Update and Arizona Thoracic Society Position Statement on Stem Cell Therapy for Lung Disease

Summary

Infusions of stem cells are increasingly being offered for a variety of diseases, including chronic lung diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and cystic fibrosis. However, the potential for harm, the lack of any proven benefit, and the high fees that many of these programs charge make recommending stem cell therapy untenable. At the time of this writing (April 2019) it appears that stem cell therapy can be safely performed, although the long-term side effects remain unknown. However, the little data available show no benefit in meaningful outcomes, such as mortality, morbidity or patient well-being, for stem cell treatment of chronic lung disorders. Patients with severe, incurable diseases may be motivated to seek innovative therapies. We encourage such patients to contact their primary care physician or pulmonologist. Clinical trials in the United States and Canada investigating stem cell therapy for lung diseases can be found on the website of the National Institutes of Health at Clinicaltrials.gov. The Arizona Thoracic Society encourages regulatory agencies to protect the public health and take appropriate action against non-investigational, for-profit stem cell clinics when appropriate.

Introduction

A central component of the mission of medical societies is to translate new scientific information into patient education. There appears to be increasing direct-to-consumer advertising of untested, unapproved, and potentially ineffective “stem-cell” treatments for a variety of diseases, including lung disorders (1). One may come across information regarding stem cell therapy for chronic obstructive pulmonary disorders and fibrotic lung disease, in the United States and worldwide, on the internet, patient support groups, or other sources. Recently, a direct mailing to the home of one of the members of the Arizona Thoracic Society was received (Figure 1).

Figure 1. Direct mailing for stem cell therapy for several diseases including COPD received by one of the members of the Arizona Thoracic Society.

These programs are often characterized by:

• Exorbitant fees
• Misrepresentation of risks and benefits
• Overreliance on, and advertisement of, patient testimony
• Poor patient follow-up
• Absence of regulatory oversight and objective clinical evidence for claimed benefits

Therefore, they differ substantially from therapies approved by legitimate regulatory agencies, from well-designed, controlled, and appropriately regulated clinical trials, and from regulated compassionate use of innovative cell therapies.

Chronic Obstructive Pulmonary Disease (COPD)

Stem cells can differentiate into several different lung cell types, including the alveolar epithelial cells. Since COPD is a disease associated with destruction of alveoli induced by cigarette smoke, the concept of rebuilding the alveoli through stem cell therapy is attractive. Pre-clinical trials in animal models have suggested regeneration of alveolar-like structures, repair of emphysematous lungs, and reduction of inflammatory responses, with the greatest success being in acute lung injury models.

Currently, regenerative therapies are divided into extrinsic therapeutic strategies and intrinsic cell therapy methods. Extrinsic cell therapy refers to the vascular infusion of (or endotracheal installation) of stem cells, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSs), mesenchymal stem cells (MSCs), and human lung stem cells (hLSCs). Intrinsic therapy refers to the delivery of small molecules (retinoid compounds have been the most studied) that can stimulate the endogenous lung stem/progenitor cells to regenerate and replace damaged structures.

A number of recent review articles have summarized the current state of research in the use of stem cells in COPD (2-4). These review articles all contain summaries of trials conducted to date using both extrinsic and intrinsic therapies. There have been several phase I clinical trials, primarily assessing safety, and a handful of small phase II clinical trials that have been negative for meaningful clinical outcomes. Sun et al. (3) point out that the available trials have all been conducted on patients with advanced COPD. The authors suggest that further research is required on how to enhance the engraftment of exogenous mesenchymal stem cells in damaged lungs. Further, considering the anti-inflammatory and immunomodulatory effects of exogenous mesenchymal stem cells, they may be most effective potentially in treating acute lung disease, as opposed to chronic progressive disease with severe structural damage.

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive debilitating lung disease of unknown etiology characterized by a combination of histological changes, including extracellular matrix (ECM) deposition, phenotypic changes of fibroblasts, and alveolar epithelial cells, the formation of fibroblastic foci, and scattered areas of aberrant wound healing interspersed with normal lung parenchyma (5).

There are two approved compounds for the treatment of IPF: pirfenidone and nintedanib. Pirfenidone is an antifibrotic compound with an unclear mechanism of action, targeting several molecules, including transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), and interleukin 6 (6). Nintedanib is a tyrosine-kinase inhibitor, targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet derived growth factor receptor (PDGFR) (7). While the use of pirfenidone and nintedanib has been shown to slow the progression of IPF, neither is curative and morbidity and mortality from IPF remains high (8,9).

Because of the inadequacy of therapy in IPF, the use of mesenchymal stem cells (MSCs) has attracted interest as a potential option. Early clinical studies have shown that the MSCs can be safely administered (5,10-12). A phase Ib study of endobronchially administered autologous adipose-derived MSCs showed not only acceptable safety outcomes, but also improvements in quality of life parameters (12). However, there were no significant differences in any of the studied functional parameters (FVC, FVC%pred. and DLCO% pred.) at baseline and 6 and 12 months following 3 endobronchial infusions of MSCs.

Cystic Fibrosis

Cystic fibrosis (CF) is a genetic syndrome usually resulting in a high mortality rate due to progressive lung disease. Several drugs targeting specific mutated cystic fibrosis transmembrane regulator (CFTR) proteins are already in clinical trials. However, new therapies, based on stem cells, are also emerging. Interest has focused on induced pluripotent stem (iPS) cells. It is possible to make iPS cells using cells from people with CF, and then use gene editing to correct CFTR mutations in those cells (13). This suggests the possibility of re-implanting the corrected iPS cells into the lungs of people with CF to generate healthy lung cells. Currently, three trials examining the safety of stem cells in cystic fibrosis are ongoing according to Clinicaltrials.gov. 

Adult Respiratory Distress Syndrome (ARDS)

Four clinical trials are listed on Clinicaltrials.gov for ARDS and stem cells; one, which involved 3 patients, has been completed (14). No outcome information is available.

Other Lung Diseases

We are unaware of any human trials at this time with outcomes in other lung diseases.

Regulatory and Legal Actions

The Food and Drug Administration (FDA) and the Attorney General of New York have both expressed concern over stem cell therapy. The concerns follow reports of three patients becoming blind after receiving injections of stem cells into the eye and twelve patients who became seriously ill after receiving injections that purportedly contained stem cells from umbilical cord blood (15,16). The FDA has issued warning letters to stem cell clinics, including one letter claiming violation of Federal law, and another 20 warnings to clinics of that their claims and actions were subject to FDA approval. The NY Attorney has filed a lawsuit against a for-profit stem cell clinic, Park Avenue Stem Cell, claiming it performed unproven procedures on patients with a wide range of medical conditions, from erectile dysfunction to heart disease (17).

