Lesson 3. Opportunistic Infections: Treatment

Overview

The introduction of effective antiretroviral therapy in the mid-1990s has played a major role in the dramatic reduction in opportunistic infection-related morbidity and mortality.[1,2,3] Despite the widespread availability and use of potent antiretroviral therapy, individuals with HIV continue to suffer significant morbidity and mortality from opportunistic infections, defined as infections that are more frequent or severe due to immunosuppression. Most opportunistic infections now occur in people with undiagnosed HIV or in persons diagnosed with HIV who are not engaged in care. Because opportunistic infections continue to occur with potentially devastating consequences, clinicians should have a core understanding of the diagnosis, prevention, and treatment of opportunistic infections. This topic review provides an overview of treatment for the most common opportunistic infections based on the Adult and Adolescent OI Guidelines.[4]

Immune Reconstitution Syndrome

After initiation of effective antiretroviral therapy and during the early phases of immune reconstitution, a paradoxical worsening of certain clinical conditions can occur; this has been termed immune reconstitution inflammatory syndrome (IRIS).[5,6] Similarly, some patients with profound immunosuppression may have undiagnosed opportunistic infections that may be exposed as a result of an immune upregulation after starting antiretroviral therapy—this has been referred to as “unmasking” IRIS, a process whereby the immune system regains the capacity to recognize antigens and pathogens that previously it was too suppressed to confront. Although IRIS may develop in the context of various infections in a patient with advanced HIV disease, the most commonly observed IRIS events involve disseminated Mycobacterium avium complex disease, cryptococcal meningitis, tuberculosis, progressive multifocal leukoencephalopathy, and cytomegalovirus retinitis.[7,8,9]

Background

Pneumocystis pneumonia (PCP) is a leading cause of morbidity and mortality in people with HIV. The causative organism, Pneumocystis jirovecii, is classified as a fungus and was previously known as P. carinii. Phylogenetic studies led to a name change in 1999 (from P. carinii to P. jirovecii).[10] Despite the organism name change, the acronym PCP is still widely used to denote Pneumocystis pneumonia. Individuals with HIV most often acquire P. jirovecii via the airborne route, and disease may occur either with newly acquired infection or by reactivation of latent infection.[10] The risk of developing Pneumocystis pneumonia increases markedly when the CD4 count drops below 200 cells/mm³.[11,12,13] In the absence of Pneumocystis pneumonia prophylaxis or use of effective antiretroviral therapy, Pneumocystis pneumonia will develop in approximately 80% of persons with AIDS. After the use of effective antiretroviral therapy became widespread, the incidence of Pneumocystis pneumonia among individuals with AIDS in the United States and Western Europe dropped substantially—from approximately 30 cases per 1,000 person-years in the mid-1990s to 3.9 cases per 1,000 person-years in 2008 through 2010 (Figure 1).[1,2]

Figure 1. Incidence of Pneumocystis Pneumonia in United States and Canada: NA-ACCORD, 2000-2010

Abbreviation: NA-ACCORD = North American AIDS Cohort Collaboration on Research and Design 

Source: Buchacz K, Lau B, Jing Y, et al. Incidence of AIDS-Defining Opportunistic Infections in a Multicohort Analysis of HIV-infected Persons in the United States and Canada, 2000-2010. J Infect Dis. 2016;214:862-72.

Clinical Manifestations

The most common clinical manifestations in patients with Pneumocystis pneumonia are a subacute nonproductive cough, progressive dyspnea (particularly dyspnea on exertion), and fever.[13,14] The pulmonary physical examination is usually normal, but in more advanced disease, rales may be present on auscultation. If untreated, individuals with Pneumocystis pneumonia may have progression of clinical disease with worsening dyspnea and hypoxemic respiratory failure.

Diagnosis

All persons with suspected Pneumocystis pneumonia should undergo evaluation to confirm the diagnosis, especially since other bacterial, mycobacterial, and fungal diseases commonly encountered among individuals with advanced immunosuppression can mimic Pneumocystis pneumonia. Nondefinitive tests can be used to support the diagnosis, but all persons with suspected Pneumocystis pneumonia should have a definitive diagnosis made.[14,15]

Nondefinitive Diagnostic Tests

The diagnosis of Pneumocystis pneumonia can be supported by several nonspecific tests.

• Chest Radiography and Chest Computed Tomography: In patients with suspected Pneumocystis pneumonia, chest imaging is almost always performed (Figure 2). In patients with Pneumocystis pneumonia, chest radiograph typically shows diffuse bilateral perihilar infiltrates; the appearance of these infiltrates is often described as ground glass and butterfly-shaped.[16,17] Approximately 15 to 20% of persons with Pneumocystis pneumonia have a normal chest radiograph, particularly those in the earlier phase of Pneumocystis pneumonia.[13,17,18] In some individuals with Pneumocystis pneumonia, pneumatoceles or cystic lesions develop; these may result in pneumothorax.[19,20] High-resolution chest computed tomography is more sensitive than chest radiography in detecting interstitial abnormalities.[16,21]
  Figure 2. Pneumocystis Pneumonia and Chest Imaging

  

  Figure 2A. Pneumocystis Pneumonia: Chest Radiograph

  This chest radiograph scan shows extensive bilateral infiltrates in an adult with HIV and Pneumocystis pneumonia.

  Source: Brian R. Wood, MD

  

  Figure 2B. Pneumocystis Pneumonia: Pneumothorax

  This chest radiograph scan shows a right lung pneumothorax (white arrows) in an adult with HIV and Pneumocystis pneumonia.

  Source: Brian R. Wood, MD

  

  Figure 2C. Pneumocystis Pneumonia: Chest Computed Tomographic (CT) Scan

  This chest CT scan shows extensive bilateral infiltrates in an adult with HIV and Pneumocystis pneumonia.

  Source: Brian R. Wood, MD
• Exercise Pulse Oximetry: Oxygen desaturation with exercise, as documented with continuous pulse oximetry, has been shown to be a feature of most persons with Pneumocystis pneumonia.[22]
• Laboratory Studies: Nonspecific laboratory findings that may support the diagnosis of Pneumocystis pneumonia include lactate dehydrogenase (LDH) greater than 500 mg/dL and a 1,3-beta-D-glucan level of 80 pg/mL or greater; the 1,3-beta-D-glucan is used for testing because it is a major component of the P. jirovecii cell wall.[23,24,25] Although the sensitivity of the beta-D-glucan test is high, the specificity is low because persons with HIV who have advanced immunosuppression are at risk for multiple other fungal pathogens that can also cause elevated beta-D-glucan levels.[25]

Definitive Diagnostic Tests

A definitive diagnosis of Pneumocystis pneumonia requires detection of organisms in respiratory secretions or tissue.[13,26] Several tests usually play a role in the definitive diagnosis of Pneumocystis pneumonia.

• Induced Sputum: An induced sputum sample using an ultrasonic saline nebulizer has a sensitivity for diagnosing Pneumocystis pneumonia that ranges from 50 to 90%, assuming the medical facility has experience with performing this test.[13,26] Spontaneously expectorated sputum should not be submitted for diagnosis of Pneumocystis pneumonia due to low sensitivity.
• Bronchoscopy: A patient with a negative induced sputum should undergo bronchoscopy with bronchoalveolar lavage (BAL), which has a sensitivity of approximately 95%; some centers go directly to BAL as the initial test.[27]
• Transbronchial or Open-Lung Biopsy: A transbronchial biopsy or open-lung biopsy can further increase the yield but is rarely required because of the high yield with BAL.
• Detection of P. jirovecii Organisms in Sample: Many laboratories now consider the direct immunofluorescent stain as the procedure of choice for identifying P. jirovecii organisms; this test has higher sensitivity than stains that can detect P. jirovecii (methenamine silver, Giemsa silver, and toluidine blue-O).[13,26,28,29] Although polymerase chain reaction (PCR) is a highly sensitive test for detecting P. jirovecii organisms, it does not accurately distinguish acute infection from colonization.[26,28,30,31]

Treatment of Pneumocystis Pneumonia

The prompt and appropriate treatment of Pneumocystis pneumonia is essential for having a good outcome for this potentially fatal opportunistic infection. Accordingly, if the diagnosis of Pneumocystis pneumonia is suspected, empiric treatment for Pneumocystis pneumonia should be started without delay while the diagnostic evaluation is underway. The Adult and Adolescent OI Guidelines provide treatment regimens and indications for the use of adjunctive corticosteroids based on the severity of the pneumonia.[15] Nontoxic-appearing individuals with suspected or diagnosed Pneumocystis pneumonia can receive treatment as an outpatient provided they have a documented PaO2 of 70 mm Hg or greater and a calculated P(A-a O2) gradient less than 35 mm Hg. For all the regimens used to treat Pneumocystis pneumonia, the duration of antimicrobial therapy is 21 days, assuming clinical improvement, although the recovery of functional status can often lag behind based on the degree of pulmonary scarring, immunosuppression, comorbidities, and/or development of IRIS.[15] Following the 21-course of therapy, patients should receive secondary prophylaxis.[15] 

Treatment of Mild-to-Moderate Pneumocystis Pneumonia

Mild-to-moderate Pneumocystis pneumonia is defined as having a PaO2 of 70 mm Hg or greater and a calculated P(A-a O2) gradient less than 35 (Table 1).[15] Individuals who are being considered for treatment as an outpatient should appear nontoxic and meet the criteria for mild-to-moderate Pneumocystis pneumonia. The preferred therapy for mild-to-moderate Pneumocystis pneumonia is oral trimethoprim-sulfamethoxazole, given in three divided daily doses.[15] If dapsone is used as an alternative therapy, it is advisable to check a glucose-6-phosphate dehydrogenase (G6PD) level prior to starting dapsone.

Treatment of Moderate-to-Severe PCP

Moderate-to-severe Pneumocystis pneumonia is defined by room air PaO2 less than 70 mm Hg or alveolar-arterial O2 gradient greater than or equal to 35 mm Hg (Table 2).[15] The preferred therapy is trimethoprim-sulfamethoxazole, but therapy for moderate-to-severe is usually started intravenously and then switched to oral therapy after clinical improvement.[15]

Use of Adjunctive Corticosteroids

For moderate-to-severe Pneumocystis pneumonia, adjunctive corticosteroids improve survival and should ideally be started as soon as antimicrobial treatment is started for Pneumocystis pneumonia (and no later than 72 hours after starting antimicrobial therapy).[13,15,32] The recommended corticosteroid regimen is prednisone 40 mg twice daily for days 1 to 5, prednisone 40 mg once daily for days 6 to 10, and prednisone 20 mg once daily for days 11 to 21. The dose of intravenous methylprednisolone, if parenteral therapy is needed, is 80% of the oral prednisone dosage (i.e., 32 mg methylprednisolone = 40 mg prednisone).

