California digging. Task 1 Interpret the chest radiograph. L. Hendriks

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1 Case history An18-yr-old male presented at the emergency department with a 4-week history of fever, coughing and dyspnoea. Symptoms presented on a holiday in California (USA) searching the desert for fossils. He attended the emergency department in California where they treated him with penicillin G after which he developed a rash. The antibiotics were discontinued and he was discharged. Five of his travel companions also suffered the same symptoms. The patient had no medical history. He did not use any medication and had never smoked. He had no pets, and had had no contact with animals. On examination, the patient appeared in good health with a temperature of 37.6 o C and a saturation of 99% without supplementary oxygen. All lymph nodes were not palpable, and on examination of the chest there was a dull percussion on the left with diminished breath sounds. Heart, abdomen and extremities showed no abnormalities. Laboratory results revealed raised inflammatory markers: C-reactive protein (CRP) 147 mg per L and leukocytes per L, and in leukocyte differentiation an increased number of eosinophils ( per L). Electrolytes, and renal and liver functions were within normal range. An arterial blood gas analysis showed normal ventilation. His ECG showed a normal sinus rhythm. The admission chest radiograph is shown in figure 1. a) b) L. Hendriks Dept of Pulmonology Atrium Medical Centre Heerlen The Netherlands lizzahendriks@yahoo.com Provenance Submitted article, peer reviewed. Competing interests None declared. Task 1 Interpret the chest radiograph. Figure 1 Chest radiograph taken on admission. HERMES syllabus link: module B.3 DOI: / Breathe March 2010 Volume 6 No 3 267

2 Answer 1 There is a large pleural fluid collection on the left side of the chest, occupying approximately one-third of the hemithorax. There is no consolidation, the right lung and pleura show no abnormalities. A computed tomography (CT) scan of the chest showed mediastinal lymphadenopathy, a large pleural effusion on the left side of the chest and three nodules on the right side of the chest (figure 2). Answer 2 This is most likely an infection, possibly atypical (high CRP and relatively low leukocytes). Because his complaints started on a vacation in in the desert, pathogens such as histoplasmosis, coccidioidomycosis and blastomycosis should be taken into consideration. A less likely, but not unthinkable, option is a systemic disease such as vasculitis or a malignancy. Task 3 How would you proceed with this patient? Figure 2 CT scan showing one of the three nodules on the right side and the pleural fluid. Task 2 What is your differential diagnosis? 268 Breathe March 2010 Volume 6 No 3

3 Answer 3 The patient was treated with ceftriaxon and ciproxin intravenously and pleural fluid was drained. Biochemistry showed an eosinophilic exudate with a ph of 7.5 (table 1). Urine tests for Legionella pneumophila and Streptococcus pneumoniae were negative; serology testing for Coxiella burnetii was negative. Blood cultures were negative, cultures of the pleural fluid showed no growth, pleural fluid cytology was negative. Rickettsiae and histoplasmosis antibodies were not detected. After ruling out these infections and combined with his trip to California and an eosinophilic pleural fluid, coccidioidomycosis was suspected. Empirical treatment with itraconazole twice daily 200 mg was started. Coccidioidomycosis serology was shown to be positive. The patient recovered and an outpatient chest CT scan after 3 months showed an improvement (figure 3); the pleural fluid and mediastinal lymphadenopathy had disappeared, although some nodules still remained. Serology for coccidioidomycosis after 3 months of treatment was negative. We continued prescribing itraconazole for another 3 months. One of the patient s travel companions also visited our emergency department. He had symptoms of fever, night sweats, coughing and involuntary weight loss (9 kg in 2 weeks). He also had mediastinal and left hilar lymphadenopathy with pleural fluid on the left side of the chest (figures 4 and 5). Laboratory results showed raised inflammatory parameters (CRP 149 mg per ml and leukocytes per L, in the leukocyte differentiation raised eosinophils were seen Table 1 Composition of eosinophilic exudate. Glucose Concentration 45 mmol per L (20%, in absolute values per L)). A pleural fluid tap showed an eosinophilic exudate and no malignant cells. Cultures were negative. Auto-immune serology was negative, as was histoplasmosis serology; however, coccidioidomycosis serology was positive. He was treated with itraconazole and achieved a favourable clinical outcome. Chest radiography after 4 months of treatment was almost normal: several small nodules remained on both sides of the chest. Serum values Lactate dehydrogenase 314 U per L 295 U per L Total protein 54.6 g per L 79.7 g per L Albumin 25.8 g per L 33.5 g per L Leukocytes per L Eosinophils 13% Figure 4 Chest radiography of the second patient. Figure 5 Thorax CT scan of the second patient. Figure 3 An outpatient CT scan 3 months after treatment with itraconazole. Breathe March 2010 Volume 6 No 3 269

