes including lung cancer, infection, pseudotumor and metastatic renal cell carcinoma. PET scans are usually positive in lung cancers. Negative PET scans have been reported with renal cell carcinoma although in the minority of instances (2). PET scans may be variably positive in pulmonary infections (3). However, the low uptake on PET scanning suggested the lesion was not malignant. Furthermore, the rapid growth combined with the low metabolic uptake also suggested the lesion is not malignant because growth of malignant stage I lung cancers and metabolic activity on PET scanning usually correlate (4).

The infectious cause of this patient’s right lower lobe abscess was never identified despite repeated sputum cultures, bronchoscopies and even a needle aspiration biopsy. Despite the negative evaluation for esophageal dysmotility, it seems most likely that aspiration caused with a subsequent anaerobic abscess was the cause of his lesions. Anaerobic organisms can be difficult to culture (5,6). The patient repeatedly denied any difficulty swallowing, water brash, etc.

It is unclear whether the original lesion identified was the same as the subsequent cavity with an air fluid level. Although progressive pneumonia can occur with aspiration, we suspect repeated aspiration as the subsequent cause of his cavity because of the improvement followed by the worsening 22 months after the initial presentation (5). However, prevention of aspiration may be difficult and it is unclear what measures could have been invoked to prevent his eventual demise.

References

1. http://www.chestx-ray.com/spn/DoublingTime.html (accessed 3-29-11).
2. Chang CH, Shiau YC, Shen YY, Kao A, Lin CC, Lee CC. Differentiating solitary pulmonary metastases in patients with renal cell carcinomas by 18F-fluoro-2-deoxyglucose positron emission tomography--a preliminary report. Urol Int 2003;71:306-9.
3. Bomanji J, Almuhaideb A, Zumla A. Combined PET and X-ray computed tomography imaging in pulmonary infections and inflammation. Curr Opin Pulm Med. 2011;17:197-205.
4. Tann M, Sandrasegaran K, Winer-Muram HT, Jennings SG, Welling ME, Fletcher JW. Can FDG-PET be used to predict growth of stage I lung cancer? Clin Radiol 2008;63, 856-863.
5. Dines DE, Titus JL, Sessler AD. Aspiration pneumonitis.  Mayo Clinic Proc 1970;45:347-60.
6. Bynum LJ, Pierce AK. Pulmonary aspiration of gastric contents. Am Rev Respir Dis 1976;114:1129-36.

This case was presented at the Great Cases session during the American Thoracic Society meeting in San Diego, CA on May 17, 2009. A link to the slides used for that presentation is below.

Click here for a PowerPoint slide presentation

A YOUNG LADY WITH VANISHING LUNG SHADOWS

Johnson Samuel MD, FRCP

Balamugesh Thangakunam, MD, DM 

Basildon University Hospital, United Kingdom 

Presented at the Great Cases Session at the American Thoracic Society International Conference, May 16, 2010 in New Orleans, LA.

Reference as: Samuel J, Thangakunam B. A young lady with vanishing lung shadows. Southwest J Pulm Crit Care 2011;2:40-4. (Click here for PDF version)

Abstract

   A previously well 20-year-old young lady who presented with nonspecific right-sided chest pain was found to have a rounded shadow on chest X-ray. Investigations to rule out malignancy revealed multiple lung masses. Initial blood tests and percutaneous image guided biopsy were inconclusive. Surgical lung biopsy revealed features suggestive of Bronchocentric Granulomatosis. Her lung shadows spontaneously resolved and there was no evidence of symptomatic or radiological recurrence on follow up for five years. Bronchocentric Granulomatosis is a rare condition particularly in non-asthmatic individuals and should be considered in the lesser-known differential diagnosis of benign lung shadows. 

Case Presentation 

History and Examination

   A 20-year-old lady presented to the Emergency department with right-sided pleuritic chest pain after watching a football match in the local pub.  A Chest radiograph showed a 1cm oval opacity in the periphery of the left upper zone. She was treated with a course of antibiotics and a repeat chest radiograph two weeks later showed an increase in the size of the opacity (Fig 1).

