How Does Genetics Influence Valley Fever? Research Underway Now To Answer This Question

John N. Galgiani, MD

Valley Fever Center for Excellence

The University of Arizona Colleges of Medicine

Tucson and Phoenix, Arizona

Introduction

Of the roughly 150,000 new infections of coccidioidomycosis (Valley Fever) that occur each year, there is an enormous range of severity and outcomes. As depicted in Figure 1, approximately a third seek medical attention because of a significant illness and even fewer of these are accurately diagnosed and reported to state officials (1).

Figure 1. Severity and outcomes of coccidioidomycosis (Valley Fever).

The community-acquired pneumonia syndrome that most symptomatic patients experience often takes many weeks to many months to completely resolve and is anything but trivial (2). Even so, for most patients, the illness is eventually self-limited whether treated or not.

In contrast, a relatively small proportion of all infections result in the spread through the blood stream beyond the lungs (extrathoracic dissemination) to produce progressive tissue destruction in skin, bones, joints, the central nervous system, and almost any other part of the body. As a result, about 160 persons die of Valley Fever each year (3).  What accounts for this striking spectrum of disease has been the subject of speculation for decades. Now two research programs have been initiated to try to answer this question.

Genetic Differences Among Persons Is The Prime Suspect

For many infectious diseases, the size of the microbial inoculum determines whether disease will result. Indeed, there are very good examples of this when the exposure to coccidioidal spores is very high. For example, when archeologists or construction projects involve soil rich in spores of Coccidioides spp., infection rates are higher and symptomatic illness is more common than found in the general population within endemic regions (4-6).  However, in such clusters, there is little or no evidence that high inoculum is more likely to result in extrathoracic dissemination.

Another possible source of differences in disease severity could be due to differences among strains of Coccidioides spp. While this cannot be entirely ruled out, the evidence that exists is not supportive. For example, in the clusters of infections cited above where likely most infections came from genetically similar spores, there is still a wide spectrum of illness. Similarly, in laboratory accidents where all persons are definitely exposed to the same strain, there are also diverse clinical manifestations (7).

In contrast to inoculum and fungal virulence, several lines of evidence implicate genetic differences among individuals as a factor responsible for disseminated infection. First and most apparent, normal control of coccidioidal infection is critically dependent on competent cellular immunity. When this is severely compromised either by an underlying disease such as AIDS (8, 9) or by immunosuppression for organ transplantation or treatment of autoimmune disorders (10-12), coccidioidal infections are very much more likely to result in extrathoracic dissemination. That broad immunosuppression is a major risk factor for disseminated Valley Fever opens up the possibility that more subtle differences in the immune response to coccidioidal infection could account for differences in disease severity. 

Secondly, men are much more likely to develop disseminated coccidioidal infection than women. Evidence for this comes from the enrollment statistics for clinical trials conducted by the Mycoses Study Group for patients with disseminated coccidioidal infection where between 1988 and 2007 three-quarters of 367 subjects were male (13-17).  Similar results are apparent in other reports as well (18-20). 

Thirdly, at least one specific genetic marker, that of B and AB blood groups, has been associated with disseminated infection (19, 21). This is not likely to be a causal relationship but does clearly suggest a genetic component.

Finally, numerous studies have implicated increased risk of certain ethnic groups for disseminated infection, most notably those of African and Filipino ancestry (22). Estimates of how much more susceptible African-Americans are to developing disseminated disease range as high as 41.9 times more than Caucasians (Table 1).

An Arizona Department of Health Services presentation in 2011 based upon chart review of reported cases found dissemination in Blacks was 25% compared to 6% in Whites, roughly a four-fold increase in incidence of dissemination. The denominator for these statistics was all cases reported to the state and therefore avoid referral bias and some other confounding factors in earlier studies.

Despite all of these associations suggesting a genetic component to a risk for disseminated infection, there have been essentially no observations as to which specific genes are involved and how genetic differences affect disease susceptibility. Dr. Stephen Holland, a physician scientist and his colleagues at the National Institutes for Health have recently identified in a small number of patients specific gene mutations which appear responsible for more severe infections. The mutated genes were the interferon-gamma receptor 1 (28), the interleukin-12 receptor beta (29), and STAT1 (30). 

As important as these findings are, all of the patients described in these reports are not typical of most patients who experience disseminated coccidioidomycosis. The patient with the interferon-gamma receptor 1 deficiency had two other opportunistic mycobacterial infections at other times in his life, and multiple opportunistic infections are not typical for patients with disseminated Valley Fever. The patients with the interleukin-12 beta deficiency were siblings from a consanguineous family. Disseminated coccidioidomycosis is very uncommon in multiple members of the same family. The two patients with the STAT1 mutation had a clinical presentation that included disseminated infection but also included a consumptive pulmonary process that was strikingly devoid of cavitation. However, Dr. Holland has identified additional patients who appear to have functional immunologic deficits, even thought he and his team were unable to determine the genetic basis for those altered responses (31). 

