HIV AIDS opportunistic infections

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Overview

Before the widespread use of potent combination antiretroviral therapy (ART), opportunistic infections (OIs), which have been defined as infections that are more frequent or more severe because of immunosuppression in HIV-infected persons, were the principal cause of morbidity and mortality in this population. In the early 1990s, the use of chemoprophylaxis, immunization, and better strategies for managing acute OIs contributed to improved quality of life and improved survival. However, the widespread use of ART starting in the mid-1990s has had the most profound influence on reducing OI-related mortality in HIV-infected persons in those countries in which these therapies are accessible and affordable.

HIV Opportunistic Infections

Bacteria

Disease	Description	Clinical Findings	Diagnosis	Prevention / Prophylaxis	Treatment
Mycobacterium avium complex (MAC)	M.avium is the etiologic agent in 95% of patients with MAC disease The greatest risk of disease occurs among patients with a CD4+ <50 cells/µL	Fever, night sweats, weight loss, fatigue, diarrhea, and abdominal pain.	Isolation of MAC from cultures of blood, lymph node or bone marrow.	Prophylaxis is indicated when CD4 < 50 cells/µL Azithromycin 1200 mg PO once weekly, OR Clarithromycin 500 mg PO BID	Clarithromycin 500 mg PO twice daily + ethambutol 15 mg/kg PO daily , OR Azithromycin 500–600 mg + ethambutol 15 mg/kg PO daily (Testing of susceptibility to clarithromycin or azithromycin is recommended)
Respiratory Disease
Enteric Infections	The most common routinely cultured enteric bacteria among HIV-infected adults in the United States are Salmonella, Shigella, and Campylobacter. Other pathogens include E. coli and C. difficile.	Severe and prolonged diarrheal disease, potentially associated with fever, bloody diarrhea, and weight loss.	The diagnosis of Gram-negative bacterial enteric infection is established through cultures of stool and blood. Stool sample for C. difficile toxin or polymerase chain reaction assay (if recent antibiotic use)	Antimicrobial prophylaxis to prevent bacterial enteric illness usually is not recommended.	Treatment should be pathogen specific. Empiric therapy: Ciprofloxacin 500–750 mg PO q12h Oral or IV hydration therapy as appropriate.
Bacillary Angiomatosis	B. henselae and B. quintana infections have been identified in HIV- infected patients The greatest risk of disease occurs among patients with a CD4+ <50 cells/µL	Cutaneous lesions (red, globular and non-blanching, with a vascular appearance), sub-cutaneous nodules.	Histopathologic examination of biopsied tissue	Primary chemoprophylaxis for Bartonella-associated disease is not recommended	Doxycycline 100 mg PO or IV q12h, OR Erythromycin 500 mg PO or IV q6h
Syphilis	Treponema pallidum is the causative pathogen. Early syphilis in HIV-infected patients may cause a transient decrease in CD4 count and increase in HIV viral load.	Primary: Single painless nodule that ulcerates (chancre) or multiple atypical chancres may be seen. Secondary: More rapid progression or severity in HIV patients. Manifestations include maculopapular skin lesions, condyloma lata, lymphadenopathy, fever, malaise, anorexia, arthralgias, and headache. Terciary: Manifestations of neurosyphilis, such as concomitant uveitis and meningitis, may be more common in HIV-infected persons. Other manifestations include cardiovascular syphilis and gummatous syphilis.	Serologic tests: VDRL, RPR, FTA-ABS, TP-PA Darkfield microscopy and tests to detect T. pallidum in lesion exudates or tissue (biopsy with silver stain) are definitive for diagnosing early syphilis	Routine serologic screening for syphilis is recommended at least annually for all HIV- infected patients who are sexually active. Prophylaxis is indicated in patients who were exposed sexually within 90 days preceding the diagnosis of primary, secondary, or early-latent syphilis in a sex partner or exposed >90 days before syphilis diagnosis in a sex partner, if serologic test results are not available immediately and the opportunity for follow-up is uncertain.	Primary: Benzathine penicillin G 2.4 million units IM for 1 dose Secondary and terciary: Benzathine penicillin G 2.4 million units IM weekly for 3 doses
Table adapted from Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents

Virus

Disease	Description	Clinical Findings	Diagnosis	Prevention / Prophylaxis	Treatment
Cytomegalovirus Infection	The greatest risk of disease occurs among patients with a CD4+ <50 cells/µL	Retinitis is the most common clinical manifestation of CMV end-organ disease Colitis occurs in 5% to 10% of patients with AIDS and CMV end-organ disease, clinical manifestations include weight loss, anorexia, abdominal pain, diarrhea, and malaise. Esophagitis occurs in a small percentage of patients	CMV viremia can be detected by PCR, antigen assays, or culture	CMV end-organ disease is best prevented by using ART to maintain CD4 count >100 cells/uL Ganciclovir or valganciclovir primary prophylaxis is not recommended. Some specialists recommend yearly funduscopic examination in patients with CD4 < 50 cells/uL	Preferred Regimen: Valganciclovir 900 mg PO daily For sight threatening lesions: Add intravitreal injections of ganciclovir or foscarnet to normal regimen.
Herpes Simplex Virus Infection	Approximately 70% of HIV-infected persons are HSV-2 seropositive and 95% are seropositive for either HSV-1 or HSV-2. The greatest risk of disease occurs among patients with a CD4+ <100 cells/µL	HSV-1: Orolabial herpes (cold sores, fever blisters). HSV-2: Genital herpes (papules, vesicles or ulcers). Non-mucosal HSV infections, such as HSV keratitis, HSV encephalitis, HSV hepatitis, and herpetic whitlow, are similar in presentation to manifestations observed in HIV-seronegative individuals	Viral culture, HSV DNA PCR, and HSV antigen detection are available methods for diagnosis of mucocutaneous lesions.	Prophylaxis with antiviral drugs to prevent primary HSV infection is not recommended.	Genital lesions (for 5-14 days): Valacyclovir 1 g PO BID, or Famciclovir 500 mg PO BID, or Acyclovir 400 mg PO TID Oral lesions (for 5-10 days): Valacyclovir 1 g PO BID, or Famciclovir 500 mg PO BID, or Acyclovir 400 mg PO TID
Varicella-Zoster Virus (VZV) Infection	The greatest risk of herpes zoster occurs among patients with a CD4+ <200 cells/µL Because most HIV-infected adults in the United States are VZV seropositive, primary varicella is an uncommon.	Varicella rash tends to have a central distribution with lesions first appearing on the head, then trunk, and finally the extremities, evolving through stages of macules, papules, vesicles, pustules, and crusts Herpes zoster manifests as a painful cutaneous eruption in a dermatomal distribution, often preceded by prodromal pain.	Diagnosis is made clinically. History of varicella or VZV exposure, a rash that began with a dermatomal pattern, and VZV serologic testing to assess prior VZV infection may be helpful.	Avoid exposure to individuals with varicella or herpes zoster. Prophylaxis with antiviral drugs to prevent varicella is not recommended. Varicella vaccination is recommended for patients with CD4 > 200 cells/µL. Post-exposure prophylaxis: VariZIG 125 IU/10 kg IM	Valacyclovir 1000 mg PO TID, OR Famciclovir 500 mg PO TID
Human Herpesvirus-8 Infection	The greatest risk of herpes zoster occurs among patients with a CD4+ <200 cells/µL	Most patients are asymptomatic Kaposi Sarcoma: nontender, purplish, indurated skin lesions. Multicentric Castleman’s disease: generalized adenopathy and fever and can progress to multi-organ failure. Primary effusion lymphoma characteristically presents with effusions of the pleural, pericardial, or abdominal spaces	Diagnosis is made with cytologic and immunologic cell markers	Screening is not recommended	Kaposi Sarcoma: Start or adjust ART Multicentric Castleman’s disease: Valganciclovir 900 mg PO BID for 3 weeks, or Ganciclovir 5 mg/kg IV q12h for 3 weeks, or Valganciclovir 900 mg PO BID + zidovudine 600 mg PO q6h for 7–21 days.
Human Papillomavirus Infection	HPV 16 and 18 are associated with cervical malignancy. HPV 6 and 11 cause 90% of genital warts.	Oral, genital, and anal warts (condyloma acuminata) are usually flat, papular, or pedunculated growths on the mucosa or epithelium. Cervical cancer can be asymptomatic or may manifest with bleeding, pain, or a palpable mass.	Diagnosis of genital and oral warts is made by visual inspection and can be confirmed by biopsy. Cytology (Pap test) and colposcopic techniques with biopsy are used to detect CIN.	HPV vaccination is recommended in HIV infected patients	Podophyllotoxin or Imiquimod self-application to warts. Cryotherapy, surgical excision, laser surgery.
Table adapted from Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents

Fungus

Disease	Description	Clinical Findings	Diagnosis	Prevention / Prophylaxis	Treatment
Pneumocystis Pneumonia (Click here for more information)	Caused by the fungus Pneumocystis jirovecii. 90% of cases occurred among patients with CD4+ <200 Incidence among HIV patients: 2-3 cases per 100 person-year	Subacute onset of progressive dyspnea, fever, nonproductive cough, and chest discomfort that worsens within days to weeks. Tachypnea, tachycardia, and diffuse dry rales are found in the physical examination.	Clinical presentation, blood tests, or chest x-rays are not pathognomonic for PCP. BAL or induced sputum samples are required for a definite diagnosis.	Start TMP-SMX prophylaxis when CD4+ <200 cells/µL or history of oropharyngeal candidiasis. Discontinue prophylaxis when CD4+ is >200 cells/µL for >3 month.	TMP-SMX Administer adjunctive corticosteroids in patients with pO2 <70 mm Hg or arterial-alveolar O2 gradient >35 mm Hg In patients not on ART, ART should be initiated, when possible, within 2 weeks of diagnosis of PCP
Mucocutaneous Candidiasis	Candida albicans is the causative agent. Oropharyngeal and esophageal candidiasis are common in HIV-infected patients The greatest risk of disease occurs among patients with a CD4+ <200 cells/µL	Oropharyngeal: Painless, creamy white, plaque-like lesions that can occur on the buccal surface, hard or soft palate, oropharyngeal mucosa, or tongue surface. Esophageal: retrosternal burning pain or discomfort along with odynophagia.	Usually diagnosed clinically based on the characteristic appearance of lesions (can be scraped off) Definitive diagnosis of esophageal candidiasis requires direct endoscopic visualization of lesions with histopathologic demonstration of characteristic Candida yeast	Routine primary prophylaxis is not recommended	Oropharyngeal: Fluconazole 100 mg PO once daily Esophageal: Fluconazole 100 mg (up to 400 mg) PO or IV daily, OR Itraconazole oral solution 200 mg PO daily
Cryptococcosis	Cryptococcus neoformans is the causative pathogen. The greatest risk of disease occurs among patients with a CD4+ <100 cells/µL	Subacute meningitis or meningoencephalitis with fever, malaise, and headache. Other symptoms such as lethargy, altered mental status, personality changes, and memory loss may be present.	CSF analysis shows mildly elevated levels of protein, low-to-normal glucose, and pleocytosis consisting mostly of lymphocytes Opening pressure in the CSF may be elevated Diagnosed through culture of blood or CSF, CSF microscopy with India ink staining, or cryptococcal antigen (CrAg) detection	Primary prophylaxis or screening for serum CrAg in asymptomatic patients is not recommended in the US Prophylactic fluconazole or itraconazole can reduce the frequency of primary cryptococcal disease in patients who have CD4 cell counts <100 cells/mm according to prospective RCT.	Induction Therapy: Liposomal amphotericin B 3–4 mg/kg IV daily + flucytosine 25 mg/kg PO QID Consolidation Therapy: Fluconazole 400 mg PO or IV once daily
Histoplasmosis	Histoplasma capsulatum is the causative pathogen. The greatest risk of disease occurs among patients with a CD4+ <150 cells/µL	Fever, fatigue, weight loss, hepatosplenomegaly, cough, chest pain, and dyspnea.	Detection of Histoplasma antigen in blood, urine or BAL is a sensitive method for rapid diagnosis of disseminated histoplasmosis and acute pulmonary histoplasmosis.	Avoid activities known to be associated with increased risk (areas contaminated of bird or bat droppings) Start prophylaxis with Itraconazole 200 mg PO once daily when CD4+ <150 cells/µL and the patients is at high risk of exposure.	Induction Therapy: Liposomal amphotericin B 3 mg/kg IV daily (for 2 weeks) Consolidation Therapy: Itraconazole 200 mg PO TID for 3 days, then BID for > 12 months
Coccidioidomycosis	Caused by a soil-dwelling fungus that consists of two species, Coccidioides immitis and Coccidioides posadasii. The greatest risk of disease occurs among patients with a CD4+ <250 cells/µL	Focal pneumonia (most common in patients with CD4 >250 cells/µL), diffuse pneumonia, cutaneous disease, meningitis, liver or lymph node involvement.	Diagnosis is confirmed by culture. Serology (IgM and IgG) is useful	Avoid activities involving exposure to infection while living in or visiting areas in which Coccidioides spp. are endemic. Chemoprophylaxis is not recommended.	Mild infections: Fluconazole 400 mg PO once daily (BII), OR Itraconazole 200 mg PO twice daily Severe infection Amphotericin B deoxycholate 0.7–1.0 mg/kg IV daily, OR Lipid formulation amphotericin B 4–6 mg/kg IV daily
Aspergillosis	Aspergillus fumigatus is the most common causative agent. The greatest risk of disease occurs among patients with a CD4+ <100 cells/µL	Symptoms of pneumonia include fever, cough, dyspnea, chest pain, hemoptysis, and hypoxemia	Lung CT: Halo of low attenuation surrounding a pulmonary nodule or a cavity. Bronchoscopic examination demonstrates ulcerative or plaque-like lesions adherent to the tracheal wall Isolation of Aspergillus spp. from respiratory secretions or the finding of septate hyphae consistent with Aspergillus spp. in respiratory samples in association with typical CT findings	Antifungal therapy is not recommended for prevention.	Voriconazole 6 mg/kg IV q12h for 1 day, then 4 mg/kg IV q12h , followed by voriconazole PO 200 mg q12h after clinical improvement.
Table adapted from Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents

Parasite

Disease	Description	Clinical Findings	Diagnosis	Prevention / Prophylaxis	Treatment
Toxoplasma gondii Encephalitis (Click here for more information)	Caused by the protozoan Toxoplasma gondii The greatest risk of disease occurs among patients with a CD4+ <50 cells/µL Primary infection occurs after eating undercooked meat containing tissue cysts or ingesting oocysts that have been shed in cat feces and have sporulated in the environment	Focal encephalitis with headache, confusion, or motor weakness and fever	Diagnosis is done with IgG antibodies. CT scan or MRI of the brain will typically show multiple contrast-enhancing lesions, often with associated edema. Definite diagnosis requires a brain biopsy. PET is helpful to distinguish between toxoplasmosis and primary CNS lymphoma.	Start TMP-SMX prophylaxis when CD4+ <100 cells/µL Discontinue prophylaxis when CD4+ is >200 cells/µL for >3 month.	Administer: Pyrimethamine, PLUS Sulfadiazine, PLUS Leucovorin
Cryptosporidiosis (Click here for more information)	Caused by the protozoan Cryptosporidium (C. hominis, C. parvum, and C. meleagridis) The greatest risk of disease occurs among patients with a CD4+ <100 cells/µL	Acute or subacute onset of watery diarrhea, nausea, vomiting, lower abdominal pain. Fever is seen in 1/3 of patients.	Microscopic examination of oocysts in stool with direct immunofluorescence.	Initiate ART Education of possibles ways of transmission (infected patients, diapers, animals) Avoid direct contact of pet stool Scrupulous handwashing is recommended.	Initiate or optimize ART for immune restoration to CD4 count >100 cells/mm3 Aggressive oral and/or IV rehydration and replacement of electrolyte loss, and symptomatic treatment of diarrhea with anti- motility agent.
Microsporidiosis	The microsporidia reported as pathogens in humans include Encephalitozoon cuniculi, Encephalitozoon hellem, Encephalitozoon intestinalis, Enterocytozoon bieneusi, Trachipleistophora hominis, Trachipleistophora anthropophthera, Pleistophora species, P. ronneafiei, Vittaforma corneae, Microsporidium sp, Nosema ocularum, Anncaliia connori, Anncaliia vesicularum, and Anncaliia algerae. The greatest risk of disease occurs among patients with a CD4+ <100 cells/µL	Clinical syndromes can vary by infecting species. The most common manifestation is diarrhea. E. bieneusi is associated with malabsorption, diarrhea, and cholangitis. E. cuniculi is associated with hepatitis, encephalitis, and disseminated disease. E. intestinalis is associated with diarrhea, disseminated infection, and superficial keratoconjunctivitis. E. hellem is associated with superficial keratoconjunctivitis, sinusitis, respiratory disease, prostatic abscesses, and disseminated infection. Anncaliia and Trachipleistophora are associated with keratoconjunctivitis. Nosema, Vittaforma, and Microsporidium are associated with stromal keratitis following trauma in immunocompetent hosts. Pleistophora, Anncaliia, and Trachipleistophora are associated with myositis. Trachipleistophora is associated with encephalitis and disseminated disease.	Examination of 3 stool samples with chromotrope and chemofluorescent stains	Patients who have CD4 counts <200 cells/µL should avoid untreated water sources. No specific chemoprophylactic regimens are known to be effective in preventing microsporidiosis.	Initiate or optimize ART with immune restoration to CD4 count >100 cells/mm3 Severe dehydration, malnutrition, and wasting should be managed by fluid support and nutritional supplements
Table adapted from Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents