First Report of Splenic Abscesses Due to Coccidioidomycosis

Shabnam Assar, MD^I and Tim Kuberski, MD, FIDSA²

¹Department of Medicine, Virginia Tech Carilion, Roanoke, Virginia USA

²Department of Medicine, University of Arizona School of Medicine-Phoenix,

Phoenix, Arizona USA

Abstract

Involvement of the spleen by Coccidioides is uncommon. It is usually associated only with disseminated infection and manifests as microscopic granulomas in the spleen. We report an immunosuppressed dermatomyositis patient who presented with splenic abscesses demonstrated on a computed tomography (CT) scan which was presumed to be bacterial in origin. At splenectomy the spleen was found to be filled with aggregates of spherules due to Coccidioides. Finding large splenic abscesses on CT scan due to Coccidioides has not been previously described. We offer a hypothesis for why the abscesses occurred in this unique patient.

Introduction

Involvement of the spleen by coccidioidomycosis is usually associated with disseminated disease, however the development of splenic abscesses has not been reported. Splenic involvement by coccidioidomycosis is usually manifest as microscopic miliary splenic granulomas which have been demonstrated at autopsy in patients with disseminated infection (1,2). We report an immunocompromised dermatomyositis patient who was found to have splenic abscesses due to Coccidioides spherules which were diagnosed at splenectomy.

Case Presentation

A 33-year-old Hispanic man with dermatomyositis for five years and a history of disseminated coccidioidomycosis for two years, presented to the emergency room because of left upper quadrant abdominal pain, fever and chills. Treatment of his dermatomyositis was ongoing over the previous five years and included prednisone, azathioprine and courses of intravenous immunoglobulin (IVIG) at doses of 2 g/kg (3). Treatments of his coccidioidomycosis over the previous two years included intravenous liposomal amphotericin B followed by oral fluconazole. The patient would periodically be non-compliant about taking the fluconazole and then experience relapses of his coccidioidomycosis which required additional courses of intravenous liposomal amphotericin B.

Physical Examination and Course: Admission vital signs - temperature 38.4⁰ C; blood pressure 147/81 mmHg; heart rate 106 bpm; respiratory rate 18 breaths/minute and pulse oximetry 90% on room air. There was pigmentation of his face consistent with dermatomyositis, tenderness in the left upper quadrant and significant weakness of all extremities. He was bedridden and could barely move his arms and legs against gravity. His medications on admission were fluconazole and prednisone. An admission CT scan of the abdomen was performed because of the left upper quadrant tenderness and revealed multiple splenic abscesses (Figure 1).

Figure 1. CT scan of abdomen demonstrating splenic abscesses (arrow).

An admission urine culture grew >10⁵ colony forming Klebsiella pneumoniae which was noted on day two of hospitalization. Blood cultures were negative. It was initially believed that the splenic abscesses were due to a Klebsiella infection because of the admitting urine culture results. Prednisone was stopped on admission and the oral fluconazole continued. Piperacillin-tazobactam was started empirically on admission. In addition, IVIG was given for a presumed dermatomyositis exacerbation. On hospital day four his abdominal pain and fevers had not improved. To avoid a splenectomy, a splenic biopsy was performed to determine the cause of the splenic abnormalities. The biopsy was consistent with a Coccidioides infection. A laparoscopic splenectomy was then preformed on hospital day seven.

The pathology on the removed spleen showed multiple necrotizing granulomatous foci containing numerous aggregated Coccidioides spherules (Figure 2).

Figure 2. Pathology of splenic abscesses demonstrating aggregated Coccidioides spherules.

Post-operatively, fluconazole was empirically replaced by voriconazole (4) and the patient was restarted on prednisone for his dermatomyositis. The fever and chills eventually resolved and he was discharged. At four months follow-up he had returned to his usual state and was encouraged to not stop taking the voriconazole.