Two Studies Now Underway Involving Arizonans To Better Understand The Genetics Of Disseminated Valley Fever

Encouraged by his recent findings, Dr. Holland has written a clinical research protocol specifically addressing patients with disseminated coccidioidomycosis. The program, entitled “The Pathogenesis and Genetics of Disseminated Coccidioidomycosis,” is open to any person over the age of 2 years who has culture or histologic proof of disseminated Valley Fever. Persons who have an already identified immunosuppressing condition or who have a medical or psychiatric condition that would interfere with providing informed consent would not be appropriate for this study. If informed consent is given, subjects will initially have blood specimens collected locally for shipment to the NIH. Then, depending upon initial results, subjects may be invited to visit the NIH for additional testing. After the initial visit, study related expenses, including travel and treatment of the disseminated Valley Fever infection, will be paid by the NIH (initial travel expenses may be covered for indigent subjects). Dr. Holland’s study is open to patients throughout the United States. However, for those close enough to down town Phoenix, it will be possible to have the initial blood and urine specimens obtained and shipment arranged by the NIH laboratory located on the Indian Health Hospital campus.  This protocol was initiated in the fall of 2014 and is currently active.

A second research initiative is investigating the increased susceptibility of those with African ancestry. Despite the findings shown in Table 1 above, an underlying problem with all estimates of increased frequency of disseminated coccidioidomycosis in African-Americans is that the relation of self-identified race/ethnicity (SIRE) is a poor surrogate for ancestral genetic origins. Genetic heterogeneity within each racial and ethnic grouping may bias associations in genetic association studies, generating both false-positive and false-negative results (32-36). Variations in the distribution of single nucleotides polymorphisms (SNPs), called ancestry informative markers (AIMs), have been found which describe the architecture of genome variations between populations (37). This discovery has led to an approach which circumvents the genetic ambiguity of SIRE categorizations.  One of the benefits of AIMs is that relatively few markers are required (about 1,500 AIMs for African-Americans) to effectively screen the entire genome. As such, we expect it to identify large chromosomal regions of differential ethnic ancestry in clinical samples. 

For this second study, anyone who is self-declared of African ancestry who has laboratory confirmed coccidioidal infection is eligible. For those who have not experienced disseminated infection, an adequate length of time off antifungal therapy is necessary (nominally two years (38)) to determine if disseminated infection is not likely to occur. Consenting subjects will be asked for a sample of saliva for genetic testing. They may also be asked for a blood specimen in the future for laboratory studies of their leukocyte response to coccidioidal antigens. Collaborators for this study are in both Phoenix and in Tucson.

Any Arizona clinician interested in referring a patient for potential inclusion in either study can contact the Valley Fever Center for Excellence at the Arizona Health Sciences Center in Tucson or the Valley Fever Center in Phoenix located at St. Joseph’s Hospital and Medical Center at their respective phone or FAX contact numbers:

Summary

After decades of interest and speculation about what possible genetic influences are involved in determining the severity of Valley Fever infections, there are now two separate studies underway to address this question, each taking a different and complementary approach. At the very least, such information would be valuable for risk stratification, either for persons wanting that information before travelling to the coccidioidal endemic area or early in the course of a new coccidioidal infection. However, depending upon the success of this research, understanding the genetics could possibly suggest new therapeutic options. Most helped by this work will be Arizonans where two-thirds of all Valley Fever infections in the United States occur.

References

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16. Galgiani JN, Catanzaro A, Cloud GA, Johnson RH, Williams PL, Mirels LF, et al. Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group. Ann Intern Med. 2000;133(9):676-86. [CrossRef] [PubMed]
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30. Sampaio EP, Hsu AP, Pechacek J, Bax HI, Dias DL, Paulson ML, et al. Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol. 2013;131(6):1624-34. [CrossRef] [PubMed]
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32. Bonilla C, Boxill LA, Donald SA, Williams T, Sylvester N, Parra EJ, et al. The 8818G allele of the agouti signaling protein (ASIP) gene is ancestral and is associated with darker skin color in African Americans. Hum Genet. 2005;116(5):402-6. [CrossRef] [PubMed]
33. Caulfield T, Fullerton SM, Ali-Khan SE, Arbour L, Burchard EG, Cooper RS, et al. Race and ancestry in biomedical research: exploring the challenges. Genome Med. 2009;1(1):8. [CrossRef] [PubMed]
34. Choudhry S, Coyle NE, Tang H, Salari K, Lind D, Clark SL, et al. Population stratification confounds genetic association studies among Latinos. Hum Genet. 2006;118(5):652-64. [CrossRef] [PubMed]
35. Shriver MD, Parra EJ, Dios S, Bonilla C, Norton H, Jovel C, et al. Skin pigmentation, biogeographical ancestry and admixture mapping. Human Genet. 2003;112(4):387-99. [PubMed]
36. Tsai HJ, Choudhry S, Naqvi M, Rodriguez-Cintron W, Burchard EG, Ziv E. Comparison of three methods to estimate genetic ancestry and control for stratification in genetic association studies among admixed populations. Hum Genet. 2005;118(3-4):424-33. [CrossRef] [PubMed]
37. Kittles RA, Weiss KM. Race, ancestry, and genes: implications for defining disease risk. Annu Rev Genomics Hum Genet. 2003;4:33-67. [Pubmed]
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Reference as: Galgiani JN. How does genetics influence valley fever? research underway now to answer this question. Southwest J Pulm Crit Care. 2014;9(4):230-7. doi: http://dx.doi.org/10.13175/swjpcc137-14 PDF

