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* From the David Geffen School of Medicine at UCLA, Critical Care and Pulmonary Services (Dr. Spinello), and Infectious Diseases (Dr. Johnson), Kern Medical Center, Bakersfield, CA.
Correspondence to: Irene M. Spinello, MD, FCCP, Assistant Clinical Professor of Medicine, David Geffen School of Medicine at UCLA, Chief, Critical Care and Pulmonary Services, Kern Medical Center, 1830 Flower St, Bakersfield, CA 93305; e-mail: spinelloi{at}kernmedctr.com
A 19-year-old Hispanic woman with an intrauterine pregnancy at 37 weeks was admitted to the labor and delivery department for tachycardia and signs of oligohydramnios. On admission, she complained of chest pain, sore throat, and dry cough of 3 weeks in duration, and fevers and dyspnea for the last 3 days. She denied photophobia, sputum production, nausea or vomiting, rigors, or night sweats, but noted a painless skin lesion on her right upper forearm for at least several weeks. She was otherwise a healthy woman originally from Mexico, with no previous medical or surgical problems. At the time of hospital admission, she was a housewife residing in central California with her husband. There was no history of sick contacts, recent travel, exposure to birds, or illicit drug use.
Physical Examination
The patient was febrile and had a temperature of 39.3°C, with a pulse rate 130 beats/min, systolic/diastolic BP of 130/47 mm Hg, and oxygen saturation of 92% on 2 L of oxygen by nasal cannula. Physical examination revealed bibasilar crackles, a gravid abdomen, and a shallow 2 x 2-cm ulcer on the right forearm with serosanguinous discharge and mild surrounding edema. The rest of her examination was unremarkable.
Laboratory Data
The laboratory tests were significant for anemia (hemoglobin, 11.2 g/dL; mean corpuscular volume, 74.5 fL), WBC count of 9.1 x 103/µL with lymphopenia (7.78%), and normal eosinophil count (0.74%). Basic metabolic panel showed mild hypokalemia (3.4 mEq/L), decreased bicarbonate (18 mEq/L), normal BUN/creatinine, and anion gap of 14, which corrected to 20, since the patient’s albumin level was only 1.6 g/dL. Apart from low albumin and elevated alkaline phosphatase (187 U/L), the rest of liver function test findings were normal. Chest radiography on hospital admission showed a diffuse reticulonodular pattern (Fig 1 ).
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Because of the patient’s illness, fetal distress, and oligohydramnios, labor was induced and a healthy baby boy was delivered. Over the next 24 h, the patient’s respiratory status deteriorated with increased work of breathing, worsening tachypnea, and hypoxia. Arterial blood gas analysis on 100% nonrebreather mask showed a pH of 7.29; PCO2, 41 mm Hg; and PO2, 46 mm Hg. The lactic acid was 3.4 mmol/L (normal range, 0.4 to 2.0). Subsequently, the patient was transferred to ICU, intubated, and administered mechanical ventilation, with the subsequent arterial blood gas analysis showing a pH 7.33; PCO2, 36 mm Hg; and PO2, 237 mm Hg on 100% oxygen.
What would be the next diagnostic test?
What is the most likely diagnosis?
Answer: Biopsy of the skin lesion
Answer: Disseminated (miliary) coccidioidomycosis
Coccidioidomycosis is a fungal infection endemic to the southwestern United States, northwestern Mexico, and parts of Central and South America. It is caused by inhalation of the infectious arthroconidia of Coccidioides immitis or Coccidioides posadii, two genetically distinct species of Coccidioides that cannot be distinguished phenotypically or clinically. This inhalation will result in symptomatic illness in approximately one third of infected persons. Disease presentations include a wide clinical spectrum that ranges from mild influenza-like illness and pneumonia to dissemination. The latter develops in approximately 1% of infected persons. The reason coccidioidomycosis is an infectious but not a contagious disease is explained by the life cycle of Coccidioides, which consists of two phases: the infectious saprobic (soil) phase, and the noninfectious parasitic (host) phase. In the saprobic phase, mycelia grow in soil. As they mature, they produce specialized barrel-shaped arthroconidia, which become airborne and are returned to the soil or are inhaled by a potential host. In the parasitic phase, the arthroconidia become spherules that reproduce by endosporulation. If infected material is returned to the soil or if sputum or pus is cultured in the laboratory, new mycelia are formed completing the cycle. The only person-to-person transmission has been indirect through exposure to contaminated fomites.
In a nonoutbreak setting, older age, smoking, and diabetes mellitus were associated with severe pulmonary coccidioidomycosis, while black race, income <$15,000/yr, and pregnancy were identified risk factors for disseminated disease. Dissemination can occur to virtually any tissue. One of the distinct presentations of disseminated coccidioidomycosis is a miliary pulmonary disease. This classic pattern of "millet seeds" is a result of hematogenous or lymphatic spread of Coccidioides and is characterized by the development of multiple coccidioidal granulomas throughout the lungs as well as other organs. Miliary coccidioidomycosis manifests as either an acute respiratory illness or as part of advanced chronic illness occurring in the context of widespread dissemination. Mortality is extremely high in patients with chronic involvement, even in the absence of an underlying immunocompromised condition. From the data collected in Kern County from 1995 to 1996, 28% of all disseminated cases involved bones and joints, 32% involved the meninges, and almost one half (46%) of all disseminated cases had infection of the skin and soft tissue.