Discussion 

This patient illustrates an unusual complication of disseminated coccidioidomycosis. Prior to the advent of CT scans, splenic granulomas were described mainly at autopsy in patients with disseminated infection. Splenic involvement at autopsy was described as granulomas due to the invasion of the Coccidioides into the spleen from the blood stream. Usually there was granuloma formation described as microscopic military nodules. Reports of gross Coccidioides abscesses in the spleen have not been described.

We considered the potential reasons for the development of splenic abscesses in this unique patient. His dermatomyositis was present for about five years and the coccidioidomycosis, two years. He had received repeated doses of IVIG for flares of his dermatomyositis prior to, and after, his Coccidioides infection. Investigating his past medical history revealed that he would develop a febrile illness when off fluconazole - usually due to non-compliance. The clinical presentation was consistent with either a relapse of his Coccidioides infection, an exacerbation of his dermatomyositis, or both. The febrile episodes would cause him to be admitted to the hospital, often into the intensive care unit, and then he would receive more IVIG for his dermatomyositis, as well as antifungals. It is known that fungemia occurs in immunosuppressed patients who have significant coccidioidomycosis (5). The fact that he had a large Coccidioides burden in his spleen suggests he likely experienced episodes of fungemia, presumably associated with his poor antifungal compliance.

Our hypothesis for why the abscesses formed in the spleen of this patient is illustrated in Figure 3.

Figure 3. Hypothesis of Coccidioides abscess formation in the spleen.

We theorized that Coccidioides endospores in the blood stream became coated with the gamma globulins when he received the IVIG given for his dermatomyositis (6).  The opsonization of the organisms by the IVIG presumably facilitated the spleen to take up viable endospores into the spleen and reticuloendothelial system (Figure 3, part 3). This resulted in the localization of the organisms promoting the formation of an abscess within the spleen (Figure 3, part 4). We suggest that these unusual circumstances of fungemia and IVIG were responsible for facilitating the appearance of abscesses in this patient's spleen.

We believe true splenic abscesses are uncommon with disseminated coccidioidomycosis. The unusual circumstances of this patient's relapsing Coccidioides infection with fungemia (due to poor compliance with antifungals) and the repeated IVIG treatments for his dermatomyositis, combined to provide a reasonable explanation for why splenic abscesses occurred in this patient.

References

1. Forbus WD, Bestebreurtje AM. Coccidioidomycosis; a study of 95 cases of the disseminated type with special reference to the pathogenesis of the disease. Mil Surg. 1946 Nov;99(5):653-719. [PubMed]
2. Fiese MJ. Coccidioidomycosis: Springfield, IL: Charles C. Thomas 1958; p 111.
3. Wang DX, Shu XM, Tian XL, Chen F, Zu N, Ma L, Wang GC. Intravenous immunoglobulin therapy in adult patients with polymyositis/dermatomyositis: a systematic literature review. Clin Rheumatol. 2012 May;31(5):801-6. [CrossRef] [PubMed]
4. Prabhu RM, Bonnell M, Currier BL, Orenstein R. Successful treatment of disseminated nonmeningeal coccidioidomycosis with voriconazole. Clin Infect Dis. 2004 Oct 1;39(7):e74-7. [CrossRef] [PubMed]
5. Rempe S, Sachdev MS, Bhakta R, Pineda-Roman M, Vaz A, Carlson RW. Coccidioides immitis fungemia: clinical features and survival in 33 adult patients. Heart Lung. 2007 Jan-Feb;36(1):64-71. [CrossRef] [PubMed]
6. Adkinson NF, Yunginger JW, Busse WW, et al. Middleton's Allergy Principles & Practice (6th ed) Philadelphia, PA: Mosby, 203; 72-73.

Cite as: Assar S, Kuberski T. First report of splenic abscesses due to coccidioidomycosis. Southwest J Pulm Crit Care. 2017;15(5):214-8. doi: https://doi.org/10.13175/swjpcc125-17 PDF 

Tip of the Iceberg: 18F-FDG PET/CT Diagnoses Extensively Disseminated Coccidioidomycosis with Cutaneous Lesions

Benjamin B. Nia¹

Emily S. Nia²

Ngozi Osondu³

John N. Galgiani^3,4

Phillip H. Kuo^2,5

¹College of Medicine, University of Texas Medical Branch, Galveston, TX, USA.