October 2014 Pulmonary Case of the Month: A Big Clot

G. Zacharia Reagle DO

Eyad Almasri MD

Stuart J. Maxwell MD

Departments of Internal Medicine, Division of

Pulmonary and Critical Care

and Emergency Medicine

UCSF Fresno

Fresno, CA

History of Present Illness:

A 63 year-old man was brought to the emergency department (ED) with a report of acute onset of dyspnea. The dyspnea had started at rest less than one hour prior to ED presentation. It quickly progressed to severe respiratory distress. His initial vital signs were recorded as a BP of 124/69, pulse of 112, respiratory rate of 26 with an oxygen saturation (SpO₂) of 88% on 15 liters per minute (lpm) of oxygen via a non-rebreather mask. He was placed on non-invasive ventilation with intermittent episodes of brief desaturation into the 60% range. He was subsequently intubated without incident. Immediately following intubation he experienced a pulseless electrical activity (PEA) cardiopulmonary arrest.

Past Medical History:

• Diabetes mellitus
• Coronary Artery Disease
• Hypertension
• Deep Venous Thrombosis

Past Surgical History:

• Coronary Artery Bypass Graft – 2 vessel

Medications:

• Atorvastatin 40mg PO daily
• Insulin glargine 10u SQ daily
• Lisinopril 10mg PO daily
• Warfarin – had been stopped due to difficulty with compliance.

Social History:

• Married
• Owns and manages a series of used car lots.
• Lifetime non-smoker
• Reports a remote history of chronic alcohol use, but quit in 2005 when he was diagnosed with coronary artery disease.
• He denied illicit drug use.

Physical Exam:

General: Intubated, on a fentanyl infusion at 50mcg per hour.

Vitals: BP: 122/63 HR: 123 RR: 24 T: 35.6

HEENT: NC/AT, PERRL, neck supple without JVD noted.

Lungs: equal chest expansion was noted with clear lung sounds.

Heart: Tachycardic and regular with a good S1 and S2, no murmurs or             gallops were appreciated.

Abdomen: soft, obese, good bowel sounds.

Extremities: cold to the touch with no edema, or clubbing.

Neurological: Nonfocal exam with suppressed Glasgow Coma Scale after       sedation for intubation.

Skin: No rashes noted.

Laboratory:

Complete Blood Count (CBC): White blood cell count (WBC) 8.8 x 1000 cells/µL, hemoglobin 14.6 g/dL,   hematocrit 43.7, platelets 191,000 cells/µL

Chemistry: Sodium 139 meq/L, potassium 3.6 meq/L, chloride 106 meq/L, bicarbonate (CO2) 19 meq/L, blood urea nitrogen (BUN) 20 mg/dL, creatinine 0.7 mg/dL, glucose 459 mg/dL, magnesium 2.0 meq/L, phosphorus 3.4 mg/dL

Liver Function Tests: Albumin 4.1 g/dL, ALP 59 U/L, AST 30 U/L ALT 31 U/L. total bilirubin 0.4 mg/dL

Coagulation: Prothrombin time 13.9 seconds, INR 1.1, activated partial thromboplastin time (aPTT) 24.2 seconds

Troponin: 0.007 ng/ml

Brain naturetic peptide (BNP): 39 pg/ml

Arterial Blood Gases (ABG): pH 7.27, pCO2 38, pO2 38

Imaging:

The patient was immediately taken for a chest CT pulmonary angiogram. As he was on the CT scan table, the CT technician discovered that his IV line was malfunctioning. Before the line could be replaced, he had several non-contrast chest CT cuts obtained (Figure 1).  

Figure 1. Images A & C are non-contrast cuts while images B & D are comparison cuts that became available after the contrast study was obtained.

How often are intravascular filling defects seen on non-contrast chest CT images and what is the positive predictive value (PPV) of non-contrast images for pulmonary embolism (PE)? (Click on the correct answer to proceed to the next panel)

1. Filling defects are often seen on non-contrast CT images and are diagnostic for pulmonary embolism.
2. Filling defects can be seen on non-contrast images but have a low PPV.
3. Filling defects indicating pulmonary embolism are never seen on non-contrast images.
4. Filling defects indicating pulmonary embolism are sometimes seen on non-contrast images and have a high PPV for PE.