4 Discussion Coccidioidomycosis is uncommon in Europe, but in California it is endemic with an incidence of 91 cases per 100,000 people a year. The incidence is increasing; probable factors include a greater number of nonimmune persons moving into endemic areas, increased travel and tourism, a growing immunocompromised population and new construction sites resulting in more dust and arthrospores in the air. In addition, both doctors and patients are more aware of the infection [1, 2]. Coccidioidomycosis was first discovered by Alejandro Posadas in 1891 in Buenos Aires, Argentina. He described a progressive disfiguring skin disease with organ complications. The first pulmonary event was described in 1937 in the San Joaquin Valley of central California: an acute respiratory syndrome called valley fever, named after the San Joaquin Valley [1]. Coccidioimycosis species consists of Coccidioides immitis and Coccidioides posadasii. Both are dimorphic fungi that are endemic to the western hemisphere from latitudes 40 o north to 40 o south, and are mostly found in arid regions in South-West USA, Mexico, Central America and South America. The two species cause the same symptoms and are morphologically identical. They can be distinguished by means of DNA testing and are epidemiologically distinct. C. immitis is geographically limited to California s San Joaquin Valley region, whereas C. posadasii is found in the desert of South-West USA, Mexico and South America [1]. Coccidioides grow as a mould in the desert soil; the life cycle consists of a mycelial and spherule phase. After a rain fall, the mycelia multiply and form arthroconidia. When it is dry and windy these are released and can be inhaled. In the lungs they transform to new spherical structures called spherules, forming endospores. Eventually they break open and are released, growing to form new spherules [1, 2]. Infection is via the respiratory tract. Incubation time is usually 7 to 21 days, but can often be longer in immunocompromised patients. The number of infections is highest in late summer and early fall because the dry climate promotes breaking of the arthroconidia, sending them airborne. Inhalation of one arthroconidium can cause disease [2]. Coccidioidomycosis can manifest in various forms. 60% of infected people remain asymptomatic. The main symptoms are: acute pneumonia, chronic progressive pneumonia, pulmonary nodules and cavities, extrapulmonary nonmeningeal disease and meningitis [1, 2]. Acute pneumonia Acute pneumonia is the primary clinical manifestation of coccidioidomycosis. Symptoms include fever, cough, dyspnoea, sputum production, pleuritic chest pain and headache. When the last two listed symptoms are severe, this strongly suggests a coccidioidal infection. Systemic symptoms include weight loss, night sweats, arthralgias, myalgias and headache. 25% of infected patients have erythema multiforme or erythema nodosum. Profound fatigue lasting for months is a frequent finding [1, 2]. Normally, symptoms resolve without any specific treatment within 2 6 weeks. 5 8% of patients with primary pulmonary disease develop chronic pulmonary or extrapulmonary coccidioidomycosis. This can occur months to several years after the primary infection. Risk factors are AIDS, lymphoma, (rheumatologic) therapies such as high-dose corticosteroids or anti-tumour necrosis factor medications, immunosuppressant therapy, diabetes, pregnancy and older age [1, 2]. Chronic progressive pneumonia Symptoms mostly resolve without treatment, but sometimes symptoms persist for >3 months. In these prolonged cases symptoms include persistent coughing, sputum production, haemoptysis and weight loss. When the pulmonary disease is progressive, inflammation, fibrosis and volume loss occurs [1]. Pulmonary nodules and cavities Nodules represent inflammatory debris-filled cavities that can develop into thin-walled cavities or resolve. These are the residual effect of the primary coccidioidal infection. In most individuals they do not cause symptoms but cough, chest pain or haemoptysis can occur [1]. Extrapulmonary nonmeningeal disease This occurs in <5% of patients if they are immunocompetent, but in 30 50% in severe 270 Breathe March 2010 Volume 6 No 3