²Department of Medical Imaging

³Department of Medicine, Section of Infectious Disease

⁴Valley Fever Center for Excellence

⁵Departments of Medicine and Biomedical Engineering

University of Arizona

Tucson, AZ, USA.

Abstract

We present a case of an immunocompetent 27-year-old African American man who was initially diagnosed with diffuse pulmonary coccidioidomycosis and started on oral fluconazole. While his symptoms improved, he began to develop tender cutaneous lesions. Biopsies of the cutaneous lesions grew Coccidioides immitis. Subsequent ¹⁸F-FDG PET/CT revealed extensive multisystem involvement including the skin/subcutaneous fat, lungs, spleen, lymph nodes, and skeleton. This case demonstrates the utility of obtaining an ¹⁸F-FDG PET/CT to assess the disease extent and activity in patients with disseminated coccidioidomycosis who initially present with symptoms involving only the lungs.

Report of Case

A 27-year-old African American man, who lived in the desert southwest of the United States for several years, with no significant past medical history presented with chest pain, weight loss, and shortness of breath. After two urgent care visits, he was admitted to the hospital with a chest radiograph showing bilateral pulmonary infiltrates (Figure 1).

Figure 1. Frontal (A) and lateral (B) chest radiography at hospital admission shows extensive reticulonodular opacities suspicious for atypical infection.

Bronchoscopy yielded Coccidioides spp., and immunodiffusion complement fixation (IDCF) was further confirmatory. Laboratory values showed elevated erythrocyte sedimentation rate (ESR) and mildly abnormal liver function tests. He was diagnosed with diffuse pulmonary coccidioidomycosis and discharged home on 400 mg of oral fluconazole per day. At initial follow-up appointment, he reported feeling significantly better with resolution of his chest pain. He was gaining weight and had increased physical activities. At three-month follow-up, he reported continued improvement but complained of three new “spots” on the skin of his lower abdomen (Figure 2).

Figure 2. Photograph of the cutaneous lesions at nine months (red arrows) that were also present at 3- and 6-month follow-up appointments.

On physical exam, the cutaneous lesions were not suspicious for disseminated infection so treatment was continued unchanged. At six-month follow-up, he displayed numerous cutaneous lesions that were now tender. A biopsy of a cutaneous lesion demonstrated Coccidioides spherules on microscopy. An ¹⁸F-FDG PET/CT scan was performed to assess the extent of disease and demonstrated FDG-avid disease involving the skin/subcutaneous tissue, lungs, spleen, multi-station lymph nodes, and the skeleton (Figure 3).

Figure 3. Coronal maximum-intensity projection (A) and axial fused (B) 18F-FDG PET/CT scan shows FDG-avid disease involving the spleen (blue arrow), osseous structures (green arrows), multiple lymph nodes stations (yellow arrows), and soft tissues, including the skin and subcutaneous tissues (red arrows).

After another month, the skin lesions improved and, on further questioning, the patient revealed that he had previously not been taking his fluconazole as prescribed. Because of the skeletal involvement uncovered by the PET/CT scan, the patient’s oral fluconazole dose was increased to 800 mg per day. At nine-month follow-up, patient reported continued improvement and resolution of majority of skin lesions, albeit with residual hyperpigmentation.  

Discussion

Coccidioidomycosis, or “Valley fever” is a fungal infection caused by inhalation of Coccidioides immitis or Coccidioides posadasii spores. Most infections cause little clinically apparent illness and result in lifelong immunity. Approximately one-third of infections produce pulmonary syndromes compatible with a community-acquired pneumonia, whereas <1% are complicated by potentially fatal blood-stream dissemination. Skin involvement is one of the most common manifestations of disseminated coccidioidomycosis. Other common sites of involvement include the bones, joints, and meninges. Unfortunately, nonspecific symptoms, the subacute nature of this disease, and lack of familiarity with this infection result in delayed diagnosis, increasing the risk of dissemination. Risk factors for disseminated coccidioidomycosis include African-American or Filipino ancestry, immunocompromised state, pregnancy, and discrete genetic defects. Coccidioides-endemic areas include parts of the southwestern United States, Central and South America (1,2).