Reference as: Reagle GZ, Almasri E, Maxwell SJ. October 2014 pulmonary case of the month: a big clot. Southwest J Pulm Crit Care. 2014;9(4):199-207. doi: http://dx.doi.org/10.13175/swjpcc118-14 PDF

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

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

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

PMH, FH, SH

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

Physical Examination

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

Spirometry

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

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

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

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

Role of Endobronchial Ultrasound in the Diagnosis and Management of Bronchogenic Cysts: Two Case Descriptions and Literature Review

Rene Franco-Elizondo MD

Soumya Patnaik MD

Kuan-Hsiang Gary Huang MD, PhD

Jorge Mora MD

Albert Einstein Medical Center

Philadelphia, Pennsylvania

Abstract

Imaging studies, such as high resolution computerized tomography (HRCT) and magnetic resonance imaging (MRI) facilitate the evaluation of mediastinal masses. However, the definite characterization of such masses can be ascertained only after tissue sampling is obtained and analyzed. Some mediastinal masses, like bronchogenic cysts, can be misdiagnosed as solid masses or lymphadenopathy in imaging studies, due to the variable densities of the cyst contents. More invasive tests, like fine needle aspiration or surgical resection of the bronchogenic cyst, may be necessary when HRCT fails to provide an initial diagnosis. We describe two such cases seen at our institution that highlight the implications of establishing a diagnosis of bronchogenic cyst with endobronchial ultrasound (EBUS) - trans-bronchial needle aspiration (TBNA) and discuss the possible therapeutic utility of EBUS-TBNA in select patients with bronchogenic cysts.

Abbreviation List

BAL - Bronchoalveolar lavage

CNS - Coagulase-negative Staphylococcus

CT – Computed tomography

EBUS - Endobronchial ultrasound

EUS – Endoscopic ultrasound

FOB - Fiberoptic bronchoscopy

HRCT - High resolution computerized tomography

MRI - Magnetic resonance imaging

RUL – Right upper lobe

TBNA - Trans-bronchial needle aspiration

VATS - Video-assisted thoracoscopic surgery

Introduction

Modern imaging, particularly high-resolution computed tomography (HRCT) and magnetic resonance imaging facilitate the evaluation of mediastinal masses. However, definite characterization is possible only after tissue sampling is obtained, typically through fine-needle aspiration or surgical resection. Herein, we report two cases of patients with mediastinal masses, where HRCT failed to provide a diagnosis. Bronchogenic cysts in both patients were ultimately diagnosed by endobronchial ultrasound (EBUS) and trans-bronchial needle aspiration (TBNA). The implications of establishing a diagnosis of bronchogenic cyst via EBUS-TBNA and therapeutic approaches are discussed.

Case 1

A 68-year-old African American woman with hypertension, diabetes mellitus type 2 and end-stage renal disease, on home hemodialysis, presented to the hospital with central stabbing chest pain, radiating to the back, accompanied by shortness of breath. An initial HRCT chest performed to rule out aortic dissection revealed a large subcarinal mass, measuring 2.3 cm x 6.5 cm x 3.8 cm (AP x transverse x height), that splayed the carina, exerting mass effect on the esophagus, raising suspicion of malignancy (Figure 1).

Figure 1. Subcarinal mass. Density ranged from 25-80 Hounsfield Units.

A separate 2.2 cm x 1.7 cm right paratracheal mass, mediastinal lymphadenopathy and many small prevascular lymph nodes were noted. These clinical and imaging findings were concerning for possible lymphoma.

A fiberoptic bronchoscopy (FOB), followed by blind TBNA of the subcarinal space using a Wang needle was attempted. Both, bronchoalveolar lavage (BAL) and TBNA were unrevealing. The patient was found to have persistent coagulase-negative Staphylococcus (CNS) bacteremia, with the first blood cultures being positive at the time of admission. A thorough evaluation, which included an echocardiogram and abdominal HRCT, failed to reveal a source of bacteremia, which was ultimately thought to be related to hemodialysis. Arrangements for outpatient EBUS evaluation of the mediastinal mass and lymphadenopathy were made and the patient was discharged.

A week later, she was readmitted for hypertensive emergency. EBUS was performed during this hospitalization and a cystic mass with heterogeneous-containing material was detected in the subcarinal space (Figure 2).

Figure 2 EBUS image of bronchogenic cyst and adjacent subcarinal lymph node.

The needle aspirate was sent for histological analysis and culture, but it was not possible to drain this cystic structure. Cytopathologic analysis showed bronchial and ciliated cells with abundant mucoid material and a diagnosis of bronchogenic cyst was made. Interestingly, the cultures from the aspirated material grew CNS. The patient was discharged with plans for a video-assisted thoracoscopic surgery (VATS) resection of the bronchogenic cyst as an outpatient.