 

Figure 1.  Chest radiograph showing a rounded opacity in left upper zone.

   She was then referred to the respiratory clinic for evaluation. She was a non-smoker with no previous medical history of note. There was no history of recent respiratory infections. Clinical examination including breast examination was entirely normal.

Investigations

    Haemoglobin was 11.2 gm/dl, white cell count 7.0 x10⁹/L, platelet count 255x10⁹/L and erythrocyte sedimentation rate 22mm/hr. Differential white cell count was normal with absolute eosinophil count 0.1x10⁹/L.  Serum angiotensin converting enzyme was 36 IU/L. Serum compliment levels were normal and tumour markers were negative. Human chorionic gonadotrophin level was not elevated. Rheumatoid factor was 38 IU/ml, autoantibodies and Human Immunodeficiency Virus tests were negative. Mantoux test was non-reactive

   Computed Tomography (CT) showed three opacities, two of which were on the right side (Fig 2).

 Figure 2.  Computerised Tomography scan of chest showing bilateral lung opacities

   A CT guided biopsy showed necrotizing chronic granulomatous inflammation with no evidence of malignancy. There were many eosinophils seen in the biopsy sample (Fig 3).

 

Figure 3.  Computerised Tomography guided biopsy of the lesion showing necrotizing granulomatous inflammation. The arrowheads indicate necrosis centre of the picture with many eosinophils. The area circled shows a granuloma including a multi-nucleated giant cell indicated by the short arrow. (High power view- formalin fixed, haemotoxylin and eosin staining).

   As the diagnosis was still uncertain and as there was the suspicion of metastatic malignancy of uncertain origin, she underwent a video assisted thoracoscopic biopsy (VATS biopsy). Histopathology of the nodule revealed abundant necrosis, surrounded by a rim of chronically inflamed fibrous tissue with focal areas of discontinuous elastic lamina (Fig 4).

Figure 4.  Video assisted thoracoscopic biopsy showing focal necrotizing granulomatous inflammation. Arrowhead indicated the central necrosis. Short arrow indicated the multi-nucleated giant cell (High power view – formalin fixed, haemotoxylin and eosin staining).

   Mycobacterial and fungal cultures were negative. There were no features of vasculitis or malignancy.  Based on the histopathology and the clinical features, a diagnosis of Bronchocentric Granulomatosis was made.

Follow up

   The patient was asymptomatic throughout she did not receive treatment. On follow up, after initial increase in size, the nodules started regressing and serial chest X-ray’s showed complete resolution of the lung lesions in four months. She has since been followed up in the respiratory clinic for five years and there was no radiological evidence of recurrence. Her serial spirometry during follow up was normal. She remains asymptomatic and has joined the police force leading an active lifestyle.

Discussion

   Bronchocentric granulomatosis is a necrotizing granulomatous inflammation of the small to medium sized bronchi and bronchioles (1). Approximately half the patients are asthmatics and among these patients, the disease appears to be a hypersensitivity reaction to inhaled allergens particularly Aspergillus fumigatus. (2,3). In the non-asthmatic group, the causative agent is usually not identified. Similar appearances have been described in patients with Pulmonary Echinococcosis, Wegener’s Granulomatosis and Rheumatoid Arthritis (4). Occasionally, it may show histological features indistinguishable from tuberculosis.

    Asthmatic patients, who are usually in the age group 20-40 years, present with worsening wheeze, dyspnoea, cough, fever and occasionally haemoptysis. Peripheral blood may show eosinophilia and Aspergillus fumigatus is commonly grown in sputum culture. Non-asthmatic patients are often asymptomatic or may present with an acute febrile illness. Radiologically, Bronchocentric Granulomatosis can present as mass lesions, alveolar infiltrates, pneumonic consolidation or reticulo-nodular opacities (5). As this can mimic malignancy as in our case, a surgical lung biopsy may be required to rule out vasculitis or malignancy.  There are no definite diagnostic criteria and diagnosis is based on clinical, radiological and pathological correlation. Some patients may need corticosteroids for rapid clinical and radiological resolution while others recover without treatment. Surgical resections have been done to firmly establish the diagnosis given the concern about malignancy. However, when there are no alarming symptoms or signs, it may be appropriate to monitor progress or consider medical treatment.