¹⁸F-FDG PET/CT is an imaging modality most commonly utilized to stage malignancies and monitor response to therapy. ¹⁸F-FDG is a radioactive analog of glucose and is taken up by inflammatory cells. Detecting and monitoring infectious and inflammatory processes can be achieved with various imaging techniques, including computed tomography, magnetic resonance imaging, and ultrasonography. However, these techniques rely primarily on structural changes, and differentiation between active and indolent infections can be difficult. PET/CT’s whole-body coverage and high sensitivity can localize all sites of disease and assess level of disease activity (3,4).

This case demonstrates the utilization of ¹⁸F-FDG PET/CT to provide a comprehensive assessment of disease extent and activity in a patient with disseminated coccidioidomycosis. Diagnosing extent of disease is particularly important in this circumstance as osseous coccidioidomycosis predominantly results in osteolytic lesions that increase risk for fractures. Additionally, soft tissue assessment may reveal clinically occult soft tissue abscesses that may require surgical debridement (5). For this patient, the PET/CT scan results provided information that prompted medication dose escalation and emphasized the need for medication compliance. If disseminated coccidioidomycosis is suspected, PET/CT may provide value for the diagnostic evaluation in selected patients.

References

1. Odio CD, Marciano BE, Galgiani JN, Holland SM.Risk factors for disseminated coccidioidomycosis, United States. Emerg Infect Dis. 2017 Feb;23(2). [CrossRef] [PubMed]
2. Nguyen C, Barker BM, Hoover S, Nix DE, Ampel NM, Frelinger JA, Orbach MJ, Galgiani JN. Recent advances in our understanding of the environmental, epidemiological, immunological, and clinical dimensions of coccidioidomycosis. Clin Microbiol Rev. 2013;26(3):505-25. [CrossRef] [PubMed]
3. Zhuang H, Alavi A. 18-Fluorodeoxyglucose Positron Emission Tomographic Imaging in the Detection and Monitory of Infection and Inflammation. Semin Nucl Med. 2002;32:47-9. [CrossRef] [PubMed]
4. Basu S, Chryssikos T, Moghadam-Kia S, Zhuang H, Torigian DA, Alavi A. Positron emission tomography as a diagnostic tool in infection: present role and future possibilities. Semin Nucl Med. 2009;39:36–51. [CrossRef] [PubMed]
5. Gupta NA, Iv M, Pandit RP, Patel MR. Imaging manifestations of primary and disseminated coccidioidomycosis. App Radiol. 2015;44(2):9-21. Available at: http://appliedradiology.com/articles/imaging-manifestations-of-primary-and-disseminated-coccidioidomycosis (accessed 7/10/17).

Cite as: Nia BB, Nia ES, Osondu N, Galgiani JN, Kuo PH. Tip of the iceberg: ¹⁸F-FDG PET/CT diagnoses extensively disseminated coccidioidomycosis with cutaneous lesions. Southwest J Pulm Crit Care. 2017;15(1):28-31. doi: https://doi.org/10.13175/swjpcc069-17 PDF 

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.