The Arizona Thoracic Society encourages further investigation into stem cell transplantation in lung disease. However, we do not at this time encourage non-investigational use of stem cells since the therapy has not been shown to have meaningful patient benefits. We also encourage state and local regulatory agencies in the Southwest to protect the public health and take appropriate action against non-investigational, for-profit stem cell clinics when appropriate.

References

1. American Lung Association. Statement on Unproven Stem Cell Interventions for Lung Diseases (July 2016). Available at: https://www.thoracic.org/members/assemblies/assemblies/rcmb/working-groups/stem-cell/resources/statement-on-unproven-stem-cell-interventions-for-lung-diseases.pdf (accessed 4/5/19).
2. Balkissoon R. Stem Cell Therapy for COPD: Where are we? Chronic Obstr Pulm Dis. 2018;5(2):148-53. [CrossRef] [PubMed]
3. Sun Z, Li F, Zhou X, Chung KF, Wang W, Wang J. Stem cell therapies for chronic obstructive pulmonary disease: current status of pre-clinical studies and clinical trials. J Thorac Dis. 2018 Feb;10(2):1084-98. [CrossRef] [PubMed]
4. Cheng SL, Lin CH, Yao CL. Mesenchymal Stem Cell Administration in Patients with Chronic Obstructive Pulmonary Disease: State of the Science. Stem Cells Int. 2017;2017:8916570. [CrossRef] [PubMed]
5. Tzouvelekis A, Toonkel R, Karampitsakos T, Medapalli K, Ninou I, Aidinis V, Bouros D, Glassberg MK. Mesenchymal stem cells for the treatment of idiopathic pulmonary fibrosis. Front Med (Lausanne). 2018 May 15;5:142. [CrossRef] [PubMed]
6. Kolb M, Bonella F, Wollin L. Therapeutic targets in idiopathic pulmonary fibrosis. Respir Med. 2017;131:49–57. [CrossRef] [PubMed]
7. Fletcher S, Jones MG, Spinks K, et al. The safety of new drug treatments for idiopathic pulmonary fibrosis. Expert Opin Drug Saf. 2016;15:1483–9. [CrossRef] [PubMed]
8. King TE, Bradford WZ, Castro-Bernardini S, et al. Phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083–92. [CrossRef] [PubMed]
9. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071–82. [CrossRef] [PubMed]
10. Tzouvelekis A, Ntolios P, Karampitsakos T, et al. Safety and efficacy of pirfenidone in severe idiopathic pulmonary fibrosis: a real-world observational study. Pulm Pharmacol Ther. 2017;46:48-53. [CrossRef] [PubMed]
11. Tzouvelekis A, Koliakos G, Ntolios P, et al. Stem cell therapy for idiopathic pulmonary fibrosis: a protocol proposal. J Transl Med. 2011;9:182. [CrossRef] [PubMed]
12. Tzouvelekis A, Paspaliaris V, Koliakos G, et al. A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. J Transl Med. 2013;11:171. [CrossRef] [PubMed]
13. The Cystic Fibrosis Foundation. Stem cells for cystic fibrosis therapy. Available at: https://www.cff.org/Research/Research-Into-the-Disease/Restore-CFTR-Function/Stem-Cells-for-Cystic-Fibrosis-Therapy/ (accessed 4/5/19).
14. Clinicaltrials.gov. Human Mesenchymal Stem Cells For Acute Respiratory Distress Syndrome (START). Available at: https://www.clinicaltrials.gov/ct2/show/results/NCT01775774?term=Stem+cells&cond=ARDS&rank=4 (accessed 4/5/19).
15. Kuriyan AE, Albini TA, Townsend JH, et al. Vision loss after intravitreal injection of autologous "stem cells" for AMD. N Engl J Med. 2017 Mar 16;376(11):1047-53. [CrossRef] [PubMed]
16. Grady D. 12 People hospitalized with infections from stem cell shots. NY Times. Dec. 20, 2018. Available at: https://www.nytimes.com/2018/12/20/health/stem-cell-shots-bacteria-fda.html?action=click&module=RelatedCoverage&pgtype=Article&region=Footer (accessed 4/9/19).
17. Abelson R. N.Y. attorney general sues Manhattan stem cell clinic, citing rogue therapies. NY Times. April 4, 2019. Available at: https://www.nytimes.com/2019/04/04/health/stem-cells-lawsuit-new-york.html (accessed 4/9/19).

Cite as: Arizona Thoracic Society*. Update and Arizona Thoracic Society position statement on stem cell therapy for lung disease. Southwest J Pulm Crit Care. 2019;18(4):82-6. doi: https://doi.org/10.13175/swjpcc020-19 PDF

*The below contributed to the update and position statement on stem cell therapy

• Bhargavi Gali, MD
• Michael B. Gotway, MD
• Kenneth S. Knox, MD
• Timothy T. Kuberski, MD
• Stuart F. Quan, MD
• George Parides, DO
• Richard A. Robbins, MD
• Gerald F. Schwartzberg, MD
• Allen R. Thomas, MD
• Lewis J. Wesselius, MD

Infected Chylothorax: A Case Report and Review

Louis Eubank¹, Luke Gabe¹, Monica Kraft¹, and Dean Billheimer²

¹Departments of Medicine and Biostatistics, College of Medicine

²Department of Biostatistics, College of Public Health

University of Arizona Health Sciences Center

Tucson, AZ USA

Abstract

Infected chylothorax is a rare complication of a rare pathology with limited literature entirely consisting of case reports, meeting abstracts, and letters to the editor. The case of a 56-year-old male with a spontaneous infected chylothorax successfully treated and discharged to home without any residual effects is described. A systematic review of the literature revealed 11 prior cases of infected chylothoraces. Their etiologies (when known), initial pleural fluid values, and treatment are described. These cases show that while infected chylothorax has a varied presentation and affects a broad range of patients, conservative management including antibiotics, pleural fluid drainage, and symptomatic relief is a safe and appropriate starting point.

Introduction

Chylothorax, a pleural effusion caused by chyle accumulation from obstruction or disruption of the thoracic duct (please see SWJPCC’s Image of the week: chylothorax for an image of non-infected chyle fluid), is a rare condition that may arise from a diversity of etiologies broadly categorized as traumatic or non-traumatic/spontaneous (1). Traumatic causes commonly include iatrogenic injury and chest trauma, although insults as minor as sneezing, light exercise and emesis have been reported (1-3). Non-traumatic chylothorax has been linked to several immunologic and infectious etiologies (1). Regardless of the underlying mechanism, chyle has classically been considered inherently bacteriostatic (1). We present a case of spontaneous infected chylothorax and the first review of infected chylothoraces reported in the literature.

