A 37-year-old man with a chronic cough
HOW LONG MUST HE BE TREATED?
On follow-up, the patient asked how long he needed to continue his antifungal regimen and if any other testing for his coccidioidal infection was necessary, since he was feeling better.
5. Which is the most appropriate response to the patient’s question?
- He can discontinue his antifungal drugs; no further testing is necessary
- He needs 14 more days of antifungal therapy and periodic serologic tests
- He needs 2.5 more months of antifungal therapy and monthly blood cultures
- He needs lifelong antifungal therapy and periodic urinary antigen levels
- He needs 5.5 more months of antifungal therapy; bronchoscopy with bronchoalveolar lavage at 1 year
How long to treat and how to monitor for coccidioidomycosis vary by patient.
Duration of therapy depends on symptoms and immune status
The severity of infection (Table 2) and the immune status are important factors that must be considered when tailoring a therapeutic regimen.
Immunocompetent patients without symptoms or with mild symptoms usually do not need therapy and are followed periodically for signs of improvement.14,18,29
Immunocompetent patients with severe symptoms typically receive 3 to 6 months of antifungal therapy.18
Immunocompromised patients (especially HIV-infected patients with CD4 counts < 250 cells/μL) need antifungal treatment, regardless of the severity of infection.14,18,29 In many cases, the type of infection will dictate the duration of therapy.
Diffuse pneumonia or extrapulmonary dissemination typically requires treatment for at least 1 year regardless of immune status.14,18 For those with HIV and diffuse pneumonia, dissemination, or meningitis, guidelines dictate that secondary prophylaxis be started after at least 1 year of therapy and improvement in clinical status; it should be continued indefinitely to prevent reactivation of latent infection.18
The guidelines say that in patients with higher CD4 counts (presumably > 250 cells/μL) and nonmeningeal coccidioidomycosis, providers may consider discontinuing secondary prophylaxis, as long as there is clinical evidence of improvement and control of the primary infection.18 However, many experts advocate continuing secondary prophylaxis regardless of the CD4 count, as the rates of relapse and dissemination are high.1,16,37
Monitoring
Regardless of the therapy chosen, disease monitoring every 2 to 4 months with clinical history and examination, radiography, and coccidioidal-specific testing is recommended for at least 1 year, and perhaps longer, to ensure complete resolution and to monitor for signs of dissemination.14,18
Which test to use is not clear. Serologic testing identifies antibodies (IgM or IgG) to coccidioidal antigens. IgM appears during the acute infection, and tests include immunodiffusion, latex agglutination, and enzymelinked immunoassays. The last two are highly sensitive but have a significant false-positive rate, and should be confirmed with the former if found to be positive.17,18 IgG appears weeks after the acute infection and can be evaluated with immunodiffusion or enzyme-linked immunoassay as well.
Keep in mind that these tests provide only qualitative results on the presence of these antibodies, not quantitative information. Furthermore, enzyme-linked immunoassay is not as accurate as immunodiffusion, which has a sensitivity in immunocompromised patients of only approximately 50%.38,39
For that reason, complement fixation titers are extremely helpful because they reflect the severity of infection, can be used to monitor the response to treatment, and can even provide insight into the prognosis.18 The sensitivity of this test in immunocompromised hosts is 60% to 70%.38 Titers can be checked to confirm the diagnosis and can be periodically monitored throughout the treatment course to ensure efficacy of therapy and to watch for reactivation of the infection.1 In fact, an initial complement fixation titer of 1:2 or 1:4 is associated with favorable outcomes, while a titer greater than 1:16 portends dissemination.18
The caveat to any serologic test (immunodiffusion, enzyme-linked immunoassay, and complement fixation) is that severely immunocompromised patients (as in our case) may not mount an immune response and may have falsely low titers even in the face of a severe infection, and therefore these tests may not be reliable.38 In these situations, urinary coccidioidal antigen detection assay (sensitivity 71%) or nucleic acid amplification of coccidioidal DNA (sensitivity 75%) may be of more help.40,41
Therefore, in the setting of HIV infection, an asymptomatic pulmonary cavity, and diffuse pulmonary involvement secondary to coccidioidal infection, lifelong antibiotics (treatment plus secondary prophylaxis) with periodic testing of urinary coccidioidal antigen levels is the best response to the patient’s question, given that his complement fixation titers were initially negative and antigen levels were positive.
CASE CONCLUDED
The patient continues to be followed for his HIV infection. He is undergoing serologic and urinary antigen testing for Coccidioides infection every 3 months in addition to his maintenance HIV testing. He is on chronic suppressive therapy with fluconazole. He has not had a recurrence of his Coccidioides infection, nor have there been any signs of dissemination.
CAVITARY LUNG LESIONS IN HIV PATIENTS
In patients with HIV, cavitary lung lesions on chest radiography can be due to a wide variety of etiologies that range from infection to malignancy. Historical clues, including environmental exposure, occupation, geographic residence, sick contacts, travel, or animal contact can be helpful in ordering subsequent confirmatory testing, especially in the case of infection.
Tuberculosis should be suspected, and appropriate isolation precautions should be taken until it is ruled out.
Laboratory testing, including the complete blood cell count with differential and CD4 count, provide ancillary data to narrow the differential diagnosis. For example, if the CD4 count is greater than 200 cells/μL, mycobacterial infection should be strongly suspected; however, lower CD4 counts should also prompt a search for opportunistic infections. In the appropriate clinical scenario, malignancies including Kaposi sarcoma, non-Hodgkin lymphoma, and bronchogenic carcinoma can be seen and should also be considered.
Nevertheless, the evaluation hinges on the sputum examination and CT scan of the chest to further characterize the cavity, surrounding lung parenchyma, lymph nodes, and potential fluid collections. Usually, further serologic tests and even bronchoscopy with bronchoalveolar lavage and transbronchial biopsy are required. Treatment should begin once the most likely diagnosis is established.
Coccidioidal pneumonia should be considered in all patients with immunodeficiency, including HIV patients, transplant recipients, those undergoing chemotherapy, and those with intrinsic immune system defects, especially if they have a history of exposure or if they are from an endemic region. Antifungal therapy should be initiated early, and dissemination must be ruled out. Suppressive therapy is mandatory for those with a severely compromised immune system, and serologic testing to ensure remission of the infection is needed. Patients who were previously exposed to Coccidioides or who vacationed or live in the southwestern United States (where it is prevalent) are at risk and may present with any number of symptoms.