Timing of Starting Antiretroviral Therapy

Individuals not on antiretroviral therapy who develop Pneumocystis pneumonia should start antiretroviral therapy within 2 weeks of the diagnosis of Pneumocystis pneumonia, if possible.[15] The recommendation to start antiretroviral therapy early is primarily based on data from a randomized, controlled trial that evaluated the timing of initiating antiretroviral therapy in 282 adults with acute opportunistic infections, including 177 (63%) with Pneumocystis pneumonia; participants randomized to early initiation of antiretroviral therapy (median 12 days after start of acute opportunistic infection treatment) experienced a lower incidence of progression to AIDS or death, as compared to those randomized to deferred initiation (median 45 days after start of acute opportunistic infection treatment).[33]

Preventing Recurrence (Secondary Prophylaxis)

All persons with HIV who are diagnosed with Pneumocystis pneumonia should receive secondary prophylaxis beginning immediately after completion of the 21-day treatment course.[15] Individuals who do not receive secondary prophylaxis have a high risk for developing another episode of Pneumocystis pneumonia. The following table addresses the preferred and alternative regimens for secondary prophylaxis, criteria for discontinuing secondary prophylaxis, and indications for restarting secondary prophylaxis.[15](Table 3)

Background

Toxoplasma gondii is a protozoan parasite that can infect humans and cause focal encephalitis, and more rarely, retinitis, pneumonitis, and disseminated disease. Most Toxoplasma disease in persons with HIV occurs from reactivation of latent organisms in patients who have a CD4 count less than 100 cells/mm³.[34,35] In the United States, prior to the availability of effective antiretroviral therapy, the incidence of Toxoplasma encephalitis among AIDS patients with a CD4 count less than 100 cells/mm³ was 40 per 1,000 person-years;[36] this rate has decreased significantly with widespread use of antiretroviral therapy and trimethoprim-sulfamethoxazole for prophylaxis.[1,2] All individuals diagnosed with HIV should be tested for IgG antibody to T. gondii at their initial medical visit if their CD4 count is less than 200 cellsmm³.[37]

Clinical Manifestations

The central nervous system is by far the most common site for the development of toxoplasmosis. Extracerebral disease, such as pulmonary or ocular involvement, occurs in about 1 to 2% of individuals with AIDS and toxoplasmosis.[38] Individuals with AIDS and Toxoplasma encephalitis characteristically present with headache, confusion, fever, and focal neurologic deficits (Figure 3).[35,37] Approximately 30% of persons with HIV and Toxoplasma encephalitis develop seizures, and those with severe disease may present with more profound changes in mental status. Abnormal findings on physical examination may include fever, hemiparesis, ataxia, altered consciousness, and cranial nerve palsies.

Figure 3. Toxoplasma Encephalitis: Symptoms and Signs

Figure 3A. Symptoms of Patients with Acute Toxoplasma Encephalitis

This graphic shows the frequency of symptoms present in 115 persons with HIV and Toxoplasma encephalitis seen at San Francisco General Hospital during the years 1981-1990.

Source: Porter SB, Sande MA. Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome. N Engl J Med. 1992;327:1643-8.

Figure 3B. Clinical Signs in Patients with Acute Toxoplasma Encephalitis

Frequency of signs present in 115 persons with HIV and Toxoplasma encephalitis; focal signs consisted of hemiparesis (39%), ataxia (30%), cranial-nerve palsies (28%), sensory deficits (12%), aphasia (8%), and hemianopia (7%).

Source: Porter SB, Sande MA. Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome. N Engl J Med. 1992;327:1643-8.

Diagnosis

Toxoplasma encephalitis is usually a presumptive diagnosis based on a combination of clinical manifestations, a positive serum anti-Toxoplasma antibody, and characteristic neuroradiographic findings.

• Anti-Toxoplasma Antibody: Among persons with acute Toxoplasma encephalitis, approximately 95% have detectable anti-Toxoplasma IgG antibodies using an enzyme-linked immunosorbent assay (ELISA), and approximately 85% have detectable antibodies using an indirect immunofluorescence assay (IFA) with a cutoff of greater than or equal to 1:16.[35]
• Brain Imaging: Contrast brain computed tomography (CT) scan shows enhancing lesions in approximately 90% of adults with HIV who have acute Toxoplasma encephalitis.[35] Individuals with AIDS and Toxoplasma encephalitis generally have multiple ring-enhancing lesions that often involve the basal ganglia (Figure 4).[35] Magnetic resonance imaging (MRI) is more sensitive than computed tomography (CT) for identifying Toxoplasma brain lesions and often shows multiple lesions when a CT scan has demonstrated only a solitary lesion. Since MRI is the more sensitive test, it is ideal to perform an MRI at the time the initial diagnosis is made and use this test to follow response to therapy.
  Figure 4. Toxoplasma Encephalitis and Brain Imaging

  

  Figure 4A. Contrast Brain Computed Tomographic (CT) Scan in Person with HIV and Toxoplasma Encephalitis

  This contrast CT scan shows multiple ring-enhancing lesions with surrounding vasogenic edema.

  Source: David H. Spach, MD

  

  Figure 4B. Brain Magnetic Resonance Imaging (MRI) Scan in Person with HIV and Toxoplasma Encephalitis

  The MRI scan shows multiple lesions.

  Source: David H. Spach, MD
• Analysis of Cerebrospinal Fluid: Ideally, a lumbar puncture should also be performed for T. gondii PCR testing on the cerebrospinal fluid (CSF) sample to help support the diagnosis; PCR for T. gondii in this setting has high specificity but low sensitivity, particularly once anti-toxoplasma therapy has been initiated.[39,40] In addition, CSF studies can help to investigate other conditions in the differential diagnosis, and CSF should be sent for cytology, culture (bacterial and fungal), cryptococcal antigen; and PCR for Mycobacterium tuberculosis, Epstein-Barr Virus (EBV), and John Cunningham (JC) Virus.[41,42]
• Brain Biopsy: In some circumstances, such as an acute life-threatening presentation or failure to respond to therapy for toxoplasmosis, a definitive diagnosis is needed; this requires detection of T. gondii organism in a clinical sample usually obtained via a stereotactic CT-guided brain biopsy (with hematoxylin and eosin staining, or ideally immunoperoxidase staining).

Treatment of Toxoplasma Encephalitis

Initial Therapy for Toxoplasma Encephalitis

Individuals with suspected Toxoplasma encephalitis should immediately receive intensive high-dose initial anti-Toxoplasma therapy. The Adult and Adolescent OI Guidelines provide recommendations for preferred and alternative regimens for the initial treatment (Table 4).[37] The preferred first-line therapies for Toxoplasma encephalitis are pyrimethamine plus sulfadiazine plus leucovorin (using weight-based dosing) or trimethoprim-sulfamethoxazole.[34,43,44] Leucovorin is used in this regimen to prevent hematologic toxicity secondary to pyrimethamine. More recently, trimethoprim-sulfamethoxazole has increasingly been used as the preferred agent for treatment due to the extremely high cost of pyrimethamine.[45] The initial treatment is for at least 6 weeks. Longer duration for acute treatment may be required if clinical manifestations or neuroradiographic findings indicate extensive disease or if the response to treatment is incomplete at 6 weeks. Following the initial treatment course, persons with HIV and toxoplasmosis should transition to chronic maintenance therapy.

Timing of Starting Antiretroviral Therapy

For persons with HIV who develop Toxoplasma encephalitis while not taking antiretroviral therapy, the optimal timing for initiating antiretroviral therapy remains unknown. Based on available data, most experts recommend starting antiretroviral therapy within 2 to 3 weeks of the diagnosis of Toxoplasma encephalitis.[37] This recommendation is primarily based on extrapolation of findings that showed early initiation of antiretroviral therapy reduces HIV progression and death in individuals with acute opportunistic infections.[33]

Response to Initial Therapy

More than 70% of individuals with HIV and Toxoplasma encephalitis have clinical and radiographic improvement within 14 days of receiving appropriate therapy for Toxoplasma encephalitis.[34,35,46] In one retrospective study, among patients with Toxoplasma encephalitis who eventually responded to anti-Toxoplasma therapy, 86% had improvement by day 7, and 91% had improvement (with respect to at least half of baseline abnormalities) by day 14 (Figure 5).[46] Thus, if by day 14, the person has not responded to therapy, the clinician should strongly consider a diagnosis other than Toxoplasma encephalitis and obtain further studies, typically including a brain biopsy, in an attempt to make a definitive or alternative diagnosis.[46]

Figure 5. Timing of Neurologic Response in Patients with Toxoplasma Encephalitis

The timing of neurologic response in 35 adults with HIV and Toxoplasma encephalitis who improved with treatment is shown. A neurologic response was defined as improvement in at least half of the baseline neurologic abnormalities.

Reproduced from Luft BJ, Hafner R, Korzun AH, et al. Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome. Members of the ACTG 077p/ANRS 009 Study Team. N Engl J Med. 1993;329:995-1000.
Reproduced with permission from the Massachusetts Medical Society. Copyright © 1993 Massachusetts Medical Society. All rights reserved.

Preventing Recurrence (Chronic Maintenance Therapy)

In the absence of chronic maintenance therapy for Toxoplasma encephalitis in persons not taking antiretroviral therapy, the rate of relapse after an initial episode of Toxoplasma encephalitis is high, with an incidence of 50 to 80% among persons surviving more than 6 to 12 months.[47] Thus, patients with Toxoplasma encephalitis who have successfully completed at least 6 weeks of acute therapy should transition to chronic maintenance therapy.[37] The preferred chronic maintenance regimens are the same as those used for initial therapy forToxoplasma encephalitis but are administered at a lower dose.[37] Both of the preferred regimens are adequate for Pneumocystis pneumonia prophylaxis. The following table addresses preferred and alternative regimens for chronic maintenance therapy, criteria for discontinuation of chronic maintenance therapy, and indications for restarting chronic maintenance therapy.[37] (Table 5)

Background

In the era prior to effective antiretroviral therapy, Mycobacterium avium complex (MAC) infection was a common complication of advanced HIV disease.[48] Mycobacterium avium complex represents a group of nontuberculous mycobacteria that are ubiquitous in the environment; the mode of transmission for these organisms is thought to occur via the lungs or gastrointestinal tract, but preventing environmental exposure is not realistic.[49] Most persons who develop disseminated MAC have a CD4 count of less than 50 cells/mm³ (Figure 6).[50] The incidence of disseminated MAC infection has declined dramatically since the early 1990s, and the incidence rate is now very low.[1,2,51,52] When cases of disseminated MAC occur, they typically involve individuals with HIV who have advanced immunosuppression and are unaware of their HIV diagnosis, or persons with HIV who are aware of their HIV diagnosis, but not engaged in medical care.

Figure 6. Risk of Developing MAC Bacteremia Related to Baseline CD4 Cell Count

Source: Nightingale SD, Byrd LT, Southern PM, Jockusch JD, Cal SX, Wynne BA. Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients. J Infect Dis. 1992;165:1082-5.

Clinical Manifestations

Persons with HIV at risk for MAC have a weak immune response to the mycobacterial organisms and thus experience minimal tissue destruction. The MAC-related clinical manifestations result from the huge burden of organisms, which interfere with tissue function and alter cytokine production.[53] Persons with disseminated MAC typically have CD4 counts of less than 50 cells/mm³ and present with nonspecific symptoms, including fatigue, fever, weight loss, diarrhea, and abdominal pain (Figure 7).[54] Physical examination findings may reveal hepatomegaly, splenomegaly, or lymphadenopathy. Common abnormal laboratory studies include anemia, increased alkaline phosphatase (often with normal bilirubin and hepatic aminotransferase levels), and an increased serum lactate dehydrogenase level.[53,54,55] Abdominal CT scan abnormalities may include multiple large retroperitoneal and mesenteric lymph nodes, hepatomegaly, splenomegaly, and a thickened small bowel wall.[56]

Figure 7. Common Clinical Manifestations of Persons with HIV and MAC Bacteremia

Source: Gordin FM, Cohn DL, Sullam PM, Schoenfelder JR, Wynne BA, Horsburgh CR Jr. Early manifestations of disseminated Mycobacterium avium complex disease: a prospective evaluation. J Infect Dis. 1997;176:126-32.