Case Report

A 56-year-old man with alcoholic cirrhosis and remote right-sided hepatic hydrothorax presented to the emergency department complaining of shortness of breath. Patient reported slowly worsening dyspnea over the last six weeks without any other symptoms that had acutely worsened on morning of presentation

Initial vital signs were temperature 38.0°C, heart rate 115, blood pressure 81/60mmHg, and respiratory rate 30 breaths/min on 4L O₂ by nasal cannula; labs significant for white blood cell count of 3100/mm³ and lactate 5.0 mmol/L (normal <2.0 mmol/L).  Physical exam demonstrated a fatigued patient with accessory muscle use on inspiration and absent breath sounds at the left lung base. Computed tomography (CT) study of the chest showed a large free-flowing left-sided pleural effusion (Figure 1A&B) as well as subacute rib fractures (Image 1C).

Figure 1. Thoracic CT on the day of presentation. Panel A: Axial view showing pleural effusion. Panel B: Sagittal view showing pleural effusion. Panel C: Coronal view showing rib fractures (white arrows).

Chart review demonstrated an emergency department visit five months previously for a fall with acute left-sided rib fractures and minimal left-sided pleural effusion.

Thoracentesis removed two liters free-flowing, brown, milky, purulent fluid; analysis significant for 58,880 total nucleated cells (32,800 RBCs), 94% neutrophils, glucose <5, LDH 573 IU/dL (serum 193 IU/dL), triglycerides 191 mg/dL, albumin 1.8 g/dL (serum albumin 2.6 g/dL, laboratory lower limit of normal 3.4 g/dL).

The patient remained hypotensive despite fluid boluses, tachypneic with increasing oxygen requirements, and a repeat lactate was 6.4 mmol/L. Norepinephrine and broad-spectrum antibiotics were started and patient was admitted to the intensive care unit.

Pleural fluid and blood cultures grew Escherichia coli resistant to fluoroquinolones. Chest x-ray showed persistent pleural effusion; a chest tube was placed which drained an additional 1.6 L over the following 24 hrs. The patient subsequently improved: serum lactate normalized within 24 hours, vasopressors were weaned within 36 hours, and supplemental oxygen was discontinued within 72 hours.

Chest tube output decreased to less than 200 ml/day within 48 hours of placement; however, repeat thoracic CT demonstrated a persistent multi-loculated left pleural effusion. Surgical evacuation and pleurodesis were considered given the lack of literature regarding intrapleural lytic therapy in infected chylothorax (a single case report described use of streptokinase in a persistent non-infected chylothorax, 1).  However, the patient’s operative risk was considered prohibitively high. He was managed conservatively with a fat-free diet to reduce chyle leak.

Eleven days after initial presentation fluid studies were significant for triglyceride 45mg/dL with negative cultures. Given that a pleural fluid triglyceride level <50mg/dL yields a less than 5% likelihood of being chylous and the clinical stability of the patient, the chylothorax was felt to be resolved (1). The patient was discharged to home twelve days after initial presentation.

The etiology of patient’s infected chylothorax was never fully elucidated. The most likely explanation is the trauma causing rib fractures also caused a traumatic chylothorax that later became infected. The thoracic duct lies alongside the vertebrae until it drains into the left brachiocephalic vein (Figure 2).

Figure 2. Thoracic duct anatomy (black arrows).

A blow to the posterior left thorax sufficient to fracture multiple ribs is more than sufficient to damage the nearby thoracic duct (1-4).  Arguing against this is most patients with large traumatic chylothoraces present within 10 days of injury (1,2).

Another explanation is the patient developed bacterial empyema secondary to hepatic hydrothorax (ascites that has passed through diaphragm from the peritoneal cavity) followed by non-traumatic chylothorax. These empyemas can demonstrate an indolent course and Escherichia coli is one of the most common causative pathogens isolated (1). Arguing against this is the patient’s previous hepatic hydrothorax was right-sided.

Finally, the chylothorax may have arisen from one of the many known causative medical pathologies (2). Chylous ascites secondary to cirrhosis that migrates into the pleural space via diaphragmatic leaks defects is a known phenomenon, albeit extremely rare (2).

In follow-up two months after discharge the patient had total resolution of respiratory symptoms and no recurrence of the effusion.

Systematic Review

Methods

A MEDLINE search (PubMed) from January 1975 to January 2018 and a Google Scholar search (all years) was conducted to identify eligible studies using the following terms: “Infected Chylothorax” (all fields) OR “Infection AND Chylothorax” (all fields) OR “Chylothorax AND Empyema” (all fields) OR “Chylous Empyema” (all fields). The inclusion criteria for studies were patients with infected non-traumatic chylothorax. A triglyceride level > 110 mg/dL or the presence of chylomicrons in pleural fluid was used to confirm the diagnosis of chylothorax; pleural fluid culture speciation was used to confirm the infection. The exclusion criteria were a lack of laboratory data and duplicate data. Two reviewers (LE, LG) independently reviewed the titles, abstracts, and, when necessary, the full text regarding the inclusion/exclusion criteria. Data extraction was performed independently by two reviewers (LE, LG) using data extraction forms defined beforehand. Discrepancies were resolved by consensus discussion with a third reviewer (MK).

Results

Eight case reports, two published abstracts, and one letter to the editor met the inclusion criteria; all eleven were included in the analysis (Figure 3, 13-23). 

Figure 3. Flow diagram of the literature review.

The general characteristics, demographics, and etiology of infected chylothorax are summarized in Table 1, the initial pleural fluid values are reported in Table 2.

Table 1. Population data.

Table 2. Initial pleural fluid values.

There were 11 patients total: six males and five females; age range 5 days-78 years, mean age 40.5 years (standard deviation 28.5 years). One patient was pharmacologically immunosuppressed while others had chronic diseases known to reduce immune system function including diabetes, excessive alcohol intake, and obesity (24-26). Four (36%) were iatrogenic. Three patients (27%) were infected with Streptococcus viridans and five (45%) were infected with Streptococcus genus. In those with available data, three of ten patients (30%) required intravenous vasopressors. No patients required ventilator management for their chylothorax (two patients were already intubated, one for acute respiratory distress syndrome, the other for unstable hemodynamics secondary to large subarachnoid hemorrhage). Two patients (18%) were managed surgically – one was specifically noted to have failed conservative management (17). Of the known outcomes, eight of nine (89%) survived to discharge and all eight remained asymptomatic at follow-up. The mean follow-up duration was 13.3 months (range 6-24 months).

Discussion

Given the paucity of published experience regarding infected chylothoraces, we believe a descriptive summary is warranted. First, there is a large variation in patient characteristics, including age range, immune competence, comorbid medical conditions, and infectious organism (eight different bacterial species and one parasite).

Second, many of the reviewed cases had a more benign presentation than might be anticipated in the context of a large, infected intrathoracic fluid collection.  Seven of the patients (73%) were hemodynamically stable on presentation and the majority of these patients had very mild chief complaints.