    Bronchocentric Granulomatosis though rare is a reassuringly benign and usually self-limiting condition, which can present with alarming radiological signs. It should be considered in the asthmatic and asymptomatic patient when other sinister causes are ruled out by definitive investigations, which may include a surgical biopsy.

Acknowledgement:

   Dr. Nazar Alsanjari, Pathology department, Basildon University Hospital, Basildon. For kindly providing the photomicrographs of the biopsy specimens.

References

1. Liebow AA. Pulmonary angiitis and granulomatosis. American Review of Respiratory Disease 1973;108:1-18.

2.  Sulavik SB. Bronchocentric granulomatosis and allergic bronchopulmonary aspergillosis. Clin Chest Med 1988;9:609-21.

3.  Koss MN, Robinson RG, Hochholzer L. Bronchocentric granulomatosis. Hum  Pathol 1981;12:632-8.

4. Bonafede RP, Benatar SR. Bronchocentric granulomatosis and rheumatoid arthritis. Br J Dis Chest 1987;81:197-201.

5. Ward S, Heyneman LE, Flint JD, Leung AN, Kazerooni EA, Miller NL. Bronchocentric granulomatosis: computed tomographic findings in five patients. Clin Radiol 2000;55:296-300.

Corresponding author:

Balamugesh Thangakunam

Speciality Doctor

Respiratory services

Basildon University Hospital

Basildon, Essex, United Kingdom

SS16 5NL

E mail: drbalamugesh@yahoo.com

This case was presented at the Great Cases session at the American Thoracic society meeting in New Orleans, LA on May 16, 2009. A link to the slides used in that presentation is below.

Slide 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) 

PET Positive Pleural Plaques Decades after Pleurodesis: Mesolthelioma?

Ellen A. Middleton¹

Jonathan C. Daniel²

Kenneth S. Knox¹

Kathleen Williams¹

Departments of Medicine¹ and Surgery², University of Arizona College of Medicine, Tucson, AZ

Reference as: Middleton EA, Daniel JC, Know KS, Williams K.  PET positive pleural plaques decades after pleurodesis: mesolthelioma? Southwest J Pulm Crit Care 2011;2:9-16. (Click here for PDF version)

Abstract 

   A 59-year-old patient was evaluated for abnormal chest CT and hypermetabolic pleural foci on FDG-PET scan. The scans were obtained as routine surveillance for resection of an in situ pancreatic tumor.  The patient had a remote history of automobile manufacturing and the abnormalities were suggestive of asbestos exposure.  Because hypermetabolic areas were concerning for pleural malignancy, a VATS lung biopsy was performed and revealed chronic talc-induced pleuritis. The patient had a history of pnemothoraces with bilateral talc pleurodesis at the age of 16. As cancer screening and surveillance increasingly relies on extensive imaging modalities, physicians should be aware of the chronic complications of talc pleurodesis and the possibility of false positive imaging tests.

Background 

   The treatment of primary spontaneous pneumothorax (PSP) varies greatly among physicians. Treatment options include observation, chest tube decompression, simple catheter aspiration, medical thoracoscopy with pleurodesis, and surgical intervention. Talc pleurodesis is often performed as part of the intervention and although both safe and effective, the long term complications of talc exposure are not well defined. Specifically, no documented cases of pleural malignancy after instillation of talc exist. We report a patient with increased pleural activity on 18-fluorodeoxyglucose positron-emission tomography (FDG-PET) mimicking mesothelioma which ultimately proved to be chronic talc-induced pleuritis decades after pleurodesis for PSP. Biopsy and definitive diagnosis via video assisted thoracoscopic surgery (VATS) changed the course of care for this patient.

Case Report

   The patient is a 59-year-old man with past medical history significant for pancreatic adenocarcinoma in situ status post Whipple procedure in January 2009. His follow up radiologic examination revealed calcified pleural-based nodules on his CT scan. The concern for malignant mesothelioma arose, particularly as he had a history of asbestos exposure while working with automobile manufacturing in his youth.

   The patient was referred to the thoracic surgery service for evaluation. FDG-PET scan was performed and pleural nodules with a maximum SUV of 13.1 were noted (Fig 1).

Figure 1. FDG-PET and CT showing bilateral pleural nodules.

    Pulmonary function testing revealed a mild restrictive ventilatory defect.  VATS was performed and the patient underwent left thoracoscopic lysis of adhesions, pleural biopsy, and wedge resections of pleural plaques adhesed to the lung. Frozen section intra-operatively was consistent with talc crystals and fibrosis. Pathologic examination later confirmed chronic pleuritis due to talc extending into lung parenchyma without evidence of granuloma, malignancy, or presence of ferruginous bodies (Fig. 2).

 

Figure 2. The patient’s biopsy specimen showing inflammation and polarizable birefringent crystals consistent with talc.

Discussion 

   Treatment of PSP with talc pleurodesis is an effective and relatively safe means of preventing recurrence. Both acute and long-term adverse effects of talc pleurodesis are few. In our patient, the FDG-PET scan was highly suspicious for malignancy and mesothelioma. A study following patients from 14 to 40 years after pleurodesis for PSP did not shown evidence of mesothelioma or increased incidence of lung cancer (1). Lange et al. (2) demonstrated that greater than two decades post pleurodesis a large percentage of patients have pleural thickening demonstrated by plain chest x-ray and this may lead to mild restrictive impairment. In the era of the FDG-PET scan, a diagnostic dilemma is emerging as it appears many of these changes can manifest as chronic inflammatory lesions with increased metabolic activity.

    Recent case reports have documented talc related pulmonary processes that appeared malignant by FDG-PET. Tenconi et al. (3) documented a case in which a patient was experiencing cough, chest pain, and weight loss associated with hypermetabolic (SUV 4.8) pleural plaques by FDG-PET scan. The patient underwent thoracotomy and total pleurectomy revealing talc pleural granulomas from a pleurodesis 42 years prior. The authors concluded that the treatment of choice for PSP should be VATS blebectomy and pleural scarring. Similarly, Ahmadzadehfar and colleagues (4) presented a patient with pleural, mediastinal, and intrapulmonary lesions demonstrating high glucose uptake on FDG-PET imaging five years following talc pleurodesis. The pathology was consistent with talc granulomatosis.

   FDG-PET is commonly used in the diagnosis of pulmonary nodules and staging of lung cancer. It is emerging as an imaging modality in the diagnosis and management of malignant mesothelioma. The International Mesothelioma Interest Group’s consensus statement states FDG-PET is an accurate and reliable tool to differentiate malignant and benign pleural lesions. The group made the recommendation that one must exercise caution when interpreting surveillance images from patients with talc pleurodesis in the setting of mesothelioma as those patients demonstrate higher average SUV (5). No mention is made of the patient that has the radiographic appearance of mesothelioma, but histologically has talc related lesions.

    Two case series have examined the progression of pleural involvement in cancer patients following pleurodesis for malignant effusion or postthoracotomy air leak.  Nguyen and colleagues (6) performed serial FDG-PET scans between 1 month and 58 months. SUV values ranged from 1.9 to 12.6 and it was concluded that FDG uptake may persist or increase over time in chronic inflammatory plaques. Kwek et al. (7) similarly evaluated patients between 10 days and 71 months after pleurodesis and found an SUV range from 2.0 to 16.3. One patient was found to have a new area of contralateral increased FDG uptake representing pleural metastasis. The authors concluded that talc deposits can lead to false positive FDG-PET scan but it is essential to monitor stability of hypermetabolic foci.  