Diagnosis

The definitive diagnosis of disseminated MAC is usually made by isolating the organism from a normally sterile body site.[49] Use of mycobacterial blood cultures to isolate MAC has become the preferred method of diagnosis: among persons with untreated disseminated MAC, obtaining two sets of blood cultures has a sensitivity of greater than 90%.[57,58] In persons with positive MAC blood cultures, the laboratory will usually detect mycobacterial growth by day 14, at which point the Mycobacterium species can be identified using DNA probes. The diagnosis of disseminated MAC is sometimes made from a lymph node biopsy or a bone marrow biopsy.

Treatment of Disseminated MAC

Initial Therapy for Disseminated MAC

The Adult and Adolescent OI Guidelines recommend that initial treatment for disseminated MAC consists of at least two active drugs—typically a macrolide plus ethambutol.[49] Although macrolide therapy alone will usually cause an initial marked decline in MAC organism burden, resistance is likely to develop with monotherapy.[49,59] Based on data from multiple studies, the preferred initial two-drug therapy consists of a macrolide, either clarithromycin or azithromycin, in combination with ethambutol.[60,61,62,63] Persons taking ethambutol require regular ophthalmologic examinations due to the risk of optic neuritis. Some experts would add a third or fourth medication in selected circumstances. In general, the treatment regimen for disseminated MAC should be continued for a minimum of 12 months.[49] The following table outlines preferred therapy, considerations for adding rifabutin as a third medication, and considerations for adding a fourth drug.[49](Table 6)

Timing of Initiating Antiretroviral Therapy

Individuals newly diagnosed with disseminated MAC who are not on antiretroviral therapy should promptly start treatment for disseminated MAC and preferably start antiretroviral therapy at the same time that treatment for MAC is initiated.[49] The recommendation to start antiretroviral therapy at the same time as starting MAC treatment is for two reasons: (1) to improve the treatment response to antimycobacterial therapy and (2) to lower the risk of developing other serious opportunistic infections. The antiretroviral regimens should be adjusted to minimize the risk of adverse drug interactions with the antimycobacterial medications.

MAC and Immune Reconstitution Inflammatory Syndrome (IRIS)

Mycobacterium avium complex IRIS is a well-documented complication following initiation of antiretroviral therapy in patients with significant immunosuppression.[64] Persons with MAC-related IRIS usually present with intraabdominal lymphadenopathy or pulmonary-thoracic disease; the risk of death from MAC IRIS appears to be low, and the long-term prognosis is favorable.[64] The management of moderate-to-severe MAC IRIS-related symptoms should start with a nonsteroidal, antiinflammatory drug, but if there is no clinical improvement or initial symptoms are severe, then more aggressive treatment of IRIS is warranted using systemic corticosteroid therapy. The corticosteroids are typically given for 4 to 8 weeks in doses equivalent to 20 to 40 mg of oral prednisone daily.[49] With severe MAC IRIS, some experts recommend repeated courses of corticosteroids or longer treatment courses. Antiretroviral therapy should typically be continued if MAC IRIS develops.

Preventing Recurrence (Chronic Maintenance Therapy)

The regimens for chronic maintenance therapy (secondary prophylaxis) in patients with MAC are exactly the same as those used for initial therapy.[49]

Discontinuing Chronic Maintenance Therapy

Discontinuing secondary MAC prophylaxis (chronic maintenance therapy) requires meeting all the following criteria:[49]

• Successful completion of at least 12 months of MAC therapy, and
• No signs or symptoms of MAC disease, and
• Has sustained (at least 6 months) increase in CD4 count to greater than 100 cells/mm³ in response to antiretroviral therapy.

Restarting Chronic Maintenance Therapy

Secondary MAC prophylaxis should be restarted if a fully suppressive antiretroviral therapy regimen is not possible and the CD4 count is consistently less than 100 cells/mm³.[49]

Background

Cryptococcosis is an opportunistic fungal infection that causes significant morbidity and mortality in persons with HIV who have advanced immunosuppression. In the United States, the incidence of cryptococcal antigenemia is 2.9% in adults with a CD4 count less than 100 cells/mm³ and 4.3% in those with less than 50 cells/mm³.[65] Most cryptococcal infections in persons with HIV are caused by Cryptococcus neoformans, though Cryptococcus gattii is increasingly recognized as a causative agent in the United States, particularly in the Pacific Northwest.[66,67,68,69] As with other opportunistic infections, the widespread use of highly active antiretroviral therapy has led to a decrease in the incidence of cryptococcal meningitis, and most cases are identified in persons with recently diagnosed HIV who have advanced immunosuppression, or in persons with established HIV who are not engaged in health care and thus are not taking antiretroviral therapy.[70]

Clinical Manifestations

Cryptococcal meningitis occurs as a result of disseminated infection and typically manifests with a more indolent presentation than acute bacterial meningitis.[71] Most patients with early cryptococcal meningitis develop nonspecific symptoms consisting of fever and headache, and approximately 65 to 75% do not have classic signs of meningeal irritation early in their course of meningitis.[71] As the disease progresses, more neurologic-specific manifestations typically develop, including altered mental status, neck stiffness, or cranial nerve abnormalities (Figure 8).[72] Approximately 10% of individuals with disseminated cryptococcal disease have cutaneous manifestations that may resemble molluscum contagiosum.[73] Individuals with HIV can develop pulmonary cryptococcal disease, with or without central nervous system involvement.

Figure 8. Clinical Manifestations of Persons with HIV and Cryptococcal Meningitis at the Time of Diagnosis

Clinical manifestations of 65 adults with HIV from France at the time of diagnosis of cryptococcal meningitis. The mean CD4 count at the time of diagnosis was 46 cells/mm³.

Source: Darras-Joly C, Chevret S, Wolff M, et al. Cryptococcus neoformans infection in France: epidemiologic features of and early prognostic parameters for 76 patients who were infected with human immunodeficiency virus. Clin Infect Dis. 1996;23:369-76.

Diagnosis

The diagnosis of cryptococcal meningitis is usually made by obtaining a positive cryptococcal antigen test on a cerebrospinal fluid sample. Among persons with HIV who have cryptococcal meningitis, the cerebrospinal fluid and serum cryptococcal antigen test are positive in more than 95% of cases, often with a very high titer.[74,75,76] A positive serum cryptococcal antigen, however, is not sufficient to diagnose central nervous system disease and all persons with suspected cryptococcal meningitis should undergo lumbar puncture, both to perform diagnostic tests for C. neoformans and to evaluate for other causes of altered mental status. Most experts would recommend performing a brain CT prior to lumbar puncture to evaluate for a brain mass lesion that could result in brain herniation during the procedure. Tests done on cerebrospinal fluid should include cryptococcal antigen, fungal culture, glucose, protein, cell count with differential, Gram's stain, and bacterial culture. More than 50% of individuals with cryptococcal meningitis have fewer than 20 leukocytes/mm³ on the CSF cell count. Opening pressure should be measured at the time of lumbar puncture in all persons with suspected cryptococcal meningitis since a significant proportion will have an elevated CSF pressure (Figure 9).[77]

Figure 9. CSF Opening Pressure in Persons with HIV and Cryptococcal Meningitis at the Time of Diagnosis

Data from 221 individuals with HIV and cryptococcal meningitis; CSF opening pressure measured prior to receiving therapy. Normal defined as pressure <190 cm H₂O.

Source: Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis. 2000;30:47-54.

Treatment of Cryptococcal Meningitis

The [71] recommended treatment of cryptococcal meningitis involves three phases: induction therapy, consolidation therapy, and chronic maintenance therapy.[71,78] Serial monitoring of cryptococcal antigen to determine response to therapy has shown minimal benefit and is not recommended.[79] 

Induction Therapy for Cryptococcal Meningitis

The recommended initial induction therapy for cryptococcal meningitis consists of either intravenous liposomal amphotericin B plus oral flucytosine or intravenous amphotericin B deoxycholate plus oral flucytosine (Table 7).[71] Liposomal amphotericin B has similar efficacy as amphotericin B deoxycholate but is associated with a lower risk of renal toxicity.[71,80] Flucytosine, when added to either liposomal amphotericin B or amphotericin B deoxycholate, results in more rapid CSF sterilization.[81] If flucytosine is used, it is ideal to check a flucytosine level after administering 3 to 5 doses of flucytosine, approximately 2 hours after taking the dose. The target serum flucytosine level is 25 to 100 mg/L. The flucytosine dose must be adjusted in persons with renal impairment.[71]

Management of Increased Intracranial Pressure

At the time induction therapy is started, cryptococcal meningitis is often associated with increased intracranial pressure (opening pressure greater than 20 cm H₂0). Appropriate management of increased intracranial pressure can improve survival and neurologic outcomes. In a retrospective study performed in the United States, investigators showed that patient outcomes strongly correlated with the use of serial lumbar punctures to manage increased intracranial pressure during the first 2 weeks of therapy for cryptococcal meningitis (Figure 10).[77] A more recent study of patients with acute cryptococcal meningitis in Africa showed a marked survival benefit if therapeutic lumbar punctures were performed.[82] The following summarizes recommendations from the Adult and Adolescent OI Guidelines for managing elevation in intracranial pressure in persons with cryptococcal meningitis.[71]

• Lowering Opening Pressure at Initial Lumbar Puncture: If the opening pressure is elevated, the recommended approach is to remove ample cerebrospinal fluid (20 to 30 mL) to reduce the opening pressure to normal (less than 20 cm H₂0), or at least by 50% if not able to achieve a normal pressure with the removal of 20 to 30 mL.[71]
• Serial Lumbar Punctures: For persons with ongoing symptoms, such as headache or confusion, serial lumbar punctures with cerebrospinal fluid drainage may be required on a daily basis to maintain opening pressure less than 20 cm H₂0; daily lumbar punctures should be continued until the opening pressure normalizes and symptoms resolve.[71]
• Use of Lumbar Drains or Ventriculostomy: If the person initially has focal neurologic deficits, or serial lumbar punctures with the removal of cerebrospinal fluid fails to control increased intracranial pressures, a lumbar drain or ventriculostomy may be required.[71,83]
• Medical Therapy for Reducing Intracranial Pressure: For persons with acute cryptococcal meningitis, attempts to treat increased intracranial pressure with medical therapy, such as mannitol, acetazolamide, or corticosteroids, is not effective and is not recommended.[71,84]

Figure 10. Patient Outcomes Related to Change in Cerebrospinal Fluid (CSF) Opening Pressure in Persons with HIV and Cryptococcal Meningitis

The graph represents outcomes of 161 individuals with HIV and cryptococcal meningitis who had lumbar puncture with opening pressure measured prior to therapy and 2 weeks after treatment. Clinical failure was defined as persistent or worsening signs and symptoms of cryptococcal meningitis after 2 weeks of therapy; mycologic failure was defined as positive CSF culture after 2 weeks of therapy.

Source: Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis. 2000;30:47-54.