Third, the available data suggest a surprisingly good prognosis considering a previously estimated morality of 10-25% in non-infected chylothoraces, depending on etiology (27). The one patient who did not survive to discharge died due to brain herniation. Those with documented outpatient follow-up were asymptomatic up to 16 months post-discharge. 

Fourth, conservative management was frequently efficacious. Eight patients (73%) were medically managed without complication and did not require extensive antibiotic duration, intrapleural lytic therapy, or surgical intervention. The decision to pursue surgical intervention is not well defined given the very limited number of cases requiring surgical management. A brief discussion of non-infected chylothoraces and their management is therefore warranted.

Non-infected chylothorax is universally described as a rare event, although its exact incidence has not been described. Chylous ascites, which sometimes shares pathogenesis with chylothorax and is one of the causes of spontaneous chylothorax, has an occurrence of one in 20,000 hospital admissions (12). Trauma accounts for approximately 50% of chylothoraces, with esophagectomy being the most common iatrogenic cause (28). Thirty percent are due to malignancy; lymphoma accounts for 70-75% of malignant cases (11). While there are no consensus guidelines on how to treat chylothoraces, many authors agree that first line treatment is conservative management with thoracentesis or chest tube drainage, fat free or medium chain triglyceride diet, and consideration of somatostatin or octreotide (1,5,11,27-29). Although somatostatin or octreotide are used at many institutions, data regarding indications & efficacy of these medications are limited and/or inconsistent – some institutions use these medications at the beginning of treatment, others only if/when initial management has failed (5,27).

Additional treatments may depend on the etiology of the chylothorax: it is suggested that earlier surgical intervention in iatrogenic traumatic chylothoraces, especially post-esophagectomy, may be beneficial (30). Conservative management is likely to fail and surgical intervention is recommended in the following situations: 1) daily drainage greater than 1000 mL chyle (adults) or greater than 100mL chyle/kg body weight (children); 2) chyle leak that persists for more than 14 days; 3) unchanged chest tube output for 7-14 days; 4) clinical deterioration (27,28).

Conservative management for infected chylothoraces appears efficacious in our small sample size with the obvious modification of treating the infection. Most antibiotics adequately penetrate the pleural space, although aminoglycosides should be avoided as they appear to be inactivated by the low pH and relative anaerobic conditions (31).

Limitations

The limitation of this systematic review was the inclusion of only case reports, abstracts, and letters to the editor and the small sample size. Unfortunately, given the rarity of infected chylothoraces, studies with sufficient sample size are unlikely to be available.

Conclusion

Infected chylothorax is a rare complication of an already rare pathology. Our case report and literature review show that it can affect any age group, can be caused by several different organisms, and has a variable presentation. Our data suggests that an initial conservative management strategy in infected chylothoraces can be a safe and effective option.

References

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4. Rodrigues AL, Romaneli MT, Ramos CD, Fraga AM, Pereira RM, Appenzeller S, Marini R, Tresoldi AT. Bilateral spontaneous chylothorax after severe vomiting in children. Rev Paul Pediatr. 2016 Dec;34(4):518-521. [PubMed]
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7. Kuan YC, How SH, Ng TH, Abdul Rani MF. Intrapleural streptokinase for the treatment of chylothorax. Respir Care. 2011 Dec;56(12):1953-5. [CrossRef] [PubMed]
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9. Pillay TG, Singh B. A review of traumatic chylothorax. Injury. 2016 Mar;47(3):545-50. [CrossRef] [PubMed]
10. Tu CY, Chen CH. Spontaneous bacterial empyema. Curr Opin Pulm Med. 2012 Jul;18(4):355-8. [CrossRef] [PubMed]
11. Skouras V, Kalomenidis I. Chylothorax: diagnostic approach. Curr Opin Pulm Med. 2010 Jul;16(4):387-93. [CrossRef] [PubMed]
12. Tsauo J, Shin JH, Han K, Yoon HK, Ko GY, Ko HK, Gwon DI.Transjugular intrahepatic portosystemic shunt for the treatment of chylothorax and chylous ascites in cirrhosis: a case report and systemic review of the literature. J Vasc Interv Radiol. 2016 Jan;27(1):112-6. [CrossRef] [PubMed]
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Cite as: Eubank L, Gabe L, Kraft M, Billheimer D. Infected chylothorax: a case report and review. Southwest J Pulm Crit Care. 2018;17(2):76-84. doi: https://doi.org/10.13175/swjpcc097-18 PDF

First-Line Therapy for Non-Small Cell Lung Cancer Including Targeted Therapy: A Brief Review

Richard A. Robbins, MD*

Thomas D. Kummet, MD**

*Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ USA

**Sequim, WA USA 

Abstract

Operative removal of non-small cell lung cancer remains the mainstay of therapy. When this is not possible, cytotoxic chemotherapy and/or radiotherapy can be given but are marginally effective in prolonging overall survival. However, with a better understanding of the pathobiology of the lung cancer cells, new targeted therapies have been developed which may produce dramatic responses in selected patients. This brief review will emphasize these newer therapies in this rapidly evolving field.

Introduction

Lung cancer is extremely common and remains by far the most frequent cause of cancer-related death with approximately 154,050 deaths estimated to occur during 2018 (1). Although lung cancer deaths have declined in men, the deaths have risen in women and now account for nearly half of all women’s cancer deaths (1). Unfortunately, the vast majority are diagnosed with advanced, unresectable disease that remains incurable (1). Overall the five-year survival rate is <1% for advanced (stage IVB) disease, while the five-year survival rate for all stages is approximately 15 % (1).

Data linking cigarette smoking to human lung cancer is incontrovertible (2). The risk increases with both the amount of smoking and the duration of smoking (2). Passive or second-hand smoke is also associated with an increase in the risk of lung cancer, although this increase is far lower than that observed with active smoking (2). Smoking cessation clearly decreases the risk of lung cancer (2).

Primary lung cancers can be divided into two main types based on their histology, small cell lung cancer and non-small cell lung cancer (NSCLC) (3). NSCLC constitute about 85% of lung cancers with the rest consisting of small cell and some rarer cancers (3). A basic understanding of the pathobiology of NSCLC has shown that the tumor cells depend on the formation of new blood vessels (angiogenesis), transfer of a phosphate group from ATP to tyrosine on proteins (tyrosine kinase), and regulation of programmed death ligands (checkpoint proteins) (4). Targeted therapy against these pathobiologic processes have shown dramatic effects in some NSCLC patients (4).