Five days later, the patient was readmitted with symptoms that were concerning for sepsis, and was thus re-started on broad-spectrum antibiotics. She was found to have Enterobacter intermedius bacteremia. She subsequently underwent VATS, with direct aspiration of the bronchogenic cyst. A resection was not performed due to technical difficulties encountered during VATS. Purulent fluid was retrieved from the cyst and Enterobacter intermedius was identified upon analysis and culture of the cyst content. The patient had no further episodes of bacteremia after eight months of follow-up.

Case 2

A 43-year-old woman without significant past medical history was referred to our institute, for evaluation of a pretracheal lymph node seen on a chest HRCT (Figure 3) done for evaluation of new onset dyspnea and wheezing. Upon auscultation, a localized wheeze was noted with deep inspiration in the right upper chest. Her physical exam was otherwise unremarkable.

Figure 3. Chest CT showing subcarinal lymphadenopathy and mass. Density of mass 9-95 Hounsfield units.

A bronchoscopic exam with EBUS evaluation of lymphadenopathy was scheduled. On FOB, the patient was found to have an incidental endobronchial mass occluding the anterior segment of the right upper lobe. EBUS exam revealed an enlarged subcarinal lymph node (8 mm) with an adjacent cystic space containing homogenous hypoechoic material (Figure 4).

Figure 4. EBUS of bronchogenic cyst. A) Cyst prior to aspiration. B) Collapsed cystic cavity with enlarged lymph node now visible.

Both the lymph node and cystic space were sampled. Ten mL of serous fluid was aspirated from the cystic space, resulting in obliteration of the cavity, as visualized on the ultrasound (Figure 5).

Figure 5.Serous aspirate from cystic cavity.

Full mediastinal staging was done, and only station 11R lymph nodes were found to be enlarged and were sampled. Endobronchial biopsies, brushings and BAL were obtained from RUL endobronchial lesion. The patient was discharged home on empiric antibiotics (amoxicillin/clavulanate) for aspirated bronchogenic cyst. Subsequent fluid analysis revealed abundant macrophages and lymphocytes, consistent with cystic fluid content. Cultures of the fluid were positive for Streptococcus viridians. Lymph node sampling failed to reveal any evidence of malignancy. Interestingly, endobronchial mass biopsies, brushings and fluid cytology also failed to show evidence of malignancy. Only reactive inflammatory cells and benign bronchial elements were detected. The patient was continued on antibiotics for ten days without any evidence of infection.

A repeat bronchoscopy was performed to re-sample the endobronchial lesion. Benign elements were confirmed on the repeat biopsy. Follow up imaging has not been performed to evaluate fluid re-accumulation, since the patient has remained asymptomatic for two months.

Discussion

Mediastinal bronchogenic cysts are congenital anomalies of tracheobronchial origin; they are believed to be a result of an abnormal budding process during the development of foregut. They are often asymptomatic at presentation but can become symptomatic in 30% to 80% of cases due to infection or other complications like compressive efforts (1).

These cysts, being lined by secretary respiratory epithelium, consist of fluid of water density; however, the amount of proteinous mucus and calcium oxalate crystals in them can vary, affecting the imaging features on CT/MRI. A chest CT may reveal spherical masses with water or soft–tissue attenuation. A chest CT may misdiagnose them as soft-tissue masses in about 43% of patients. High attenuation on a chest CT can be a result of calcium oxalate or protein content, or can be due to infection of the cyst content (2, 3).

Due to the variable density in the cyst’s content, bronchogenic cysts can be misdiagnosed as masses or lymphadenopathy on non-invasive testing, as noted in our patients. EBUS can be of great help in diagnosing these lesions. Ultrasound provides an excellent delineation between tissues of different densities, and the absence of flow with color Doppler allows for differentiation from vascular structures. Ultrasonography allows a better delineation of cystic lesions and characterization of their contents (e.g. hypoechoic, isoechoic, heterogeneous, etc.), thereby providing useful diagnostic information. Needle aspiration of cyst contents can bring about not only cytological confirmation of the diagnosis, but also identification of complications such as infected bronchogenic cysts.

Our cases highlight the usefulness of EBUS in the diagnosis of bronchogenic cysts. In the first case, the diagnosis of bronchogenic cyst was made only after EBUS imaging and content aspiration were obtained, despite the initial chest HRCT specifically done to evaluate this mass. In the second case, EBUS imaging established the diagnosis in the absence of any suggestive findings on the HRCT.

The treatment of choice remains the complete surgical resection of the secreting mucosal lining, particularly in complicated cysts (11, 12). However, some authors have reported cases of successful treatment of bronchogenic cysts with EBUS-guided aspiration (4-8). In one case, a patient was followed up for eighteen months without evidence of recurrence (8). The rationale behind this approach is that complete drainage of the cyst obliterates the cyst cavity and prevents further fluid re-accumulation. In our first case, though complete drainage was not achieved with EBUS due to its thick mucoid content, aspiration of the cyst by VATS resulted in resolution without fluid re-accumulation. In our second case, resolution of the cyst was achieved via EBUS-TBNA drainage. These cases underscore the usefulness of aspiration of bronchogenic cysts as an alternative therapeutic approach to surgery in certain scenarios.