Skin involvement in coccidioidomycosis is not just limited to being a site of dissemination. Erythema nodosum, presenting as multiple painful nodules limited to the extremities, is a common dermatologic finding in primary coccidioidomycosis infection and can be used as a strong prognostication tool. It is highly associated with a relatively benign nature of coccidioidomycosis. This association holds true for pregnant patient population even more so than for the general population. Patients without erythema nodosum have a higher dissemination rate and recover less frequently than patients with erythema nodosum.
Coccidioides has a number of pathogenic features that promote its ability to cause disseminated disease. Primarily, the thick hyphal outer wall of arthroconidia resists phagocytosis. Secondly, a spherule of coccidioidomycosis produces hundreds of endospores, whereas other fungi generally produce from 1 to 20 daughter cells. And finally, a fibrillar material is released that inhibits polymorphonuclear cells access to the emerging endospores. The increased severity and risk for dissemination in pregnant women is attributed to the depressed cell-mediated immunity of pregnancy and to the direct stimulation of growth of Coccidioides resulting from the high serum levels of estradiol and progesterone in pregnant women. It is thought that Coccidioides does not cross the placenta because of its large size (40 to 70 µm). Moreover, thrombotic and chronic granulomatous reaction in the placenta appears to wall off the infection from the villous circulation. Fetal intrauterine infection rarely occurs despite a large number of documented cases of Coccidioides placentitis. In rare neonatal cases of coccidioidomycosis, the infection is acquired at birth by contact with or aspiration of infectious material originating in the mother’s vagina. Our patient delivered a healthy baby boy despite the fact that the pathologic examination of the placenta showed multiple coccidioidomycosis microabscesses.
Treatment options for coccidioidomycosis depend on the severity of the disease, dissemination, and the site of dissemination. The treatment generally consists of amphotericin B deoxycholate (or less toxic lipid-based amphotericin) and azoles or a combination of the two. Amphotericin B deoxycholate has been used in pregnant patients for approximately 5 decades without apparent significant adverse effect on the pregnancy or the fetus. In recent years, lipid preparations of amphotericin B are increasingly preferred over amphotericin B deoxycholate. The rationale for this is based on the demonstrable reduction in toxicity of lipid-based amphotericin. In the absence of comparative trials for Coccidioides infections, the cumulative clinical experience with the lipid-based amphotericin preparations is now adequate to consider them suitable replacements for amphotericin B deoxycholate. For > 20 years, azoles have been part of the therapeutic armamentarium for coccidioidomycosis. Ketoconazole was used first but was later replaced by fluconazole and itraconazole. The latter has been used to a lesser extent largely due to the problems with its bioavailability. There are new agents that have activity against Coccidioides, such as posaconazole, voriconazole, and caspofungin, but the evidence of their efficacy and safety is limited to case reports only. Table 1 presents a summary of treatment guidelines for disseminated disease based on recommendations from Infectious Diseases Society of America.
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Because of a high index of suspicion for miliary coccidioidomycosis in the present patient, empiric therapy with lipid complex amphotericin was started and a punch biopsy of the skin lesion was performed. It demonstrated abundant spherules with endospores within the squamous epithelium and granulomatous inflammation of the dermis and subcutaneous fat (Fig 2 ). The diagnosis was further confirmed with positive serology and BAL culture results. For the next 10 days, the patient’s PaO2/fraction of inspired oxygen ratio remained < 150 despite the use of lung protective ventilation, recruitment maneuvers, and oxygen diffusion improvement utilizing the concept of continuous intrapulmonary percussive ventilation. At the end of the 2-week course, despite appropriate therapy, the patient died from ARDS and related complications. The final chest radiograph showed complete opacification of both lungs and pneumomediastinum (Fig 3 ).
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Pregnancy is a risk factor for disseminated coccidioidomycosis.
One half of all disseminated cases involve skin and soft tissue, while the other half is almost evenly divided between meningeal and skeletal involvement.
Erythema nodosum is highly associated with a relatively benign nature of coccidioidomycosis, especially for pregnant patients. Patients without erythema nodosum have a higher dissemination rate and recover less frequently than patients with erythema nodosum.
The increased severity and risk for dissemination in pregnant women is attributed to the depressed cell-mediated immunity of pregnancy and to the direct stimulation of growth of Coccidioides resulting from the high serum levels of estradiol and progesterone in pregnant women.
The cumulative clinical experience with the lipid-based amphotericin preparations is now adequate to consider them suitable replacements for amphotericin B deoxycholate.
Footnotes
Dr. Spinello declares no conflict of interest. Dr. Johnson has been research support/consultant/speaker for Merck & Co, and Pfizer.
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