NSCLC is divided into 4 stages designated by roman numerals (5). The stages are based on the size of the tumor; whether it has metastasized locally or distally; and use the TNM classification where T designates tumor size; N regional lymph node metastasis; and M distant metastasis. Stages I and II are limited to the chest but stage III has metastasized to the pleura and/or regional lung lymph nodes. Stage IIIA means the cancer has metastasized to lymph nodes that are on the same side of the chest as the cancer (ipsilateral) while stage IIIB signifies metastasis to lymph nodes on the opposite side of the chest (contralateral). Stage IV denotes there are distant metastasis outside the chest. The above is admittedly an oversimplification and there are subtle nuances that define the stages which can be found at the National Cancer Institute website (5).

An overall summary of standard preferred by the National Cancer Institute for NSCLC by stage is shown in Table 1 (6).

Table 1. Standard preferred therapy for NSCLC by stage (6).

Surgery

Operative removal of the lung cancer is the cornerstone of management for patients with early-stage (stages I–II) NSCLC and selected patients with stage IIIA disease (7). Lobectomy is the operation of choice for localized NSCLC based on a randomized trial of lobectomy versus more limited resection (8). Operative intervention should be offered to all patients with stage I and II NSCLC who clinically are medically fit for surgical resection. However, patients may be unable to undergo a lobectomy for a variety of reasons such as: 1. severely compromised pulmonary function; 2. multisystem disease making lobectomy excessively hazardous; 3. advanced age; or 4. refusal of the operation. Some patients who cannot tolerate a full lobectomy but may be able to tolerate a more limited sublobar operation (6). For patients in whom complete tumor resection cannot be achieved with lobectomy, sleeve lobectomy is recommended over pneumonectomy because it preserves pulmonary function (6). In addition, the question of whether video-assisted thorascopic surgery (VATS) is equivalent to thoracotomy for patients with lung cancer comes up often, particularly in patients that are less than ideal surgical candidates. In a series of 741 patients with stage IA NSCLC, 5-year survival was similar but VATS was associated with fewer complications and a shorter length of hospital stay (9).  Therefore, VATS is an optional surgical approach particularly in poorer risk patients.

Radiotherapy

Although lobectomy is the treatment of choice for NSCLC patients with early-stage disease, some are unable to undergo an operation due to reasons listed above. For those patients, radiotherapy can be administered with curative intent, albeit with lower overall survival rates when compared to surgery (10,11).

The radiation oncology community is excited about the potential of stereotactic body radiation therapy (SBRT) (12,13). SBRT is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body (except the brain). Although there is no data yet, trials are ongoing comparing SBRT with surgery in early stage NSCLC.

Adjuvant Therapy

Adjuvant chemotherapy. Adjuvant chemotherapy is chemotherapy that is given in addition to either surgical and/or radiation therapy. Data from recent randomized adjuvant clinical trials and a meta-analysis support the use of adjuvant chemotherapy in NSCLC (14). A 5.4% five-year survival benefit was observed in a meta-analysis of five randomized trials compared to observation. Not surprisingly, the survival benefit varied according to stage but the benefit was most pronounced for patients with stage II and IIIA disease. Survival benefit in patients with stage IB disease did not reach statistical significance. Importantly, patients with stage IA disease appeared to do worse with adjuvant chemotherapy, and therefore, is not currently recommended.

Adjuvant radiotherapy. The PORT meta-analysis of 2,128 patients demonstrated that the use of post-operative radiotherapy was associated with a detrimental effect on survival (15,16). The decrease in survival was more pronounced for patients with lower nodal status. The PORT meta-analysis has been criticized for its long enrolment period and use of different types of machines, techniques and radiation doses. Despite these criticisms, three randomized phase III trials support the PORT meta-analysis’ conclusion that the use of post-operative radiotherapy provides no survival benefit (17-19). For patients with N2-positive disease, however, a retrospective analysis demonstrated higher survival for those patients who had received post-operative radiotherapy (20). On the basis of the above studies, most do not recommend routine post-operative radiotherapy with the possible exception of those with N2 disease.

Locally Advanced Disease

About a third of patients with NSCLC present with disease that remains localized to the thorax but may be too extensive for surgical treatment (stage III) (21). Concurrent chemotherapy and radiation therapy is considered the standard therapy for this situation but results in only a modest, although statistically significant, survival benefit compared with sequential administration (21). However, significant toxicity results from this approach and so it is usually offered only to those with good performance status.

Surgery after chemotherapy in patients with N2 disease was tested in two randomized trials. A European trial used three cycles of cisplatin-based chemotherapy, then randomized the patients to surgery or sequential thoracic radiotherapy (22). There was no significant difference in overall survival or progression-free survival. An American trial used a slightly different protocol (23). Patients with N2 disease were given two cycles with concurrent radiotherapy and then randomized to further radiation or surgery. This trial showed a better progression free survival with surgery but no difference in overall survival.

Metastatic Disease

About 40% of patients with NSCLC present with advanced stage IV disease. Until recently, cytotoxic chemotherapy was the cornerstone of treatment for stage IV disease but is now recommended as first line therapy alone only for patients with low or no expression of markers for targeted therapy (24). Unfortunately, in stage IV NSCLC standard cytotoxic chemotherapy alone is minimally effective. A meta-analysis that included 16 randomized trials with 2,714 patients demonstrated that cytotoxic chemotherapy offers an overall survival advantage of only 9% at 12 months compared with supportive care (25). Two-drug chemotherapy (doublets) appears to be superior to either a single agent or three-drug combinations (26). Cisplatin-based doublets are associated with a marginal one-year survival benefit compared with platinum-free regimens (27). Platinum-free regimens can be given as an alternative especially in patients who cannot tolerate platinum-based treatment (24). Although gemcitabine, vinorelbine, paclitaxel or pemetrexed are often added to either cisplatin or carboplatin, the choice of the second drug does not appear to matter in increasing survival (28).

Targeted Therapies

Starting in the early 2000s, NSCLC subtypes have evolved from being histologically described to molecularly defined. The use of targeted therapies in lung cancer based on molecular markers is a very rapidly changing field. At the time this article was being written (February 2018) the information was current but recommended therapies are likely to change with development of new therapies and research. It is important to point out that despite these advances, there remains no cure for stable IV NSCLC. Table 2 represents a summary of targets and targeted therapy along with the American Society of Clinical Oncology (ASCO) recommendations for stage IV NSCLC as of February 2018 (24).

Table 2. Targets and targeted therapies for NSCLC (24).

*Currently not recommended for clinical use by ASCO.

The need for adequate tissue to perform molecular studies creates challenges for pulmonologists doing bronchoscopic procedures. Whereas it was previously adequate to obtain diagnostic material. However, it is now important to obtain adequate tissue to perform additional molecular testing to allow determination of whether targeted therapies are appropriate. Sometimes tissue is inadequate which might necessitate a second procedure if clinically warranted.  