Evaluation After Course of Induction Therapy

If there is substantial clinical improvement after completing the 2-week induction course, lumbar puncture should be performed to obtain cerebrospinal fluid fungal cultures.[71] If the patient does not improve clinically, then induction therapy should be continued until the cerebrospinal fluid cultures are negative.[71]

Consolidation Therapy for Cryptococcal Meningitis

After at least 2 weeks of successful initial induction therapy, with success measured by significant clinical improvement and a negative cerebrospinal fluid culture, consolidation therapy with oral fluconazole can be started and continued for at least 8 weeks (Table 8).[71] The preferred consolidation dosing of fluconazole is 800 mg once daily (AI), but if a clinically stable person has evidence of negative cerebrospinal fluid culture and has been initiated on antiretroviral therapy, the dose of fluconazole can be decreased to 400 mg once daily (AII).[71] If the patient improves clinically, but the cerebrospinal fluid cultures are positive after 2 weeks of induction therapy, then use a higher dose of fluconazole (1,200 mg once daily) and repeat the lumbar puncture 2 weeks later. The duration of consolidation therapy is 8 weeks from the time of negative CSF culture.[71] Monitoring serum and/or cerebrospinal cryptococcal antigen titers is not recommended.[71]

Cryptococcal Meningitis and IRIS

A paradoxical worsening of cryptococcal meningitis occurs in up to 30% of persons with HIV who start antiretroviral therapy at the same time (or soon after) they start treatment for cryptococcal meningitis.[85] If cryptococcal meningitis-associated IRIS develops, it is often life-threatening. Baseline factors associated with an increased risk of developing cryptococcal meningitis-associated IRIS include lack of prior antiretroviral therapy, high baseline HIV RNA, low white blood cell count in cerebrospinal fluid, and a high cerebrospinal fluid fungal burden.[7] The challenge of such cases is differentiating between cryptococcal meningitis treatment failure, a new central nervous system disorder, or IRIS. Persons with IRIS typically have negative cerebrospinal fluid fungal cultures, whereas those with treatment failure will have positive cultures. If a new central nervous system problem and treatment failure are ruled out, and IRIS is the most likely diagnosis, antiretroviral therapy and antifungal therapy should be continued in conjunction with careful lowering of intracranial pressure, if indicated. Mild cases can be managed with nonsteroidal antiinflammatory medications, and most experts would use oral corticosteroids in severe cases.

Timing of Initiating Antiretroviral Therapy

To reduce the risk of IRIS in patients with cryptococcal meningitis, the Adult and Adolescent OI Guidelines recommend delaying initiation of antiretroviral therapy for 4 to 6 weeks after starting treatment for cryptococcal meningitis, ideally after negative CSF cryptococcal cultures have been obtained.[71] A 2014 study from Uganda and South Africa demonstrated that deferral of antiretroviral therapy for 5 weeks was associated with a significant improvement in survival, as compared with initiating antiretroviral therapy at 1 to 2 weeks, especially among patients with a low white blood cell count in the cerebrospinal fluid.[86] Several additional studies support the approach of deferring antiretroviral therapy for at least several weeks.[87,88]

Maintenance Therapy for Cryptococcal Meningitis

Maintenance therapy with fluconazole 200 mg once daily is required for at least 1 year after successful induction and consolidation treatment of cryptococcal meningitis.[71] Separate studies have shown that fluconazole is superior to intravenous amphotericin B and to oral itraconazole for chronic maintenance therapy, so the latter two are not recommended.[89,90] The following table addresses the preferred regimen for maintenance therapy, criteria for stopping maintenance therapy, and indications for restarting maintenance therapy.[71](Table 9)

Additional Treatment Considerations

The following summarizes the recommended treatment approach for: (1) cryptococcal infection that does not involve the lungs or central nervous system (CNS), (2) diffuse cryptococcal pulmonary disease, and (3) asymptomatic persons with Isolated cryptococcal antigenemia.[71] Note that all asymptomatic persons with HIV who have cryptococcal antigenemia should have their CSF evaluated for occult cryptococcal meningitis.[71]

• Treating Non-CNS Extrapulmonary, Diffuse Pulmonary Disease, or Asymptomatic Patients with Isolated Cryptococcal Antigenemia (Serum LFA titer ≥1:640) without evidence of CNS Disease: The recommendation is to use the same treatment as recommended for cryptococcal meningitis, but without the need for follow-up lumbar puncture and CSF analysis.[71]

• Treating Non-CNS Focal Pulmonary Disease or Asymptomatic Patients with Isolated Cryptococcal Antigenemia (Serum LFA titer ≤1:320), without evidence of CNS Disease: The recommended treatment is fluconazole 400 to 800 mg PO daily for 10 weeks, followed by fluconazole 200 mg daily, with a total duration of therapy of 6 months.[71]

Background

Cytomegalovirus (CMV) is a double-stranded DNA virus in the herpes family that can cause invasive disease, including retinitis, colitis, and central nervous system disease, in persons with advanced immunosuppression (CD4 count less than 50 cells/mm³).[91,92] Among people with HIV, retinitis is the most common form of CMV end-organ disease. Typically, CMV disease in people with HIV and advanced immunosuppression occurs due to reactivation of latent CMV infection. Among men with HIV who have sex with men, CMV-positive antibody rates are greater than 90%. Additional risk factors for the development of clinical CMV disease include previous opportunistic infections, a high HIV RNA level (greater than 100,000 copies/mL), and a high level of CMV viremia.[93] Following the widespread availability and use of effective antiretroviral therapy, the incidence of CMV retinitis has declined by more than 90%.[93,94,95,96,97]

Clinical Manifestations

Retinitis

Individuals with CMV retinitis most often develop one or more of the manifestations commonly referred to as the four “F's”: floaters, flashes, field deficits, or failing vision.[98] These manifestations can represent loss of peripheral and central vision. Individuals with CMV retinitis do not have pain related to the lesions, nor do they present with redness of the eye. Although only one eye is usually involved at the initial presentation, CMV disease can progress to affect the contralateral eye, particularly in individuals who are not on antiretroviral therapy.[94] On dilated funduscopic examination, the CMV-associated retinal lesions typically appear as yellow or white patches caused by retinal necrosis, with or without hemorrhage, usually following a vascular distribution; the findings of CMV retinitis should not be confused with findings caused by HIV retinopathy (Figure 11).[92]

Figure 11. Retinitis Findings on Fundoscopic Examination

Figure 11A. Normal Retina

This image of a normal retina identifies important landmarks visible with a hand-held ophthalmoscope. The macula is in the center of the retina; it contains densely packed cones that specialize in visual acuity and color vision. The fovea is the central depression within the macula. The optic nerve transmits impulses from the retina to the brain and the visible portion of the optic nerve is known as the optic nerve head or optic disc. Retinal veins and arteries are prominently seen extending from the optic nerve.

Figure 11B. Cytomegalovirus Retinitis, Central Portion of Retina

This retinal photograph taken from a person with HIV and cytomegalovirus retinitis shows an opacified, edematous retina (yellow) and hemorrhage (red); the retinitis involves the optic nerve head and extends adjacent to the macula along the retinal blood vessels. This lesion is considered an immediate sight-threatening lesion.

Figure 11C. Cytomegalovirus Retinitis, Brushfire Pattern

This retinal photograph taken of a person with HIV and cytomegalovirus retinitis shows extensive retinitis in a brushfire pattern in the upper and right region of the image. In the area farthest to the upper right, retinal necrosis and atrophy have led to retinal pigment epithelial change, as evident by the darkly pigmented appearance.

Figure 11D. Cytomegalovirus Retinitis, Smoldering Lesion

This retinal photograph is taken from a person with HIV in whom cytomegalovirus retinitis (arrow) developed in a slower fashion ("smoldering CMV retinitis"). This "smoldering" type of lesion often does not cause noticeable symptoms and may escape detection until it extends closer to the site-threatening region (zone 1).

Figure 11E. HIV Retinopathy

This retinal photograph taken of a person with HIV retinopathy shows multiple cotton wool spots. These cotton wool spots represent nerve fiber layer infarcts, identical to those often seen in persons with hypertension or diabetes mellitus. These lesions do not cause symptoms and resolve spontaneously.

Gastrointestinal

Odynophagia is usually the most prominent symptom with CMV esophagitis.[99] Persons with HIV and CMV colitis typically have weight loss, malaise, anorexia, abdominal pain, debilitating diarrhea (sometimes bloody), and potentially develop gastrointestinal perforation as a life-threatening complication.[100,101]

Neurologic

Less frequently, individuals with HIV and CMV infection can have neurologic manifestations, including myelitis, polyradiculomyelopathy, encephalitis, and ventriculitis.[102] In the absence of antiretroviral therapy or anti-CMV treatment, CMV end-organ disease will inevitably progress over a matter of days to weeks.

Diagnosis

Most individuals with HIV and CMV retinitis, colitis, or other end-organ disease have CMV viremia that can be detected by PCR, antigen assays, or culture, but testing for CMV viremia is not recommended for the diagnosis of CMV-related end-organ disease.[92,93]

Retinitis

The diagnosis of CMV retinitis is a clinical diagnosis based on characteristic findings observed during a dilated funduscopic examination by an ophthalmologist.[92,93] With a handheld monocular direct ophthalmoscope, a clinician can visualize all of zone 1 (including the optic nerve head and the macula), less than half of zone 2, and none of zone 3 (Figure 12). Thus, all patients suspected of having CMV retinitis should see an ophthalmologist for a full retinal examination. Obtaining PCR of aqueous or vitreous specimens can be helpful but is not practical in most situations.

Figure 12. Retinal Anatomic Zones

This illustration shows a schematic representation of an entire retina with superimposed anatomic zones (as defined by the UCLA CMV Retinopathy Study Group). Using a standard direct ophthalmologic examination, only a small portion of the retina is visualized (all of zone 1 and some of zone 2). Zone 1 comprises less than 10% of the entire retina. The retina lines most of the inner wall of the back of the eyeball and it is comprised of thin, multi-layered neural tissue; the retina receives and transmits images. The medial region is also known as the nasal region and the lateral region is also referred to as the temporal region.

Source: The retinal anatomic zones are based on the classification in Holland GN, Buhles WC Jr, Mastre B, Kaplan HJ. A controlled retrospective study of ganciclovir treatment for cytomegalovirus retinopathy. Use of a standardized system for the assessment of disease outcome. UCLA CMV Retinopathy. Study Group. Arch Ophthalmol. 1989;107:1759-66.
Illustration credit: David Ehlert, Cognition Studio.

Gastrointestinal

The diagnosis of CMV esophagitis or colitis is suggested by observing mucosal ulcerations on endoscopy, but a definitive diagnosis requires characteristic biopsy findings showing intranuclear and intracytoplasmic inclusions.[101] Abdominal computed tomographic scans may show colonic thickening, but this finding is nonspecific.