5 immunocompromised patients. Extrapulmonary disease suggests haematogenous spread of the infection to other organs of the body. Skin, bone (skull, hands, feet, spine and tibia) and joints (90% unifocal, mostly ankles and knees) are the most common sites; spread to the central nervous system is the most dangerous [1, 2]. Meningitis This is often catastrophic and results in long-term morbidity. The most common presentation is headache but mental status changes and neurological deficits can be present. It usually involves the basilar meninges [1, 2]. Coccidioidomycosis may be suspected after a thorough anamnesis with compatible physical findings or after chest radiography showing infiltrates, pleural effusion (5 10%) or hilar adeno pathy, this occurs in 25% of coccidioidal infections [1, 3, 4]. On routine laboratory evaluation, an elevated erythrocyte sedimentation rate with peripheral blood eosinophilia can be seen if coccidioidomycosis is present. Pleural fluid is usually an eosinophilic exudate [1, 3]. Spherules can be observed on direct smears of any infected bodily fluid, using calcifluor white or cytologic stains. The definite method for diagnosing coccidioidomycosis is isolation of the organism from clinical specimens. It grows on most culture media within a couple of days, but is very contagious, so laboratory personal must be warned [1, 2]. Detection of antibodies against coccidioidomycosis is helpful in the diagnosis, and is also useful to monitor patients undergoing therapy. It also has prognostic value: a serum complement factor (CF) titre of 1:2 or 1:4 is associated with a favourable outcome, whereas a CF titre of 1:16 or greater is associated with disseminated disease. In immunocompromised patients, titres are not always reliable. Skin testing has a low sensitivity and specificity in endemic areas [1, 2]. Usually, treatment is not necessary when there is no extrapulmonary disease. As previously mentioned, most symptoms resolve within a few weeks without any specific treatment. Risk factors for dissemination, severe comorbidity, severe infection and a CF titre of 1:16 are indications for treatment. Criteria for a severe infection are: weight loss of >10%, intense night sweats persisting for >3 weeks, pulmonary infiltrates within both or more than one-half of one lung, or symptoms persisting for >2 months [1, 5]. Treatment consists of antifungal therapy including: ketoconazole (400 mg per day orally), itraconazole (200 mg twice a day orally or i.v.), fluconazole ( mg per day orally or i.v) and in very severe cases, or as initial treatment in meningitis, amphotericin B ( mg per kg per day orally or i.v). Newly available antifungal agents include voriconazole and caspofungin, but they have not yet approved by the US Food and Drug Administration [5]. The duration of therapy ranges from months to years; long-term suppressive doses are necessary to prevent relapses. Immunocompromised patients and patients with meningitis require lifelong therapy [5]. In most cases, nodules and cavities do not require therapy. When enlargement occurs, reevaluation with cultures and CF titres is necessary to determine whether the infection is active and therapy should be started [1, 5]. Follow-up is necessary for all patients with the infection. It should include repeated patient encounters every 3 6 months for up to 2 yrs to document radiographic resolution or to identify complications as early as possible [5]. This case stresses the importance of a thorough medical and travel anamnesis. We described two patients who developed coccidioidomycosis after their holiday in California. Both patients were treated with itraconazole due to the severity of their symptoms. After 3 months of treatment both patients showed improvement on chest CT scans. References 1. Parish JM, Blair JE. Coccidioidomycosis. Mayo Clinic Proc 2008; 83: Stevens DA. Coccidioidomycosis. N Engl J Med 1995; 332: Crum NF, Lederman ER, Stafford CM, et al. Coccidioidomycosis: a descriptive survey of a reemerging disease. Clinical characteristics and current controversies. Medicine (Baltimore) 2004; 83: Batra P. Pulmonary coccidioidomycosis. J Thorac Imaging 1992; Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis 2005; 41: Breathe March 2010 Volume 6 No 3 271