Vascular Growth Factors

Epidermal Growth Factor Receptor (EGFR). The EGFR pathway represents the pioneer of personalized medicine in lung cancer. EGFR is a transmembrane receptor that is highly expressed by some NSCLCs. Binding of ligands (epidermal growth factor, tumor growth factor-alpha, betacellulin, epiregulin or amphiregullin) to the extracellular EGFR domain results in autophosphorylation through tyrosine kinase activity (29). This initiates an intracellular signal transduction cascade that affects cell proliferation, motility and survival (29). Inhibition of ligand and EGFR binding or the activation of tyrosine kinases inhibit the downstream pathways resulting in inhibition of cancer cell growth (29).

Initial studies showed that most patients with NSCLC had no response to the tyrosine kinase inhibitor (TKI), gefitinib, which targets phosphorylation of EGFR (30). However, about 10 percent of patients had a rapid and often dramatic clinical response (30). An explanation for these results occurred with the identification of mutations of the tyrosine kinase coding domain (exons 18–21) of the EGFR gene. Subsequent research linked these mutations to the clinical response to gefitinib (31,32). Although about 10% of Caucasian NSCLC have these mutations, the mutations were observed more commonly in Asian patients, particularly non-smoking women (33). There is now overwhelming and consistent evidence from multiple trials that all the approved EGFR-TKIs (gefitinib, erlotinib, or afatinib) have greater activity than platinum-based chemotherapy as the first-line treatment of patients with advanced NSCLC with activating EGFR mutations (24).  These agents have more favorable toxicity profiles than platinum-based chemotherapy and have demonstrated improvements in quality of life. The choice of which EGFR-TKI to recommend to patients should be based on the availability and toxicity of the individual therapy. Randomized clinical trials are ongoing comparing EGFR-TKIs. The results of these trials may help refine this in the future.

Despite high tumor response rates with first-line EGFR-TKIs, NSCLC progresses in a majority of patients after 9 to 13 months of treatment. At the time of progression, approximately 60% of patients (regardless of race or ethnic background) are found to have a Thr790Met point mutation (T790M) in the gene encoding EGFR (34). The presence of the T790M variant reduces binding of first-generation EGFR-TKIs to the leading to disease progression (34). Osimertinib is an irreversible EGFR-TKI that can bind to EGFR despite the T790M resistance mutations and has recently become clinically available (35). Currently it is recommended for T790M mutations that occur after the first-line EGFR-TKIs have failed (24).

Cetuximab is a monoclonal antibody directed against EGFR itself. In the past, addition of cetuximab to cisplatin doublet chemotherapy in EGFR positive tumors was usual. However, cetuximab has recently been shown to shorten progression free survival with some adverse effects and is no longer recommended (24).

Vascular endothelial growth factor (VEGF). Angiogenesis, the formation of new blood vessels, is a fundamental process for the development of solid tumors and the growth of secondary metastatic lesions. Vascular endothelial growth factor (VEGF) acts to promote normal and tumor angiogenesis. Bevacizumab, a recombinant, humanized, monoclonal antibody against VEGF, was previously recommended as first-line therapy in stage IV NSCLC patients without a contraindication. However, the most recent ASCO guidelines finds insufficient evidence to recommend bevacizumab in combination with chemotherapy as first-line treatment (24).

Other Kinase Inhibitors. Receptor tyrosine kinase 1 (ROS1) and the structurally similar anaplastic lymphoma kinase (ALK) are enzymes that are critical regulators of normal cellular activity. In NSCLC rearrangements of these genes can cause them to act as oncogenes, or genes that transform normal cells into cancer cells. Rearrangements in the ROS1 or ALK genes are found in a small percentage of patients with NSCLC. Crizotinib is a molecule that blocks both the ROS1 and ALK proteins. Crizotinib reduced tumor size in ALK+ or ROS1+ positive patients although the most recent ASCO guidelines consider the evidence only moderate with ALK+ and weak with ROS1+ patients (24,36-8).

Checkpoint Inhibitors. An important part of the immune system is its ability to tell the difference between normal cells and those that are “foreign”. To do this, it uses “checkpoints”, molecules on certain immune cells that need to be activated (or inactivated) to start an immune response (39). NSCLC can use these checkpoints to avoid being attacked by the immune system. Programmed cell death protein 1 (PD-1) is a checkpoint protein on T cells. It normally acts as an “off switch” when it attaches to programmed death-ligand 1 (PD-L1), a protein on some normal (and cancer) cells. Some NSCLCs have large amounts of PD-L1, which helps them evade immune attack. Monoclonal antibodies that target either PD-1 or PD-L1 can block this binding and boost the immune response against NSCLC cells. In patients with NSCLC with >50% of their tumor cells PD-1+ (tumor proportion score >50%), pembrolizumab, a monoclonal antibody against PD-1, significantly prolonged progression-free and overall survival compared to platinum-based chemotherapy (40). Based on this trial, pembrolizumab is now recommended by ASCO for patients with a tumor proportion score >50% for PD-1 (23). A number of other PD-1 (e.g., nibolumab) and PD-L1 inhibitors (e.g., atezolizumab, avelumab, durvalumab) exist but ASCO recommends only pembrolizumab at this time (39,40). As more of these checkpoint inhibitors are developed and tested this will likely change.

Second and Third-Line NSCLC Therapy

Second and third-line therapy for NSCLC is beyond the scope of this brief review. It is a rapidly evolving field which should include close collaboration between the pulmonologist, oncologist and other members of the patient’s NSCLC treatment team.

After an initial response, lung cancers can become resistant to therapy. One example mentioned above is the development of the T790M mutation in EGFR+ NSCLC.  In selected instances rebiopsy of the primary tumor or metastases can direct a new, effective therapy. Obviously, it is not possible to rebiopsy every NSCLC patient after failure of the initial therapy. However, other techniques are being investigated. One is liquid biopsy where blood is drawn and subjected to molecular techniques to determine a possible cause for tumor resistance.  Multiple liquid biopsy molecular methods are presently being examined to determine their efficacy as surrogates to the tumor tissue biopsy (41).

Future Directions

The combination of a variety of existing therapies for NSCLC is being evaluated. These will likely yield revised recommendations for therapy. In addition, a variety of therapies, both existing for other cancers, or newer therapies in development are being tested.  These include both monoclonal antibodies and biologic inhibitors (Table 3).

Table 3. Potential new targeted therapies for NSCLC (42,43).

The numbers of pathways and drugs being tested is very impressive and the clinical responses can be dramatic in some patients. One might be tempted to conclude that these therapies might result in a “cure” for NSCLC. However, most of these mutations occur in a small minority of NSCLCs. Furthermore, even if initially successful, resistance to targeted therapies may quickly develop limiting their clinical usefulness in NSCLC.