Neurologic

The diagnosis of CMV central nervous system disease is usually made based on compatible clinical findings in conjunction with a positive cerebrospinal fluid PCR test for CMV.[103]

Treatment

The Adult and Adolescent OI Guidelines recommendations for the treatment of CMV disease vary based on the organ system affected.[93]

Initial Treatment of CMV Retinitis

The treatment of CMV retinitis depends on whether the individual has sight-threatening retinitis or peripheral lesions; lesions are considered sight-threatening if they are within 1,500 microns of the fovea.[93] The preferred initial treatment for immediate sight-threatening retinitis consists of induction therapy with intravenous ganciclovir or oral valganciclovir.[93] Some clinicians supplement the systemic therapy of immediate sight-threatening CMV retinitis with repeated intravitreal injections of either ganciclovir or foscarnet, given every 7 days until lesion inactivity is achieved.[93] For small peripheral lesions that are not vision threatening, providing induction therapy with oral valganciclovir is usually sufficient.[93] Even if the ocular clinical manifestation are unilateral, systemic therapy helps to prevent disease in the contralateral eye. The following table summarizes preferred and alternative treatments for CMV retinitis, including treatment for sight-threatening and peripheral  lesions.[93] (Table 10) 

Cytomegalovirus Retinitis and IRIS

The ocular form of CMV-associated IRIS, typically referred to as immune reconstitution uveitis, is characterized by inflammation in the anterior chamber or vitreous; vision loss from macular edema, cataracts, or epiretinal membranes can occur.[95,104,105,106] Immune reconstitution uveitis tends to occur in the first 3 months after starting antiretroviral therapy but can occur even years after treatment of acute CMV retinitis.[93]  The risk of developing CMV-associated IRIS is highest when the CMV disease involves more than 30% of the retina.[107] The treatment of immune reconstitution uveitis typically consists of continued CMV treatment with the addition of corticosteroids (intravitreal or oral).[93,108]

Maintenance Therapy for CMV Retinitis

After completion of 14 to 21 days of induction therapy for CMV retinitis, persons should transition to chronic maintenance therapy.

• Preferred Therapy: The initial intravenous ganciclovir induction therapy should be followed by maintenance therapy with either oral valganciclovir 900 mg once daily or intravenous ganciclovir 5mg/kg once daily. If oral therapy was used for the initial therapy, it should be followed by maintenance therapy with oral valganciclovir 900 mg once daily.
• Alternative Therapy: If foscarnet or cidofovir is required for initial therapy, either can be continued for maintenance therapy, but expert consultation is advised since these agents are very likely to cause significant toxicity if continued for prolonged periods of time.

Discontinuing Maintenance Therapy for CMV Retinitis

Chronic maintenance therapy for CMV retinitis can be discontinued when the following criteria are met:

• At least 3 to 6 months of CMV treatment has been completed, and
• No retinal lesions are active, and
• The CD4 count is above 100 cells/mm³ for 3 to 6 months in response to antiretroviral therapy, and
• An ophthalmologist has been consulted.

Note: After stopping maintenance therapy, ophthalmologic monitoring for early detection of CMV relapse should ideally be performed every 3 months to evaluate for early relapse of retinitis and to detect immune reconstitution uveitis. After sustained immune reconstitution has occurred, periodic ophthalmologic examinations should be performed as indicated and feasible.

Restarting Chronic Maintenance Therapy

Chronic maintenance therapy should be restarted if the CD4 count decreases to less than 100 cells/mm³.

Treatment of CMV Esophagitis or Colitis

The following summarizes the Adult and Adolescent OI Guidelines recommendations for the preferred and alternative therapies for CMV esophagitis or colitis.[93] The preferred therapy is intravenous ganciclovir and the duration of therapy is 21 to 42 days or until clinical symptoms resolve.[93,109,110] (Table 11) 

Treatment of CMV Pneumonia and CMV Encephalitis

There are limited, mostly anecdotal, data for the treatment of CMV pneumonia and CMV neurological disease. The recommended treatment for CMV pneumonia consists of either intravenous ganciclovir or intravenous foscarnet.[93] For neurological disease, many clinical experts would initiate a combined antiviral intravenous regimen of ganciclovir and foscarnet, despite the toxicities associated with using these drugs simultaneously.[93]

Adverse Effects Associated with CMV Therapy

Cytopenias (anemia, thrombocytopenia, neutropenia) are the most important toxicity associated with ganciclovir and valganciclovir use. The neutropenia can be mitigated by using granulocyte colony-stimulating factor (G-CSF).[93,111] During induction with ganciclovir or valganciclovir, a complete blood count and serum creatinine should be monitored at least twice weekly and then once weekly during maintenance. Foscarnet use can be associated with nephrotoxicity and electrolyte derangements. Toxicity monitoring during foscarnet therapy should include serum electrolytes and serum creatinine at least twice weekly during induction and once weekly while on maintenance treatment. Intravenous cidofovir use can lead to nephrotoxicity, ocular hypotony, and neutropenia. Aggressive intravenous fluid hydration and oral probenecid administration immediately prior to cidofovir dosing can help to attenuate renal issues.[93]

Timing of Initiating Antiretroviral Therapy

Among persons with HIV who develop CMV retinitis, the risk of developing CMV-associated IRIS is greater when antiretroviral therapy is immediately started versus deferring antiretroviral therapy until the CMV retinitis is initially controlled.[112] Individuals with newly diagnosed CMV who are not on antiretroviral therapy should promptly start treatment for CMV retinitis or CMV end-organ disease and then start antiretroviral therapy no more than 2 weeks later.[93] There is also a significant concern for development of CMV-related IRIS in persons who have CMV neurologic disease.

Background

Progressive multifocal leukoencephalopathy (PML) is a focal demyelinating disease of the central nervous system caused by reactivation of the John Cunningham (JC) virus in persons who have impaired immunity, most often in the setting of HIV-associated immunosuppression.[113] Infection with JC virus is common, and antibodies to JC virus are detected in more than 80% of humans worldwide.[114] Although the incidence of PML has decreased with the widespread use of effective antiretroviral therapy, mortality remains high for those persons with HIV who develop PML.[115,116]

Clinical Manifestations

Persons with HIV who develop PML typically present with subacute, progressive focal neuropsychiatric signs and symptoms, including cognitive disturbances, visual changes, limb paresis, hemisensory deficits, dysmetria, and ataxia.[114,117,118] The clinical presentation with PML may be difficult to distinguish from severe HIV-associated dementia or a slowly evolving stroke.[113,119] Approximately 15 to 20% of persons with PML will have at least one seizure.[120,121] Headache, fever, acute encephalopathy, and spinal cord manifestations are rare. In persons with AIDS, if immunosuppression is not reversed with antiretroviral therapy, PML will have a relentless progression and will lead to death within 6 months.[113]

Diagnosis

Brain biopsy is the gold standard for diagnosis, but it is not usually performed since a presumptive diagnosis can be made based on brain magnetic resonance imaging (MRI) findings. Brain MRI usually shows focal white matter lesions that correlate anatomically to the patient’s neurological deficits; these multiple high-signal intensity lesions are best seen on T2-weighted and FLAIR sequences (Figure 13).[113] In addition, 70 to 90% of persons with PML who are not taking antiretroviral therapy have a positive JC virus DNA PCR in the cerebrospinal fluid (this number drops to about 60% among persons who are taking antiretroviral therapy).[122] Detection of JC virus in the cerebrospinal fluid is not necessary to confirm the diagnosis of PML if the clinical picture and brain MRI findings are consistent with the diagnosis, but may support the diagnosis of PML in atypical cases. Plasma PCR detection of JC virus DNA can be a useful adjunct test, especially when CSF is not readily available, with the test having high specificity but relatively low sensitivity.[122]

Figure 13. Magnetic Resonance Imaging (MRI) in Person with HIV and Progressive Multifocal Leukoencephalopathy

This T2-weighted MRI scan shows diffuse confluent lesions most prominent in the occipital lobes.

Source: David H. Spach, MD

Treatment

There is no specific antiviral therapy for JC virus.[113] The cornerstone for the treatment of PML in persons with HIV is antiretroviral therapy, with resultant immune restoration.[122] Antiretroviral therapy should promptly be initiated or optimized in all persons with HIV who are diagnosed with PML. Among those with HIV and PML who receive effective antiretroviral therapy, the 1-year survival rate is only 55 to 60%, and survivors often have some permanent neurologic deficits.[113,123] Multiple therapies have been attempted for treatment of PML in persons with HIV, but none (except for antiretroviral therapy-related immune reconstitution) has been shown to be effective (Table 12).[122] The Adult and Adolescent OI Guidelines specifically recommend against the use of the following therapies for PML in persons with HIV: intravenous cytarabine, intrathecal cytarabine, cidofovir, mefloquine, mirtazapine, olanzapine, ziprasidone, cyproheptadine, risperidone, and interferon-alfa, and check-point inhibitors such as pembrolizumab.[122]

Timing of Initiating Antiretroviral Therapy

Individuals with HIV newly diagnosed with PML who are not on HIV antiretroviral therapy should immediately start on a fully suppressive antiretroviral therapy.[122] There is no rationale to delay therapy since there is no known effective antiviral therapy specific for PML that could be used to reduce the JC virus load prior to starting HIV antiretroviral therapy. Individuals diagnosed with PML who are taking antiretroviral therapy but do not have optimal suppression of HIV should receive a fully suppressive antiretroviral regimen.

Management of Immune Reconstitution Syndrome

Persons with HIV may develop PML immune reconstitution syndrome in the first weeks to months after starting antiretroviral therapy. The increased inflammation in the central nervous system may potentially cause mass effect and herniation. For individuals with a contrast-enhanced imaging that shows significant inflammation, use of corticosteroids can be considered.[122] There is no consensus on the dosage or duration of corticosteroids for PML IRIS; the Adult and Adolescent OI Guidelines suggest one approach modeled on treating flares of multiple sclerosis, which is to start with a 3- to 5-day course of intravenous methylprednisolone (1 gram per day) and then transition to oral prednisone 60 mg once daily and taper over 1 to 6 weeks.[122] Some experts recommend obtaining a brain MRI at 2 to 6 weeks after starting corticosteroid therapy to reevaluate edema and inflammation, which can inform the corticosteroid dosing schedule and establish a new radiographic baseline. Antiretroviral therapy should not be discontinued in this setting.[122] 

Background

Esophageal candidiasis remains a significant cause of morbidity in persons with HIV, but the incidence has declined markedly since the widespread use of highly effective antiretroviral therapy [97]. When esophageal candidiasis occurs, it usually involves individuals with a CD4 cell count less than 100 cells/mm³.[124] Candida albicans is the most common species involved, but non-albicans species (C. dubliniensis, C. glabrata, C. tropicalis) can also cause disease.[125] In addition, Candida glabrata is associated with azole resistance among patients with advanced immunosuppression, particularly those who have received repeated or prolonged courses of oral fluconazole.[126,127,128]

Clinical Manifestations

Esophageal candidiasis usually causes retrosternal burning pain and odynophagia.[129,130] Persons with HIV and esophageal candidiasis often also have oropharyngeal candidiasis, which typically presents with painless, creamy white plaques or patches on the tongue, buccal mucosa, or pharynx that can be easily scraped off with a tongue blade.

Diagnosis

A presumptive diagnosis of esophageal candidiasis is based on typical clinical symptoms and response to empiric antifungal treatment; a definitive diagnosis can be made with endoscopic evaluation with visualization and obtaining fungal culture (with speciation), but this approach is generally reserved for patients who do not respond within 7 days after starting antifungal therapy.[129,131] If endoscopy is performed, it should evaluate for other potential causes of esophagitis.

Treatment

Initial Therapy

For initial treatment of esophageal candidiasis, the preferred therapy should be oral or intravenous fluconazole.[129,132,133] The recommended initial course of treatment for esophageal candidiasis is 14 to 21 days.[129] Multiple alternative options are available.[129](Table 13).