Contrary to the above mentioned cases, other case reports have pointed out life-threatening complications after bronchogenic cyst drainage with EBUS-guided FNA, such as pneumonia (9) or purulent pericardial effusion (10). As mentioned elsewhere, empiric antibiotic therapy should be given when a cystic lesion is drained via EBUS-TBNA (13). It should be noted, however, that in some of these case reports, infection post-EBUS-TBNA occurred despite giving empiric antibiotics (9), as in our first case.

The risk of infection should be underscored, as evidenced by the first case; particularly the less frequently reported possibility of bronchogenic cyst infection from bacteremia. The initial EBUS-TBNA cyst aspirate grew CNS, similarly to the blood cultures that were obtained prior to the blind TBNA sample of the mediastinal lesion. This suggests that the contamination of the cyst content could have been due to seeding from CNS bacteremia. However, the final VATS aspirate of the cyst grew Enterecoccus intermedius, which was likely to have been introduced by the EBUS-TBNA at the time of diagnosis. This infection occurred despite the use of antibiotics before and after the procedure. In this regard, the available literature is scant. In a study conducted by Steinfort et al. (14), incidence of bacteremia after EBUS-TBNA was found to be 7%, comparable to reported incidence of bacteremia from regular FOB. It is important to note that although none of these patients experienced clinical signs of infection, none of the biopsies were taken from cystic structures. Data evaluating EBUS-TBNA of mediastinal cystic lesions is conflicting. In a report of 22 patients undergoing EUS-TBNA of suspected mediastinal cyst and receiving periprocedural antibiotics, no infectious complications were found (15). However, several case reports of serious infectious complications after EBUS-TBNA have also been published (16).

Conclusion

Diagnosis of bronchogenic cysts cannot always be made with commonly used chest-imaging modalities such as X-ray or CT. EBUS has proven to be a useful diagnostic tool in the evaluation of some mediastinal masses. Although surgical resection remains the treatment of choice, complete aspiration, by VATS or EBUS, can be a successful therapeutic alternative in patients who are not candidates for surgery. However, the risks should be carefully assessed in each patient, with particular awareness of potential infectious complications. When this approach is taken, empiric antibiotics are recommended.

References

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8. Casal RF, Jimenez CA, Mehran RJ, Eapen GA, Ost D, Sarkiss M, Morice RC. Infected mediastinal bronchogenic cyst successfully treated by endobronchial ultrasound-guided fine-needle aspiration. Ann Thorac Surg. 2010; 90(4):e52-3. [CrossRef] [PubMed]
9. Hong G, Song J, Lee KJ, Jeon K, Koh WJ, Suh GY, Chung MP, Kim H, Kwon OJ, Um SW. Bronchogenic cyst rupture and pneumonia after endobronchial ultrasound-guided transbronchial needle aspiration: a case report. Tuberc Respir Dis (Seoul). 2013;74(4):177-80. [CrossRef] [PubMed] 
10. Gamrekeli A, Kalweit G, Schäfer H, Huwer H. Infection of a Bronchogenic cyst after ultrasonography-guided fine needle aspiration. Ann Thorac Surg. 2013;95(6):2154-5. [CrossRef] [PubMed]
11. Cioffi U, Bonavina L, De Simone M, Santambrogio L, Pavoni G, Testori A, Peracchia A. Presentation and surgical management of bronchogenic and esophageal duplication cysts in adults. Chest. 1998;113(6):1492-6. [CrossRef] [PubMed] 
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14. Steinfort DP, Johnson DF, Irving L.B. Incidence of bacteraemia following endobronchial ultrasound-guided transbronchial needle aspiration. Eur Respir J. 2010:36(1):28-32. [CrossRef] [PubMed] 
15. Fazel A, Moezardalan K, Varadarajulu S, Draganov P, Eloubeidi MA. The utility and the safety of EUS-guided FNA in the evaluation of duplication cysts.GastrointestEndosc. 2005; 62(4):575-80. [CrossRef] [PubMed]
16. Jenssen C, Alvarez-Sánchez M. V., Napoléon B and Faiss S. Diagnostic endoscopic ultrasonography: assessment of safety and prevention of complications. World J Gastroenterol. 2012;18(34):4659–76. [CrossRef] [PubMed]

Reference as: Franco-Elizondo R, Patnaik S, Huang K-H G, Mora J. Role of endobronchial ultrasound in the diagnosis and management of bronchogenic cysts: two case descriptions and literature review. Southwest J Pulm Crit Care. 2014;9(2):115-22. doi: http://dx.doi.org/10.13175/swjpcc096-14 PDF

Azathioprine Associated Acute Respiratory Distress Syndrome: Case Report and Literature Review

Dmitriy Scherbak, D.O.

Ruth Wyckoff, M.D.

Clement Singarajah, M.D.