Targeted therapies may also have potential as adjuvant therapies. In support of this concept, a recent phase 3 study compared durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy (44). The progression-free survival was 16.8 months with durvalumab versus 5.6 months with placebo (p<0.001). It seems likely that more trials using targeted therapy earlier in cancer therapy will be done.

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Cite as: Robbins RA, Kummet TD. First-line therapy for non-small cell lung cancer including targeted therapy: A brief review. Southwest J Pulm Crit Care. 2018;16(3):157-67. doi: https://doi.org/10.13175/swjpcc038-18 PDF 

Necrotizing Pneumonia: Diagnosis and Treatment Options

Brian D. Skidmore, BS¹ and Veronica A. Arteaga, MD²

¹College of Medicine and ²Department of Medical Imaging

Banner-University Medical Center

University of Arizona

Tucson, AZ USA

Abstract

We present the case of a patient who was initially diagnosed with community-acquired pneumonia that was later discovered to have necrotizing changes. The case illustrates the challenges in diagnosing necrotizing pneumonia and the preferred treatment methods.

Case Presentation

History of Present Illness

The patient is a 51-year old woman who presents with right upper lobe pneumonia and a failed outpatient regimen of levofloxacin. She returned one week after being seen in the emergency department with worsening dyspnea, productive cough, and fever in addition to new symptoms of right chest pain and post-tussive emesis. The chest pain is stabbing in quality and constantly present. She denied any calf pain/swelling, previous history of deep venous thrombosis, or long trips or travels.

Physical Exam

Upon admission, blood pressure was 103/56 with a pulse of 114 and respiratory rate of 18. Her temperature was 38.1 °C (100.5 °F) but spiked at 39.5 °C (103.1 °F) and her SpO₂ was 94.0% on room air. Her breathing was unlabored and her lungs were clear to auscultation bilaterally except for crackles in the right upper lung field. The remainder of the exam was unremarkable.

Laboratory and Imaging

A chest radiograph was initially obtained and showed a right upper lobe consolidation consistent with community-acquired pneumonia (Figure 1).

Figure 1. Chest radiograph showing right upper lobe consolidation with possible volume loss.

One week later, a contrast-enhanced chest CT was performed and revealed a heterogeneously enhancing right upper lobe consolidation with cavitation and foci of air diagnostic of necrotizing pneumonia (Figure 2).

Figure 2. Contrast-enhanced chest CT showing right upper lobe pneumonic consolidation with peripheral enhancement, central necrosis, and small foci of air.

Laboratory studies revealed a markedly elevated C-reactive protein of 16.61 mg/dL and a white blood cell count of 18,000 cells/ μL. In addition, the red blood cell count, hemoglobin, and hematocrit were all reduced with values of 3,390,000 cells/ μL, 10.0 g/dL, and 31.0% respectively.

Hospital Course

A chest CT was ordered and the patient was diagnosed with necrotizing pneumonia. She was given IV vancomycin and piperacillin-tazobactam as empiric therapy. Tylenol was administered for fever management and steroids were deferred because her CURB-65 score for pneumonia severity was 0.

Attention was then given to identifying the infectious agent. Blood and respiratory cultures were obtained and a TB test was ordered. The cultures showed no growth and the TB test was negative. A bronchoalveolar lavage showed a highly neutrophilic cell count, however no pathogen was ever identified.

Given improvement with empiric therapy, during her hospital course she was discharged on oral amoxicillin and clavulanate until follow up with pulmonary in outpatient 6 weeks later. Imaging at that time showed post inflammatory changes and no evidence of infection.

Discussion

Necrotizing pneumonia is a rare complication of bacterial lung infections affecting 4% of all patients with community-acquired pneumonia (1). The infection can be patchy, segmental, or involve the entire lung. While the pathogenesis of necrotizing pneumonia is not clearly defined, most studies indicate that it is either an inflammatory response to toxins produced by the pathogen or it is the result of associated vasculitis and venous thrombosis. Patients typically present with common symptoms of pneumonia such as fever, cough, shortness of breath, and chest pain but can also rapidly develop hemoptysis, septic shock, and respiratory failure as the necrosis progresses (2). Because necrotizing pneumonia is associated with increased morbidity and mortality, it is important to distinguish it from non-necrotizing cases (3).

The diagnosis of necrotizing pneumonia may be difficult to make because of its similar presentation to non-necrotizing pneumonias and the limitations of standard chest radiographs. Chest radiographs may show an area of consolidation but are limited in identifying the extent of parenchymal disease (Figure 1) (2). Therefore, contrast-enhanced chest CT is an optimal exam for diagnosing necrotizing pneumonia. Disease may first appear as an in-homogeneously enhancing consolidation with focal areas of low attenuation (Figure 2).  Foci of air may subsequently develop in these areas of hypo-enhancing necrotic tissue indicating cavitation (4).

Laboratory studies may also be helpful in diagnosing necrotizing pneumonia. When compared to pneumonias without a necrotizing component, patients with necrotizing pneumonia show more elevated white blood cell counts and inflammatory markers (1). In one study, patients with necrotizing pneumonia had an average WBC count of 14,970/μL, an average ESR of 70 mm/h, and an average CRP of 18.8 mg/dL. Average values for patients with non-necrotizing pneumonia were significantly lower at 10,130/μL, 48 mm/h, and 11.4 mg/dL respectively (p<0.001) (3). These changes are also evident in the presented case with elevated WBC and CRP values of 18,000/μL and 16.61 mg/dL.

Necrotizing pneumonia is initially treated with intravenously administered broad-spectrum antibiotics that should target pathogens that commonly cause necrotizing changes. The most common microbes are Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae, however several other bacteria species may also cause necrosis (Table 1) (2).

Transition to oral antibiotics may be considered for patients that show improvement (1). A more focused treatment plan should be initiated once a specific pathogen is identified, however this is only accomplished in approximately 26% of cases (3).

Surgical resection may also be considered for patients who show no progress on antibiotic therapy and continue to decline. However the optimal timing and indications for surgery are not clearly defined. The extent of the resection should always be as conservative as possible and commonly involves debridement or segmentectomy of the damaged tissue. In cases where the parenchyma is extensively affected, lobectomy or pneumonectomy may be required (2).