Therapy During Pregnancy

During the first trimester of pregnancy, intravenous amphotericin B is recommended for the treatment of esophageal candidiasis.[129] Data derived from women with vulvovaginal candidiasis suggest that fluconazole should not be used in the first trimester due to the risk of spontaneous abortion and, with doses greater than 150 mg per day, the risk of cardiac septal closure defects.[134,135,136] Use of agents other than amphotericin B to treat esophageal candidiasis in pregnancy is not recommended,either due to inadequate data in pregnancy or known teratogenic effects.[129] 

Timing of Starting Antiretroviral Therapy

Antiretroviral therapy should be initiated without delay in patients with Candida esophagitis.[129]

Chronic Suppressive Therapy

Chronic suppressive therapy for Candida is not recommended for persons with isolated episodes of esophageal candidiasis because therapy for acute episodes of disease is effective, mortality from candidiasis is low, drug interactions can occur, and suppressive therapy may increase drug-resistant species.[129] The use of chronic suppressive therapy for persons with esophageal candidiasis is usually limited to situations when individuals with a CD4 count less than 200 cells/mm³ have severe bouts of esophageal candidiasis or frequent recurrences.[129] If the decision is made to administer chronic suppressive therapy for patients with esophageal candidiasis, the recommended options are:

• Fluconazole 100 to 200 mg PO daily, or
• Posaconazole oral solution 400 mg PO twice daily, or
• Posaconazole tablet 300 mg PO daily

Background

Histoplasmosis is a fungal infection caused by Histoplasma capsulatum, which is endemic to the Central and South-Central United States (especially the Mississippi and Ohio River Valley areas), as well as to many regions of Latin America.[137,138] Histoplasma infections are acquired through inhalation, and asymptomatic extrapulmonary infection is common. Individuals with HIV who have a CD4 count below 150 cells/mm³ have an increased risk of developing symptomatic illness following acute infection, and most cases in nonendemic areas are attributed to reactivation of latent infection.[139,140] The incidence of symptomatic histoplasmosis declined after the introduction of potent antiretroviral therapy.[1]

Clinical Manifestations

Histoplasma infection can be asymptomatic or symptomatic, acute or chronic, and focal or disseminated. Disseminated disease often develops in persons with HIV, particularly in those who have a CD4 count of less than 150 cells/mm³.[138,139] Symptoms of disseminated histoplasmosis may include fever, fatigue, weight loss, hepatosplenomegaly, cough, chest pain, and dyspnea.[141] Approximately 50% of cases include respiratory complaints; chest radiography often shows diffuse or patchy opacities that can mimic Pneumocystis pneumonia (Figure 14). Less often, the chest radiograph shows focal infiltrates, nodules, or cavities. Persons with HIV and histoplasmosis may also have hepatosplenomegaly (25%), lymphadenopathy (25%), sepsis (10 to 20%), central nervous system involvement (10 to 20%), or gastrointestinal involvement (10 to 20%).[138] Some with disseminated disease may have oral lesions.[142] In rare situations, individuals with disseminated histoplasmosis may develop hemophagocytic syndrome, also known as hemophagocytic lymphohistiocytosis (HLH), which is a dysregulated immune response to infection that causes a multisystem illness characterized by fever, hepatosplenomegaly, and cytopenias.[143,144]

Figure 14. Chest Radiograph of a Person with HIV and Disseminated Histoplasmosis

This chest radiograph in a person with HIV and disseminated histoplasmosis shows subtle diffuse ground-glass pulmonary infiltrates.

Source: David H. Spach, MD

Diagnosis

The following summarizes the main laboratory tests used in diagnosing histoplasmosis.

• Histoplasma Antigen: Disseminated histoplasmosis in persons with HIV is usually diagnosed by detecting Histoplasma antigen in blood or urine (Figure 15).[138,145,146] Results with the Histoplasma antigen assay (on urine or serum samples) are typically available in 1 to 2 days. Evaluation of tests for the diagnosis of disseminated histoplasmosis in adults with HIV has shown that sensitivity was 100% with urinary antigen and 92% with serum antigen.[147]
  

  Figure 15. Estimated Sensitivity of Diagnostic Tests for Disseminated Histoplasmosis in Persons with HIV

  These data reflect the sensitivity of four different tests used to diagnose histoplasmosis in persons with HIV who have disseminated histoplasmosis. These data include samples from blood, bone marrow, respiratory secretions, or localized skin lesions.

  Source: Wheat J. Endemic mycoses in AIDS: a clinical review. Clin Microbiol Rev. 1995;8:146-59.
• Serologic Testing: Testing for antibodies to H. capsulatum is not very useful for the diagnosis of disseminated histoplasmosis in persons with HIV.[145,146,148]
• Peripheral Blood Smear: In some cases, peripheral blood smears and biopsy samples of involved tissues may show budding yeasts (Figure 16).[149]
  

  Figure 16. Disseminated Histoplasmosis and Peripheral Blood Smear

  This peripheral blood smear from a person with HIV shows a cluster of intracellular Histoplasma capsulatum organisms (white arrow). Blood cultures subsequently grew Histoplasma capsulatum.
• Culture: Although more than 85% of adults with HIV and disseminated histoplasmosis will have a positive culture for H. capsulatum from a body source (blood, bone marrow, respiratory secretion, or skin lesions), obtaining a culture has limited clinical diagnostic utility since the organism usually takes several weeks to grow.[146]
• Bronchoalveolar Lavage Fluid: The detection of Histoplasma antigen in bronchoalveolar lavage fluid may be helpful for the diagnosis of acute pulmonary histoplasmosis infections.[145,150]
• Cerebrospinal Fluid: Typical cerebrospinal fluid findings among individuals with Histoplasma meningitis include lymphocytic pleocytosis, elevated protein, and low glucose. Confirming a diagnosis of Histoplasma meningitis can be challenging due to poor sensitivity of most diagnostic tests—fungal stains are usually negative, and cerebrospinal fungal cultures are positive in less than 40% of individuals. Cerebrospinal fluid testing for Histoplasma antibodies and antigen can aid with diagnosing Histoplasma meningitis, as detection of either Histoplasma antibodies or antigen in the cerebrospinal fluid confirms active central nervous system Histoplasma infection.[145,151] Often, a presumptive diagnosis of Histoplasma meningitis is made when an individual with CNS infection has evidence of disseminated histoplasmosis at another site and no other obvious etiology for their neurological symptoms.[145]

Treatment

The Adult and Adolescent OI Guidelines for the treatment of disseminated histoplasmosis in persons with HIV are based on the severity and type of disease, and level of immunosuppression.[145] Treatment consists of induction therapy, maintenance therapy, and long-term suppressive therapy. The duration of the induction period is at least 2 weeks for treatment of disseminated disease and 6 weeks for treatment of meningitis.[145] The following table summarizes the Adult and Adolescent OI Guidelines recommendations for the treatment of severe disseminated histoplasmosis, less severe histoplasmosis or acute pulmonary histoplasmosis in individuals with a CD4 count less than 300 cells/mm³, and Histoplasma meningitis.[145] Liposomal amphotericin B is the preferred treatment for induction therapy for moderately severe to severe disease and meningitis, whereas itraconazole is preferred for treatment of less severe disseminated disease (Table 14).[145] Acute pulmonary histoplasmosis in individuals with HIV and a CD4 count greater than 300 cells/mm³ should be managed the same as immunocompetent individuals.[145,152]

Monitoring Drug Levels

• Itraconazole: Serum itraconazole levels should be checked after 2 weeks of therapy, with a target itraconazole serum level of 1-2 µg/mL.[145] The risk of side effects and toxicities with itraconazole increases with serum levels greater than or equal to 5 µg/mL.[145,153] In general oral itraconazole liquid formulation (administered on an empty stomach) is better absorbed, albeit less well tolerated, than the oral capsules.

• Voriconazole: For persons intolerant of itraconazole, alternative agents include posaconazole, voriconazole, or fluconazole.[154] If voriconazole is used, serum trough levels should be measured 5 days after treatment initiation. The therapeutic level is between 1 and 5 µg/mL; levels higher than 5 µg/mL can lead to drug toxicities, including neurotoxicity and hepatotoxicity.
• Posaconazole: Posaconazole serum levels should be measured 5 days after treatment initiation—the therapeutic level is greater than 1 µg/mL.

Timing of Initiating Antiretroviral Therapy

Individuals diagnosed with histoplasmosis should start on antiretroviral therapy as soon as possible after starting antifungal treatment for histoplasmosis. Available data suggest that IRIS infrequently occurs in persons with HIV who have disseminated histoplasmosis.[145,155]

Long-Term Suppressive Therapy

For individuals with severe disseminated disease or central nervous system infection, after at least 12 months of maintenance itraconazole therapy, the oral itraconazole dose should be reduced from 200 mg twice daily to 200 mg once daily for long-term suppressive therapy. The alternative for long-term suppressive therapy is oral posaconazole 300 mg daily, oral voriconazole 200 mg twice daily, or oral fluconazole 400 mg daily. The following table addresses use of long-term suppressive therapy, criteria for discontinuing long-term suppressive therapy, and indications for restarting long-term suppressive therapy.[145] (Table 15)

Background

Bartonella species cause a wide range of clinical infections, including cat scratch disease, trench fever, retinitis, relapsing bacteremia, endocarditis, bacillary angiomatosis, and bacillary peliosis hepatitis.[156,157,158] There are more than twenty Bartonella species, but B. henselae and B. quintana are the two species that can cause disease among persons with HIV.[159] Transmission of B. henselae occurs via cat scratches and fleas (cats are the zoonotic reservoir), whereas B. quintana is transmitted primarily by lice and is epidemiologically linked with homelessness (humans are the presumed reservoir).

Clinical Manifestations

Among persons with HIV, Bartonella infections show a predilection for the skin, liver, and spleen.[158,159] In persons with a CD4 count below 100 cells/mm³, bacillary angiomatosis typically manifests as nodular, vascular skin lesions that can be confused with Kaposi's sarcoma lesions. Bartonella infection can also cause fever, culture-negative endocarditis, osteomyelitis, peliosis hepatitis, and other invasive manifestations.[160] Less commonly, persons with HIV and Bartonella infection develop disseminated disease and present with systemic symptoms, such as fever, weight loss, and night sweats.

Diagnosis

The diagnosis of bacillary angiomatosis is usually made based on clinical manifestations combined with a variety of testing modalities, including histologic findings on a skin biopsy sample, a positive Bartonella serologic test, or a positive molecular polymerase chain reaction (PCR) test on a tissue sample obtained from a biopsy or resection.[157,161,162,163] Bartonella skin lesions can mimic many other conditions, including Kaposi’s sarcoma, pyogenic granuloma, fibrosarcoma, and epithelioid sarcoma.[156,161] If a skin biopsy is performed to evaluate skin lesions of unknown cause, the diagnosis of Bartonella can be made by Warthin-Starry silver staining that shows characteristic bacilli or direct detection of Bartonella organisms using PCR techniques. Isolating Bartonella species in culture is very difficult.

Treatment

The approach to treating Bartonella infection depends on the organ involved (Table 16).[157] In general, doxycycline is a preferred agent, often in combination with other agents, for treatment of Bartonella infection.