Conclusion

   As the population ages, the medical community can expect to see an increased number of patients who underwent talc pleurodesis decades previously. The utility of FDG-PET imaging to define malignant disease is likely limited in patients whose history includes talc pleurodesis. Physicians must be aware of the  pitfalls of emerging radiologic modalities Documented reports of FDG-PET false positives for pleural malignancy include asbestos reaction, pleurisy, recent surgery, radiotherapy, and pleural effusion secondary to inflammatory processes (7). Review of prior CT scans to evaluate the progression or stability of pleural plaques is essential. False-positive results can be devastating to patients, and often lead to invasive procedures.

References

1. Chappell AG, Johnson A, Charles J. A survey of the long-term effects of talc and kaolin pleurodesis. British journal of diseases of the chest. 1979; 73:285-288.
2. Lange P, Mortensen J, Groth S. Lung function 22-35 years after treatment of idiopathic spontaneous pneumothorax with talc poudrage or simple drainage. Thorax. 1988 Jul; 43:559-61.
3. Tenconi S, Luzzi L, Paladini P, Voltolini L, Gallazzi MS, Granato F, Gotti G. Pleural granuloma mimicking malignancy 42 years after slurry talc injection for primary spontaneous pneumothorax. Eur Surg Res. 2010; 44:201-3.
4. Ahmadzadehfar H, Palmedo H, Strunk H, Biersack HJ, Habibi E, Ezziddin S. False positive 18F-FDG-PET/CT in a patient after talc pleurodesis. Lung Cancer. 2007; 58:418-21.
5.  Nowak AK, Armato SG 3rd, Ceresoli GL, Yildirim H, Francis RJ. Imaging in pleural mesothelioma: A review of imaging research presented at the 9th international meeting of the International Mesothelioma Interest Group. Lung Cancer. 2010;70:1-6.
6.  Nguyen NC, Tran I, Hueser CN, Oliver D, Farghaly HR, Osman MM. F-18 FDG PET/CT characterization of talc pleurodesis-induced pleural changes over time:a retrospective study. Clin Nucl Med. 2009 Dec; 34 (12) :886-90. 
7. Kwek BH, AquinoSL, Fischman AJ. Fluorodeoxyglucose positron emission tomography and CT after talc pleurodesis. Chest. 2004;125:2356-60.

Corresponding author:

      Kathleen Williams, DO

      Assistant Professor of Medicine

      Pulmonary Critical Care Division

      1501 N Campbell Ave

      Tucson, AZ 85724-5030

      Tel: (520) 626-6114 Fax: (520) 626-6970

Author Contributions:

      - Acquisition of data: Dr. Daniel

      - Drafting of the manuscript: Dr. Middleton 

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

Abbreviation List:

      CT- Computed tomography

      FDG-PET- Positron-emission tomography with 18-fluorodeoxyglucose

      PSP- Primary spontaneous pneumothorax

      VATS - Video-assisted thoracoscopic surgery

The Development of Glossopharyngeal Breathing and Palatal Myoclonus in a 29 Year Old after Scuba Diving

Cristian Jivcu, MD

Manoj Mathew, MD

David M Baratz, MD

Allen R Thomas, MD 

Banner Good Samaritan and Phoenix VA Medical Centers

Phoenix, AZ

Reference as: Jivcu C, Mathew M, Baratz DM, Thomas AR. The development of glossopharyngeal breathing and palatal myoclonus in a 29 year old after scuba diving. Southwest J Pulm Crit Care 2011;2:3-6. (Click here for PDF version)