References

1. Nicolaou EV, Bartlett AH. Necrotizing pneumonia. Pediatr Ann. 2017;1;46(2):e65-e68. [CrossRef] [PubMed]
2. Tsai YF, Ku YH. Necrotizing pneumonia: a rare complication of pneumonia requiring special consideration. Curr Opin Pulm Med. 2012;18(3):246-52. [CrossRef] [PubMed]
3. Seo H, Cha SI, Shin KM, et al. Clinical relevance of necrotizing change in patients with community-acquired pneumonia. Respirology. 2017;22(3):551-8. [CrossRef] [PubMed]
4. Walker CM, Abbott GF, Greene RE, Shepard JO, Vummidi D, Digumarthy SR. Imaging Pulmonary Infection: Classic Signs and Patterns. AJR Am J Roentgenol. 2014;202(3) 479-92. [CrossRef] [PubMed]

Cite as: Skidmore BD, Arteaga VA. Necrotizing pneumonia: diagnosis and treatment options. Southwest J Pulm Crit Care. 2017;15(6):274-7. doi: https://doi.org/10.13175/swjpcc137-17 PDF

Valley Fever (Coccidioidomycosis): Tutorial for Primary Care Professionals

John N. Galgiani, MD

Valley Fever Center For Excellence

The University of Arizona

Tucson, AZ

Preface

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

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

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

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

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

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

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

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

Overview  of Coccidioidomycosis

History

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

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

Table 1. Valley Fever at a Glance

Mycology

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

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

Figure 1. The life cycle of Coccidioides spp.

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

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

Epidemiology

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

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

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

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

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

Spectrum of Disease

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

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

Table 2. Spectrum of Coccidioidomycosis

Current Therapies

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

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

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

The Importance of Valley Fever in Primary Care

Case Reporting

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

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

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

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

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

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

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

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

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

Value of Early Diagnosis

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

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

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

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

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

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

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

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

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

Table 4. The Value of Early Diagnosis

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

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

Primary Care Management of Coccidioidomycosis

Overview

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

Spectrum of Clinical Manifestations of Valley Fever

Consider the Diagnosis

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

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

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

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

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

Table 5. The Clinical Manifestations of Valley Fever

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

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

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

Selecting Patients for Evaluation

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

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

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

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

Order the Right Tests

Detection of Anticoccidioidal Antibodies in Serum: Serologic Tests

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

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

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

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

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

Tube Precipitin (TP) Antibodies

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

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

Complement Fixing (CF) Antibodies

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

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

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

Immunodiffusion Tests (IDTP, IDCF)

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

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

Enzyme-linked Immunoassays (EIA)

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

Latex Tests

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

Cultures for Coccidioides spp. 

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

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

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

Handling of Specimens

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

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

Laboratory Evaluation

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

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

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

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

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

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

Skin Testing

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

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

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

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

Check for Risk Factors

The First Step Postdiagnosis

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

Immunosuppression

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

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

Diabetes Mellitus

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

Pregnancy

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

Other Risk Factors

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

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

Check for Progressive Pulmonary Syndromes or Disseminated Disease

Assessing Complications

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

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

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

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

Persistent or Slowly Resolving Pneumonia

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

Pulmonary Cavitation

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

Chronic Fibrocavitary Pneumonia

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

Diffuse Fulminant Pneumonia

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

Extrapulmonary Dissemination

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

Initiate Management

Strategies for Uncomplicated Early Infections

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

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

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

Figure 4. Managing uncomplicated coccidioidomycosis.

Health Education and Recommendations to the Patient and Family

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

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

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

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

Frequency of Follow-Up Health Care Visits

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

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

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

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

Monitoring the Course of Infection

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

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

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

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

Table 7. Suggested Plan for Follow-up Visits.

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

Antifungal Therapy

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

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

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

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

Physical Therapy Reconditioning As an Approach to Persistent Fatigue

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

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

Conclusion

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

References

1. Tsang CA, Anderson SM, Imholte SB, et al. Enhanced surveillance of coccidioidomycosis, Arizona, USA, 2007-2008. Emerg Infect Dis. 2010;16(11):1738-44. [CrossRef] [PubMed]
2. Chang DC, Anderson S, Wannemuehler K, et al. Testing for coccidioidomycosis among patients with community-acquired pneumonia. Emerg Infect Dis. 2008;14(7):1053-9. [CrossRef] [PubMed]
3. Valdivia L, Nix D, Wright M, et al. Coccidioidomycosis as a common cause of community- acquired pneumonia. Emerg Infect Dis. 2006;12(6):958-62. [CrossRef] [PubMed]
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5. Yozwiak ML, Lundergan LL, Kerrick SS, Galgiani JN. Symptoms and routine laboratory abnormalities associated with coccidioidomycosis. West J Med. 1988;149(4):419-21. [PubMed]
6. Wieden MA, Lundergan LL, Blum J, et al. Detection of coccidioidal antibodies by 33-kDa spherule antigen, Coccidioides EIA, and standard serologic tests in sera from patients evaluated for coccidioidomycosis. J Infect Dis. 1996;173(5):1273-7. [CrossRef] [PubMed]
7. Kuberski T, Herrig J, Pappagianis D. False-positive IgM serology in coccidioidomycosis. J Clin Microbiol. 2010;48(6):2047-9. [CrossRef] [PubMed]
8. Blair JE, Currier JT. Significance of isolated positive IgM serologic results by enzyme immunoassay for coccidioidomycosis. Mycopathologia. 2008;166(2):77-82. [CrossRef] [PubMed]
9. Santelli AC, Blair JE, Roust LR. Coccidioidomycosis in patients with diabetes mellitus. Am J Med. 2006;119(11):964-9. [CrossRef] [PubMed]
10. Blair JE, Mayer AP, Currier J, Files JA, Wu Q. Coccidioidomycosis in elderly persons. Clin Infect Dis. 2008;47(12):1513-8. [CrossRef] [PubMed]
11. Ampel NM, Giblin A, Mourani JP, Galgiani JN. Factors and outcomes associated with the decision to treat primary pulmonary coccidioidomycosis. Clin Infect Dis. 2009;48(2):172-8. [CrossRef] [PubMed]
12. Blair JE, Chang YH, Cheng MR, et al. Characteristics of patients with mild to moderate primary pulmonary coccidioidomycosis. Emerg Infect Dis. 2014;20(6):983-990. [CrossRef] [PubMed]
13. Galgiani JN, Ampel NM, Blair JE, et al.; Infectious Diseases Society of America. Coccidioidomycosis. Clin Infect Dis. 2005;41(9):1217-23. [CrossRef] [PubMed]
14. Kerrick SS, Lundergan LL, Galgiani JN. Coccidioidomycosis at a university health service. Am Rev Respir Dis. 1985;131(1):100-2. [PubMed]

Additional Selected References

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

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

Common Mistakes in Managing Pulmonary Coccidioidomycosis

 John N. Galgiani MD¹

Kenneth Knox MD^1,2

Craig Rundbaken DO³

John Siever MD⁴

¹Valley Fever Center for Excellence and ²Arizona Respiratory Center

University of Arizona College of Medicine, Tucson, Arizona;

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

And

⁴Arizona Pulmonary Specialists, Phoenix, Arizona

Abstract

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

Introduction

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The consequences of coccidioidal pneumonia: Their management and mismanagement.

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

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

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

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

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

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

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

New advocacy for improving the care of patients with coccidioidomycosis.

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

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

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