• Bacillary Angiomatosis, Peliosis Hepatis, Bacteremia, and Osteomyelitis: The treatment of choice for bacillary angiomatosis, peliosis hepatis, bacteremia (without endocarditis), and osteomyelitis is doxycycline or erythromycin.[156,157]
• Central Nervous System: For infections of the central nervous system, the recommended treatment is doxycycline, with or without rifampin.[156,157]
• Endocarditis: If endocarditis is confirmed, the preferred treatment is intravenous doxycycline plus rifampin for 6 weeks, followed by doxycycline alone for at least 3 months.[156,157]

Treatment Duration

The treatment duration for all Bartonella infections in persons with HIV is at least 3 months. Alternative therapies for Bartonella infections (other than for endocarditis) include azithromycin or clarithromycin.

Timing for Initiating Antiretroviral Therapy

For most persons with HIV and Bartonella infection, antiretroviral therapy does not need to be delayed. If, however, the individual is diagnosed with ophthalmic Bartonella infection, most experts recommend antiretroviral therapy should be delayed until the patient has completed a 2- to 4-week treatment course with doxycycline plus rifampin.[157]

Background

Coccidioidomycosis is caused by a soil-dwelling fungus, Coccidioides immitis, and may cause a wide spectrum of clinical diseases among individuals with HIV. The risk of developing symptomatic coccidioidomycosis in persons with HIV is significantly increased in persons with a CD4 count less than 250 cells/mm³ who live (or previously lived) in a region endemic for coccidioidomycosis. In persons with HIV, rates of coccidioidomycosis have been higher in Black individuals than in White persons.[164] The incidence of coccidioidomycosis has decreased in the era of potent antiretroviral therapy.[165]

Clinical Manifestations

In adults with CD4 cell count greater than 250 cells/mm³, coccidioidomycosis typically presents as an acute or subacute localized pulmonary infection that mimics community-acquired pneumonia. Persons with lower CD4 counts may develop diffuse pneumonia with reticulonodular infiltrates (that may resemble Pneumocystis pneumonia) or disseminated extrapulmonary infection that may cause skin lesions, meningitis, or involvement of lymph nodes or liver.[166,167,168] Cutaneous findings in acute coccidioidomycosis infection may include erythema multiforme or erythema nodosum, whereas cutaneous findings in disseminated disease may include papules, pustules, nodules, and ulcerated lesions.

Diagnosis

The initial evaluation of a person with suspected coccidioidomycosis should be guided by the clinical manifestations. The diagnosis is made based on the clinical presentation combined with laboratory testing that may include serologic tests, antigen testing, histologic staining, and fungal cultures.[167,169,170] A definitive diagnosis can be established with a positive culture of the organism from a clinical sample or by detecting spherules on histopathological examination of tissue.[167]

• Serologic Testing: For individuals with HIV who have symptoms consistent with coccidioidomycosis, serologic testing is the most frequently used test to make a presumptive diagnosis. A negative serologic test, however, does not exclude the diagnosis, since the formation of antibodies takes several weeks after initial infection.[167] As such, repeat serological testing should be performed every 1 to 2 weeks in individuals without a diagnosis who exhibit a clinical syndrome compatible with coccidioides disease.[167] For persons with HIV who have suspected coccidioidomycosis, the EIA (for IgG and IgM) is the recommended initial diagnostic test, but the sensitivity of this test is significantly reduced in those with a low CD4 count.[167,171] Accordingly, serologic testing should not be considered reliable for ruling out coccidioidomycosis in persons with HIV who have advanced immunosuppression.[166,172] In addition, problems have been reported with false-positive IgM EIA Coccidioides serologic tests.[173] If the EIA test is positive (for either IgG or IgM), the result should be confirmed using immunodiffusion or complement fixation tests.[167]
• Antigen Testing: A Coccidioides antigen test is commercially available and can be performed on urine, serum, or other body fluids of individuals with active disease. This antigen test is most useful for the diagnosis of extra-thoracic disseminated coccidioidomycosis, especially coccidioidal meningitis.[167,172,174,175]
• Real-Time Polymerase Chain Reaction: To help establish a diagnosis of coccidioides, real time PCR (RT-PCR) can be performed on formalin-fixed tissue or unfixed clinical specimens. Although there is a commercially available Coccidioides RT-PCR assay, it has not been approved by the FDA for use in people with HIV due to a lack of data in this population.[167,176]
• Fungal Culture: The diagnosis of coccidioidomycosis can be confirmed by isolating C. immitis from a clinical specimen (bronchoalveolar lavage fluid, cerebrospinal fluid, or tissue sample).[167] When performing fungal cultures in an attempt to isolate C. immitis, the microbiology laboratory must have established biocontainment procedures to prevent infection in laboratory staff.
• Staining: The diagnosis of coccidioidomycosis can be made by identifying characteristic Coccidioides spherules (8 to 10 microns in diameter) that contain multiple endospores (2 to 5 microns in diameter); depending on the clinical sample, the staining may be performed on a wet mount (using saline or potassium hydroxide) of a sample or on a histopathology specimen (usually with hematoxylin and eosin staining).

Treatment

Initial Treatment

The initial treatment of coccidioidomycosis is based on whether the disease is considered mild (e.g. focal pneumonia) or severe (e.g., disseminated or diffuse pulmonary disease) (Table 17).[167] The recommended treatment for persons with mild disease is fluconazole (400 mg once daily) or itraconazole (200 mg three times daily for 3 days, then 200 mg twice daily once daily); if bone or joint disease is present, itraconazole is preferred. For disseminated disease or diffuse pulmonary disease, which carry high mortality rates, the recommended therapy is amphotericin B (or lipid formulation of amphotericin B).[166,167] In persons with severe non-meningeal disease, initial therapy with amphotericin B should be continued until clinical improvement has occurred, and then treatment can be switched to oral fluconazole or oral itraconazole. To treat coccidioidal meningitis, the Adult and Adolescent OI Guidelines recommend using high-dose fluconazole (400 to 800 mg intravenously or orally), in consultation with an expert.

Discontinuation of Therapy

Discontinuation of therapy for coccidioidomycosis depends on the type and severity of the coccidioidomycosis infection, the CD4 cell count, whether virologic suppression on antiretroviral therapy has been achieved, and if continued monitoring for recurrence can be performed using serial chest radiograph and coccidioidal serology (Table 18).[167]

Background

Cryptosporidiosis is an intestinal infection caused by the protozoan parasite Cryptosporidium (Figure 17).[177,178] The life cycle of this organism in humans is complex, and all stages of development can take place within a single host.[177] Cryptosporidiosis can be transmitted through contaminated water sources (including swimming pools, lakes, and public water supplies), can persist despite chlorination, and can also be transmitted from person to person, especially among men who have sex with men.[179] In the current HIV era, the incidence of cryptosporidiosis in persons with HIV is very low (less than 1 case per 1,000 person-years).[1,179]

Figure 17. Cryptosporidium

This illustration is showing Cryptosporidium oocysts with sporozoites.

Source: Centers for Disease Control and Prevention

Clinical Manifestations

The incubation period for cryptosporidiosis is typically 7 to 10 days.[177] Infection of the gastrointestinal tract by Cryptosporidium impairs absorption and enhances secretion, typically manifesting as watery diarrhea and often accompanied by nausea, vomiting, and intestinal cramping. The severity and duration of disease depend on the host immune response, ranging from an asymptomatic or mild self-limited illness, to chronic low-level diarrhea, to a profuse cholera-like illness. For persons with HIV, the CD4 cell count is a strong predictor of illness severity (Figure 18).[180] In a retrospective analysis, adults with HIV and self-limited cryptosporidiosis had a mean CD4 count of 312 cells/mm³ versus a mean CD4 count of 57 cells/mm³ in those with persistent infection. In some cases, biliary complications (primarily cholangiopathy)can develop from Cryptosporidium infection.[181]

Figure 18. Relationship of CD4 Cell Count and Cryptosporidiosis Disease in Persons with HIV

Source: Reproduced with permission from: Flanigan T, Whalen C, Turner J, Soave R, Toerner J, Havlir D, Kotler D. Cryptosporidium infection and CD4 counts. Ann Intern Med. 1992;116:840-2. The American College of Physicians is not responsible for the accuracy of the translation.

Diagnosis

Diagnostic testing for Cryptosporidium should be performed in persons with HIV and acute diarrhea, chronic diarrhea, or biliary tract disease, especially if their CD4 count is less than 200 cells/mm³.[177,181] The diagnosis can be made by identifying oocysts in stool or tissue; the recommended test to identify Cryptosporidium depends on the available tests at the laboratory used by the clinician (Figure 19).[182]

• Ova and Parasite Examination of Stool: Routine ova and parasite testing does not detect Cryptosporidium and thus should not be relied on to diagnose Cryptosporidium.
• Modified Acid-Fast Stain: The modified acid-fast stain, which stains the organism red, is the most common method used to detect Cryptosporidium on microscopic examination of a stool sample.
• Immunofluorescence Antigen Testing: Many centers now offer detection of Cryptosporidium using direct immunofluorescence antigen testing, most often with an enzyme-linked immunoassay (ELISA). 
• Enteric Pathogen PCR Panel: Some laboratories now have a multiplex enteric pathogen panel for evaluating patients with diarrhea.[183] This test is a molecular assay that utilizes PCR technology. Most of these panels will detect common bacterial, viral, and parasitic pathogens. Many, but not all, include detection of Cryptosporidium. These multiplex molecular tests are often better at identifying cases of   i infection than direct microscopy.[184,185,186]

Figure 19. Techniques for the Diagnosis of Cryptosporidiosis

Figure 19A. Modified Acid-fast Staining of Stool Samples Showing Cryptosporidium Oocysts

Thee black arrows point to multiple Cryptosporidium oocysts.

Image courtesy of Carolyn Wallis, Harborview Medical Center Microbiology Laboratory.

Figure 19B. Immunofluorescence Microscopy for Detection of Oocysts

Oocysts of Cryptosporidium parvum (smaller ovals on left and top) and Giardia intestinalis (larger ovals and lower right) stained with immunofluorescent antibodies.

Source: Centers for Disease Control and Prevention

Treatment

Treatment of cryptosporidiosis includes a combination of antiretroviral therapy-related immune reconstitution, supportive symptomatic therapy, and the use antimicrobial agents that have activity against Cryptosporidium (Table 19).[179,187,188]

• Antiretroviral Therapy and Immune Reconstitution: The most important aspect of treatment for cryptosporidiosis is immune restoration with antiretroviral therapy.
• Supportive Therapy: Since immune reconstitution may take months, supportive care plays a vital role in managing symptoms and may include oral rehydration, intravenous rehydration, replacement of electrolytes, and symptomatic treatment of diarrhea.
• Antimicrobial Therapy: Antimicrobial treatments have been studied, including nitazoxanide, paromomycin, or azithromycin, but none of these options has been consistently effective in the absence of antiretroviral therapy.[189,190,191,192,193] Some experts recommend giving a trial of nitazoxanide or paromomycin in addition to antiretroviral therapy, a recommendation based on a few studies that demonstrated improvement in diarrhea symptoms and reduced parasite burden in individuals with CD4 counts greater than 50 cells/mm³.[179,192,193,194]

• Timing of Antiretroviral Therapy: Since antiretroviral therapy is the mainstay of cryptosporidiosis treatment for patients with HIV, antiretroviral therapy should be started as soon as possible after the diagnosis of cryptosporidiosis.[179]

Background

Microsporidiosis is a ubiquitous group of protists (single-celled organisms that do not fit into any other category) that are related to fungi. Infection with microsporidia is usually acquired by drinking untreated water or ingesting water from lakes, pools, or hot tubs.[195,196]

Clinical Manifestations

The clinical syndromes usually correlate with the infecting Microsporidia species (Figure 20).[197] Most often, persons with microsporidiosis present with nonbloody diarrhea, although certain Microsporidia species can cause encephalitis, ocular disease, sinusitis, myositis, or disseminated disease. The incidence of microsporidiosis has declined with the widespread use of antiretroviral therapy.