Introduction

   Palatal myoclonus is a rare movement disorder characterized by brief, rhythmic involuntary movements of the soft palate.  Palatal myoclonus is further subdivided into “essential palatal tremor” (EPT) and “symptomatic palatal tremor” (SPT).  EPT is characterized by involvement of the tensor veli palatini, myoclonus that might persist during sleep, as well as ear clicks, usually the patient’s presenting complaint.  The MRI and neurological exam are normal in EPT.  SPT is characterized by involvement of the levator veli palatini and myoclonus which consistently perseveres during sleep.  The MRI shows olivary hypertrophy and clinical features may include ataxia, dysarthria and nystagmus, depending on the size of the lesion¹.  Glossopharyngeal breathing is a technique used by deep-sea divers to increase lung vital capacity, which is also useful in patients with ventilator dependence from poliomyelitis and Duchenne muscular dystrophy.  To date there have been no reported cases of palatal myoclonus and glossopharyngeal breathing occurring simultaneously.  We present the case of a 29 year-old female with palatal myoclonus and glossopharyngeal breathing after scuba-diving.

Case Presentation

   A 29 year-old female presented to her physician with complaints of fevers, chills, rapid shallow breathing, ear clicks and inspiratory “spasms of the neck.” The symptoms started three days after a week-long scuba-diving trip.  She reported a total of four consecutive and uneventful dives no deeper than 50 feet.  Her descents and ascents were well-controlled.  On initial presentation she was ruled-out for pulmonary embolism and was discharged home.  Two months after first presentation she was referred to our office with persistent symptoms of ear clicks, intermittent headaches and neck spasms.  The headaches were bilateral, starting in the occipital region, radiated frontally to the eyes and felt “like a hang-over.”  The neck spasms which initially occurred with a frequency of one with every breath had decreased to one spasm every 2-3 breaths (click here for video-requires Quiktime).  Symptoms of dyspnea, wheezing, cough were absent and the rest of her medical history, including a psychiatric history, was unremarkable. Her vital signs showed a blood pressure of 110/76; Heart rate of 85 beats per minute; Temperature of 99F; Respiratory Rate of 16, and oxygen saturation of 100% while breathing room air.  On exam palatal tremor was noted with every breath, and glossopharyngeal breathing occurred every 1-2 breaths. Cranial nerves II – XII were intact and no difficulty was noted with swallowing or speaking.  Her strength was 5/5 in bilateral upper and lower extremities, and her biceps, brachioradialis and patellar reflexes were normal (+2).  Her gait was normal.  The rest of the physical exam was normal.  Her workup included a normal chest X-ray and a normal MRI of the brain. Notably absent in the brain MRI was olivary hypertrophy.  She was started on clonazepam for palatal myoclonus and neck spasms which were consistent with glossopharyngeal breathing.   After one week of administration the patient reported symptomatic improvement.  By week 2 the palatal myoclonus and glossopharyngeal breathing had completely resolved.

Discussion

   Glossopharyngeal breathing was first noted in 1951 when a respirator-dependent poliomyelitis patient with a paralyzed diaphragm was noted to be “gulping air” and increased his vital capacity from 250cc to 600cc ².  In our case the glossopharyngeal breathing was unintentional, and occurred after a scuba-diving trip.  There are no reported cases of this entity in the medical literature.  Furthermore there have been no reported cases of symptomatic palatal tremor in the setting of glossopharyngeal breathing.  A possible explanation of this co-existent entity can be found through anatomic relationships.  The glossopharyngeal nerve is involved in the movements used in glossopharyngeal breathing.  This nerve also sends a branch to the pharyngeal plexus, which in turn innervates the levator veli palatini, the muscles involved in SPT.  An overstimulation of the glossopharyngeal nerve could theoretically result in glossopharyngeal breathing as well as palatal myoclonus.

Summary

   Palatal myoclonus and glossopharyngeal breathing are usually two unrelated clinical findings.  Our conclusion is that an overstimulation of the glossopharyngeal nerve through inadvertent air-gulping during scuba-diving resulted in symptomatic palatal tremor and unintentional glossopharyngeal breathing.  Treatment with benzodiazepines resulted in complete symptom resolution.

References

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