Phoenix VA Healthcare System

Phoenix, AZ

Abstract

A 58-year-old Caucasian man treated with azathioprine to prevent rejection of an orthotopic liver transplant, presented to the Carl Hayden VA Medical Center with rapid respiratory decline and appeared septic. He required urgent intubation, mechanical ventilator support and empiric antibiotics. His clinical picture and imaging studies were consistent with acute respiratory distress syndrome; however, extensive infectious work up failed to reveal an offending organism. Review of his current medications implicated azathioprine and upon discontinuation of this agent, the patient made a rapid recovery. He was subsequently extubated, transferred out of the ICU and soon discharged home in good health.

Prescribed for organ transplant rejection and a wide array of autoimmune diseases, azathioprine has been rarely correlated with pneumonitis and rapid respiratory failure. No reported cases were found in which azathioprine was used to treat liver transplant rejection and associated with development of the adult respiratory distress syndrome (ARDS). However, there have been ARDS cases in which azathioprine was used for other purposes. We review all the available cases of azathioprine associated ARDS. The patients in these reports had similar clinical symptoms on presentation as our patient: hypoxia, febrile episodes and rapid development of ARDS with no infectious etiology. Most notable is the rapid resolution of ARDS after discontinuation of azathioprine.

Although azathioprine toxicity related respiratory failure is rare, this correlation should still be considered in the differential for immunosuppressed patients presenting with rapid pulmonary decline. Further studies are needed and warranted to better correlate this connection, but it is imperative to recognize that the relationship exists.

Introduction

Since its first use in 1961, azathioprine (a derivative of 6-mercaptopurine) has been used as a steroid sparing immunosuppressive agent in numerous disorders including prevention of graft rejection for solid organ transplantation (1-2). Azathioprine side effects are commonly gastrointestinal complaints such as nausea and vomiting, occurring in ~19% of patients. Laboratory abnormalities such as leukopenia are also common (17%) with thrombocytopenia and anemia being less common (3-4%) (3). Hepatotoxicity has been reported as well. Pulmonary toxicity is not usually noted as a side effect (1). Sixteen cases have been reported in the literature implicating azathioprine with pulmonary toxicity (1-2, 4-12). In 10 of these cases, the patient developed acute respiratory distress syndrome (ARDS) (1,2,6,8,9,11).

Pulmonary infections have been the leading cause of complications in immunosuppressed recipients of solid organs (13). Therefore, when a patient presents with respiratory distress, an abnormal chest x-ray and fevers, such infections are high on the differential, but the possibility of lung injury resulting from the immunosuppressive agent is often overlooked (1). We present a case of azathioprine induced ARDS in a liver transplant recipient and review the available ARDS cases associated with azathioprine use.

Case Report

We present a 58-year-old white man with a past medical history of end-stage liver disease due to hepatitis C cirrhosis and hepatocellular carcinoma who received an orthotopic liver transplant (OLT) 9 months prior to presentation. He was being treated with azathioprine 150mg daily and tacrolimus 1.5 mg daily to prevent rejection. He presented to the emergency department 9 months after his transplant with shortness of breath and increasing hypoxia. He was admitted to the intensive care unit where he developed respiratory failure that night requiring intubation and ventilator support. He had fevers as high as 105.1⁰F. He had pancytopenia with white blood cell count (WBC) 2.3 thousand cells at presentation, hemoglobin (HGB) 9.8 g/dL and platelets (PLT) 119 thousand cells.

Chest x-ray showed bilateral patchy pulmonary infiltrates. CT of the chest was done as well showing bilateral ground glass opacities and diffuse scattered pulmonary consolidations (Figure 1).

Figure 1. Representative images from chest CT with contrast done on admission showing diffuse ground glass opacities and scattered pulmonary consolidations.

Since he was immunosuppressed he was started on empiric antibiotic coverage with vancomycin, levofloxacin, pipercillin/tazobactam, gancyclovir and fluconazole. Trimethoprim-sulfamethoxazole was added on day 2 of hospitalization. A bronchoscopy with bronchial alveolar lavage (BAL) was done prior to antibiotics. Cell count and differential showed 160 white blood cells, 11% segmented neutrophils and 3% eosinophils, the other 86% of cells were pulmonary macrophages/monocytes and reactive respiratory epithelial cells. No organisms or evidence of malignancy were seen. BAL cultures showed no growth on bacterial, viral, acid fast or mycology cultures. Influenza A and B and a pneumocystis smear were also negative. Blood cultures were taken twice during the patient’s hospitalization during febrile episodes and showed no growth both times in two sets of cultures. On day 6 of hospitalization anti-microbial therapy was discontinued.

The patient’s clinical status continued to deteriorate. Chest x-rays continued to show increasing bilateral pulmonary infiltrates (Figure 2).

Figure 2. Chest x-ray at worst (hospital day 8) showing worsening bilateral pulmonary infiltrates.