Figure 20. Correlation of Clinical Manifestations with Different Microsporidia Species

Diagnosis

The diagnosis of microsporidiosis is usually made by directly detecting Microsporidia in a clinical sample with a stain. Microscopic diagnosis typically involves examination under high magnification (1000x) and use of a special selective stain, depending on whether the specimen is tissue, stool, or fluids. Stains utilized include modified trichrome stains (Figure 21) or fluorochromes (Chromotrope 2R, Calcofluor White, or Uvitex 2B).

Figure 21. Microsporidiosis Identified on Modified Trichrome Stain

Image courtesy of Carolyn Wallis, Harborview Medical Center Microbiology Laboratory.

Treatment

Effective treatment of microsporidiosis usually requires immune restoration with antiretroviral therapy; antiretroviral therapy should be started or optimized as quickly as possible after the diagnosis of microsporidiosis.[197] Available data suggest that most individuals experience resolution of symptoms caused by enteric microsporidiosis once the CD4 count increases to greater than 100 cells/mm³.[188,197,198] Initial treatment often includes supportive care (rehydration and nutritional supplementation). Depending on the organ system involved and the species of microsporidia identified, additional therapeutic measures are recommended (Table 20).[197,199,200]

Gastrointestinal Infections Caused by Enterocytozoon bieneusi

Individuals with gastrointestinal Enterocytozoon bieneusi infection should receive antiretroviral therapy; if they have diarrhea and dehydration, they should receive fluid support and antimotility agents. The medications fumagillin and TNP-470 (a synthetic analog of fumagillin) have shown activity against E. bieneusi, but these agents are not routinely available in oral formulations in the United States.[199,200] It may be possible to get fumagillin, in severe cases, as a compassionate use medication from Sanofi in France (Sanofil Compassionate Use/Managed Access Program).[197] One study suggested clinical improvement with nitazoxanide to treat diarrhea caused by E. bieneusi, but the benefit was minimal in persons with low CD4 cell counts.[201] If fumagillin is not available, nitazoxanide is recommended as the best option to treat E. bieneusi-induced diarrhea.[197] Albendazole may have benefit in treating diarrhea or systemic disease caused by Microsporidia other than E. bieneusi or Vittaforma corneae.[202,203,204]

Intestinal and Disseminated Infection (not E. bieneusi and Vittaforma corneae)

For intestinal and disseminated microsporidiosis (non-ocular) that is caused by a Microsporidia species other than E. bieneusi and Vittaforma corneae, the recommended treatment is antiretroviral therapy plus albendazole 400 mg twice daily; this therapy should be continued until the individual’s CD4 cell count is greater than 200 cells/mm³ for more than 6 months while receiving antiretroviral therapy.[197]

Disseminated Infection Caused by Trachipleistophora or Anncaliia

For persons with HIV who have disseminated disease caused by Trachipleistophora or Anncaliia, the recommended treatment is antiretroviral therapy, supportive therapy, and combination oral antimicrobial therapy with itraconazole 400 mg daily and albendazole 400 mg twice daily.

Microsporidiosis Ocular Infection

For ocular infection caused by a Microsporidia species, the recommended therapy is topical fumagillin eye drops combined with oral albendazole (to treat systemic infection that is often present); treatment should be continued until the infection is resolved and the CD4 count is greater than 200 cells/mm³.[197] Topical fumagillin needs to be made by a specialty compounding pharmacy.

Timing of Antiretroviral Therapy

Antiretroviral therapy is the mainstay of treatment for persons with HIV and microsporidiosis and should be initiated immediately.[197]

Background

Cystoisospora belli (formerly Isospora belli) is a parasite that primarily affects immunocompromised persons in tropical and subtropical areas of the world.[205,206] Infection is acquired via the ingestion of food or water that is contaminated with human feces that contain C. belli oocysts.[206,207] Most persons with HIV who develop cystoisosporiasis have a CD4 count less than 250 cells/mm³ and have current or past residence in a high-risk geographic region; in the United States, most cases of cystoisosporiasis occur in persons who have recently immigrated from (or traveled to) Haiti or Latin America.[208,209,210]

Clinical Manifestations

Individuals with HIV and cystoisosporiasis typically develop watery diarrhea, nausea, vomiting, intestinal cramping, anorexia, and low-grade fever.[209] These symptoms often resemble those seen with other gastrointestinal opportunistic infections in persons with HIV. Several reports have documented cases of extraintestinal disease, including involvement of gallbladder, lymph nodes, and spleen, but such cases are rare.

Diagnosis

The diagnosis of cystoisosporiasis is usually made by direct visualization on a stool sample (Figure 22). The most common method for diagnosis is use a modified acid-fast stain on a stool sample and identifying oocysts that are relatively large (15 to 20 microns in diameter).[211] The unsporulated Cystoisospora oocysts appear elliptical, with one or both ends slightly tapered.[206] Modified acid-fast staining of a stool sample can identify C. belli oocysts. In the early phase, oocysts have an internal granular mass and as they mature, one or two internal sporoblasts may be seen. The C. belli oocysts are approximately 30 by 15 microns in size and are distinctly larger and more oval than the C. parvum oocysts (4 to 6 microns in diameter) and Cyclospora spp. oocysts (6 to 10 microns in diameter).[206] Several techniques, other than modified acid-fast staining, have been used on wet mounts to identify C. belli, including bright-field microscopy, differential interference contrast, and ultraviolet fluorescence microscopy. More recently, molecular diagnostic methods using PCR (Enteric Multiplex PCR) have increasingly been used as a diagnostic tool for gastrointestinal pathogens, but many of the commercially available tests do not include C. belli in the testing panel.

Figure 22. Cystoisospora belli Diagnostic Stains

Figure 22A. Cystoisospora belli Oocyst with Granular Mass

Modified acid-fast smear of stool sample showing Cystoisospora belli oocyst with internal granular mass (zygote).

Image courtesy of Carolyn Wallis, Harborview Medical Center Microbiology Laboratory.

Figure 22B. Cystoisospora belli Oocyst with Internal Sporoblast

Image courtesy of Carolyn Wallis, Harborview Medical Center Microbiology Laboratory.

Figure 22C. Wet Mount Staining Techniques for Cystoisospora belli

These stool sample wet mount tests show three wet mount techniques for diagnosing Cystoisospora belli: bright-field microscopy (A and D); differential interference contrast (DIC) (B and E); and blue UV fluorescence microscopy (C and F). The images on the top row (A, B,and C) show C. belli with a single internal sporoblast, and the images on the bottom row (C, D, and E) show two internal sporoblasts.

Source: Centers for Disease Control and Prevention.

Treatment

Treatment of Acute Infection

Treatment of acute cystoisosporiasis includes supportive care (rehydration and nutritional supplementation) and antimicrobial therapy targeted against C. belli (Table 21).[212]

• Preferred Therapy: Several treatment studies in persons with HIV showed good responses to trimethoprim-sulfamethoxazole.[208,209,213] Based on available data, the preferred acute therapy consists of trimethoprim-sulfamethoxazole (160/800 mg) 4 times daily for 10 days, with twice-daily dosing considered an acceptable option.[212] Some experts prefer to initiate treatment with trimethoprim-sulfamethoxazole (160/800 mg) twice daily and increase the dose to four times daily—if symptoms worsen or persist—and possibly extend the duration of acute therapy up to 4 weeks.
• Alternative Therapy: Alternatives include pyrimethamine or ciprofloxacin.[214] Note that pyrimethamine may not be easily available due to the extremely high cost of this medication.
• Timing of Initiating Antiretroviral Therapy: Aantiretroviral therapy should be initiated at the time treatment for cystoisosporiasis is started, unless there is concern that the antiretroviral therapy medications will not be absorbed well.[212]

Chronic Maintenance Therapy

Individuals with HIV and a CD4 count less than 200 cells/mm³ have a high rate of relapse with cystoisosporiasis and thus should receive chronic maintenance therapy with trimethoprim-sulfamethoxazole (160/800 mg) 3 times weekly (Table 22).[212] Pyrimethamine or ciprofloxacin may be options for those unable to take trimethoprim-sulfamethoxazole.[212]

Discontinuing Chronic Maintenance Therapy

Chronic maintenance therapy for cystoisosporiasis in persons with HIV can be discontinued if the following criteria are met:

• The person has experienced a sustained increase in CD4 count to above 200 cells/mm³ for more than 6 months in response to antiretroviral therapy, and
• There is no evidence of active C. belli infection.

• In people with HIV, major opportunistic infections primarily affect those with a CD4 count of less than 200 cells/m³.
• In some people with HIV, major opportunistic infections are unrecognized prior to the initiation of antiretroviral therapy and can paradoxically worsen in the setting of immune recovery (immune reconstitution inflammatory syndrome [IRIS]).
• Adults with HIV who have a CD4 count below 200 cells/mm³ are at significant risk of developing Pneumocystis pneumonia; the recommended therapy is trimethoprim-sulfamethoxazole, and the use of adjunctive corticosteroids improves survival for individuals with moderate-to-severe disease.
• Toxoplasma encephalitis is typically caused by reactivation of latent organisms in persons with a CD4 count below 100 cells/mm³; Toxoplasma encephalitis is usually a presumptive diagnosis based on characteristic clinical and neuroradiographic findings combined with a positive serum anti-Toxoplasma antibody.
• Mycobacterium avium complex is a non-tuberculous mycobacterial infection that can cause multiorgan disease in persons with a CD4 count of less than 50 cells/mm³; therapy requires a prolonged course with at least two active drugs.
• Patients with cryptococcal meningitis typically have a CD4 count of less than 100 cells/mm³. Initial antifungal therapy with liposomal amphotericin B and flucytosine is recommended for the induction phase. All persons with elevated intracranial pressure should have this managed through serial therapeutic lumbar punctures with CSF removal. Initiation of antiretroviral therapy should be delayed until completion of 2 to 10 weeks of antifungal therapy.
• Cytomegalovirus (CMV) has the potential to cause retinitis in persons with HIV who have a CD4 count below 50 cells/mm³. Therapy usually consists of ocular injections of antiviral medications combined with systemic CMV therapy. Persons with HIV can also develop gastrointestinal and neurologic CMV infections.
• Progressive multifocal leukoencephalopathy (PML) is a focal demyelinating disease caused by the JC virus; immune restoration with antiretroviral therapy is the mainstay of therapy.
• Candida esophagitis typically occurs only in patients who have a CD4 count below 100 cells/mm³. Treatment requires 2 to 3 weeks of antifungal therapy, preferably with fluconazole.
• Histoplasma and Coccidioides can cause a wide spectrum of clinical diseases in persons with HIV in the setting of immunosuppression; severe infection may require treatment with intravenous amphotericin B. The liposomal formulation of amphotericin B causes less renal toxicity than standard amphotericin.
• Multiple intestinal parasites (e.g., Cryptosporidium, Microsporidium, Cystoisospora) can cause intestinal disease in persons with HIV; treatment generally includes supportive care and antiretroviral therapy to restore immune function.