References

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25. Cole GT, Xue JM, Okeke CN, Tarcha EJ, Basrur V, Schaller RA, et al. A vaccine against coccidioidomycosis is justified and attainable. Med Mycol. 2004;42(3):189-216. [CrossRef] [PubMed]
26. 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]
27. Vinh DC, Schwartz B, Hsu AP, Miranda DJ, Valdez PA, Fink D, et al. Interleukin-12 receptor beta1 deficiency predisposing to disseminated Coccidioidomycosis. Clin Infect Dis. 2011;52(4):e99-e102. [CrossRef] [PubMed]
28. Vinh DC, Masannat F, Dzioba RB, Galgiani JN, Holland SM. Refractory disseminated coccidioidomycosis and mycobacteriosis in interferon-gamma receptor 1 deficiency. Clin Infect Dis. 2009;49(6):e62-e5. [CrossRef] [PubMed]
29. Ampel NM, Hector RF. Measuring cellular immunity in coccidioidomycosis: the time is now. Mycopathologia. 2010;169(6):425-6. [CrossRef] [PubMed]
30. Santelli AC, Blair JE, Roust LR. Coccidioidomycosis in patients with diabetes mellitus. Am J Med. 2006;119(11):964-9. [CrossRef] [PubMed]
31. 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]
32. Pappagianis D, Zimmer BL. Serology of coccidioidomycosis. Clin Microbiol Rev. 1990;3:247-68. [PubMed]
33. Saubolle MA, McKellar PP, Sussland D. Epidemiologic, clinical, and diagnostic aspects of coccidioidomycosis. J Clin Microbiol. 2007;45(1):26-30. [CrossRef] [PubMed]
34. Smith CE, Saito MT, Simons SA. Pattern of 39,500 serologic tests in coccidioidomycosis. JAMA. 1956;160:546-52. [CrossRef] [PubMed]
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41. 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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48. Ampel NM, Ryan KJ, Carry PJ, Wieden MA, Schifman RB. Fungemia due to Coccidioides immitis. An analysis of 16 episodes in 15 patients and a review of the literature. Medicine (Baltimore). 1986;65:312-21. [CrossRef] [PubMed]
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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.

May 2015 Pulmonary Case of the Month: Pneumonia with a Rash

Richard A. Robbins, MD

Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ

History of Present Illness

A 77-year-old man underwent a thoracic CT scan  for follow up of a known thoracic aneurysm.  However, he had been feeling tired for about a week with a cough, night sweats and fever. He had no shortness of breath, wheezing or known history of lung disease.

Past Medical History, Social History and Family History

He has a history of hypertension and a known thoracic aortic aneurysm. There was a  surgical repair of his right clavicle after a motor vehicle accident. He is single and has lived in Arizona for over 50 years. He just returned from a trip to California where he visited Disneyland. He does not smoke. Family history is noncontributory.    

Current Medications

• Dutasteride
• Levothyroxine
• Atorvastatin

Physical Examination

His physical examination was reported as unremarkable. SpO2 was 95% on room air.

Radiography

Figure 1. Representative images from his thoracic CT scan showing a left lower lobe consolidation (red arrows). Panel A: coronal projection in lung windows. Panel B: axial view in lung windows.

Which of the following is appropriate at this time? (Click on the correct answer to proceed to the second of four panels)

1. Begin empiric antibiotics
2. Bronchoscopy with bronchoalveolar lavage
3. Sputum Gram stain and culture
4. 1 and 3
5. All of the above

Reference as: Robbins RA. May 2015 pulmonary case of the month: pneumonia with a rash. Southwest J Pulm Crit Care. 2015;10(5):203-7. doi: http://dx.doi.org/10.13175/swjpcc044-15 PDF 

A 61 Year Old Immunosuppressed Man With A Symptomatic Pulmonary Infiltrate

Carmen Luraschi-Monjagatta¹

Amber Noon¹

Neil Ampel¹

Suzette Chavez¹

Mitch Goldman²

Kenneth S  Knox¹

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

Indiana University School of Medicine, Indianapolis, IN²

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

Abstract

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

Case Presentation

History of Present Illness

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

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

Physical examination

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

Laboratory findings

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

 

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

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

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

Hospital course

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

Discussion

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

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

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

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

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

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

Summary

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

References

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

Corresponding author:

Kenneth S Knox, M.D.

Associate Professor of Medicine, University of Arizona

Southern Arizona VA Health Care System

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

Tucson, AZ 85723

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

Acknowledgment:

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

Author Contributions:

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

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

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

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

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

Abbreviations:

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