The diagnosis of acute respiratory distress syndrome (ARDS) was established. His ventilator settings followed the NHLBI ARDS Network protocol, and on day 6 he was even placed in a prone position. On day 7 of hospitalization his white blood cell count dropped to a nadir of 0.5 thousand cells, hemoglobin dropped to 6.5 g/dL and platelets down to 69 thousand cells). Azathioprine was discontinued due to the pancytopenia and due to finding a few case reports in which it was implicated in ARDS. Within 3 days of azathioprine discontinuation (day 10 of hospitalization), the patient’s chest x-rays and pulmonary function had dramatically improved and he was successfully extubated by the fifth day of azathioprine being withdrawn (day 12 of hospitalization). Daily chest x-rays showed continued resolution of infiltrates (Figure 3).

Figure 3. Chest x-ray from hospital day 15 showing dramatic improvement of infiltrates after azathioprine discontinuation.

He improved rapidly and was discharged from the ICU on day 17 and discharged home from the hospital on day 18 with complete resolution of his pulmonary symptoms. His azathioprine was not restarted but he resumed tacrolimus for immunosuppression. Six months after admission, the patient was in good health with no clinical symptoms.

Discussion

Azathioprine is a nitroimidazole derivative of 6-mercaptopurine (4). It was first used in 1961 and has since become a common medication for treatment of numerous auto-immune disorders and as an immunosuppressant in transplant recipients (1). It has been described to have several reversible dose dependent side effects including bone marrow suppression, hepatotoxicity, anorexia, nausea and vomiting (4). Hypersensitivity reactions have also been described and include fevers, rigors, arthralgia, myalgia, cutaneous reactions, headaches, interstitial nephritis, pancreatitis, dyspnea, cough and pneumonitis (1-4, 6).

In our case the patient developed pneumonitis and ARDS which resolved rapidly after the discontinuation of azathioprine. A review of the literature using broad search terms in OVID, Pub-Med and Google Scholar revealed only 10 articles constituting 16 cases of pulmonary toxicity linked to azathioprine. Detailed analysis showed only 5 reported cases of ARDS linked to azathioprine toxicity (2,6,8,9,11), and a single case series of 7 cases of which 2 also have an infectious etiology (1). Data from these cases are summarized on table 1.

Table 1. Cases of Azathioprine induced ARDS in the literature.

The four remaining articles not appearing in table 1 were excluded because they either represented an immediate hypersensitivity reaction to azathioprine or had infectious pneumonitis which could have contributed to the development of ARDS (4,5,10,12).

Neither our case nor those in the literature contain irrefutable proof that azathioprine was directly responsible for lung injury. However, the similarities between the cases in which the patient survived lead us to conclude that azathioprine is involved in this adverse reaction. First, all 8 cases in which the patient survived show a rapid improvement within one to two weeks after discontinuation of azathioprine. Second, all of these patients present in the same way with hypoxia, pulmonary infiltrates, and fevers. Third, none of the cases show any other possible causes and the ones that go to biopsy have non-specific findings (UIP or diffuse alveolar damage) (1,2,6,7,11). These observations are circumstantial, but the diagnosis of drug-induced pulmonary toxicity is usually based on clinical history of drug exposure and the absence of other known causative agents. Additionally, diffuse interstitial pulmonary disease is the most common form of lung pathology caused by drugs (1,14).

Leukopenia or pancytopenia were present in our case as well as 4 of the 10 reported cases (6,8,9,11). No other side effects from azathioprine were reported in any of the cases. Therefore ARDS is likely a unique effect and unrelated to other potential side effects of azathioprine. The dose of azathioprine was widely variable in the known cases (25-150mg daily) leading us to believe that the development of ARDS is not dose-dependent. All of the cases had patients who had been on azathioprine for months (years in one case) prior to developing pneumonitis or ARDS, leading us to speculate that ARDS is not an acute hypersensitivity. It may be that ARDS development is a function of dose effect over time.

Although there are very few reported cases, It is possible that azathioprine induced lung injury is more common than it appears. When an immunosuppressed patient presents with respiratory distress, some form of infectious etiology is usually involved and the immunosuppressants are often discontinued (1). It is possible that in some of these cases azathioprine itself is the cause or may at least contribute to the development of ARDS. We believe it is important that azathioprine lung toxicity be included in the differential for ARDS causes because prompt discontinuation of azathioprine has led to rapid recovery and good outcome in 8 of the 10 known cases (1,2,6,8,9,11).

Acknowledgments

Sarah Waybright, Pharm.D. and Lindsay Kittler, Pharm.D. The clinical pharmacists who noted case reports of azathioprine causing pulmonary toxicity and recommended it’s discontinuation in our patient.

References

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Reference as: Scherbak D, Wyckoff R, Singarajah C. Azathioprine associated acute respiratory distress syndrome: case report and literature review. Southwest J Pulm Crit Care. 2014;9(2):94-100. doi: http://dx.doi.org/10.13175/swjpcc087-14 PDF