common aids-associated opportunistic infectionshiv impairs the immune system, leaving the infected...

CME Infectious diseases

Clinical Medicine Vol 8 No 5 October 2008 539

© Royal College of Physicians, 2008. All rights reserved.

HIV impairs the immune system, leavingthe infected person susceptible to avariety of infections, called ‘oppor-tunistic’ infections (OI). The effect ofHIV on the immune system is monitoredby measuring the CD4 (T-helper)lymphocyte count in the blood:

• About 600–1,200 cells/µl: normal,indicating that the immune systemhas not undergone sufficient damageto put the individual at risk foropportunistic illness. Suchindividuals are unlikely to requiretreatment or benefit from highlyactive antiretroviral therapy(HAART).

• Below 350 cells/µl: there is someimpairment of immune functionwhich should prompt considerationof HAART.

• Below 200 cells/µl: imminent risk ofserious OIs or other complicationsof HIV disease. Prompt treatment isrecommended.1

The development of secondary OIs inpatients with HIV infection also resultsfrom interactions between specific organ-isms and host defences. AIDS-defininginfections such as Pneumocystis pneu-monia (caused by P. jiroveci) tend to occurlater in the course of HIV infection whenthere is substantial depletion of the CD4cells.2 The late emergence of P. cariniipneumonia (PCP) relates to the relativelylow pathogenicity of P. carinii comparedwith other organisms like Mycobacteriumtuberculosis. The latter organism cancause disease earlier in the course of HIVinfection. Figure 1 shows schematicallythe sequence of OIs in the natural historyof HIV.

Pneumocystis pneumonia

PCP is the most common life-threateninginfection in patients with AIDS in Europeand the USA. In the initial years of theepidemic it was responsible for up to 85%of all respiratory episodes.3 The incidenceof PCP as the first AIDS-defining condi-tion still remains substantial, although itis progressively declining with the wide-spread use of prophylaxis and HAART.4

Although the causative agent of pneu-mocystosis was long considered a proto-zoan, studies of ribosomal RNA from theorganism have shown greater homologywith fungi. In 2001, P. carinii was offi-

cially reclassified as a fungus and wasrenamed P. jiroveci. Despite the namechange, the disease is still referred to asPCP (Pneumocystis pneumonia). Such areclassification has no immediate clinicalimportance, but it may suggest newtherapeutic approaches.

P. jiroveci has both intracystic andextracystic forms. The cysts are oval orround, approximately 5–8 µm in diam-eter, and contain 4 to 8 intracystic organ-isms (sporozoites). The sporozoites arenucleated and measure approximately1–2 µm in diameter. The extracystic form(trophozoite) measures 2–5 µm in diam-eter. It is pleomorphic and often has aneccentric nucleus.

The disease ranges in severity from amild infection with a normal chest radi-ograph and an indolent course to respira-tory failure requiring assisted ventilationwhere the mortality may exceed 90%.5

ELC Ong MBBS MSC FRCP FRCPI DTMH,

Consultant Physician and Honorary Senior

Lecturer, Department of Infection and

Tropical Medicine, Newcastle General

Hospital, Newcastle upon Tyne

Clin Med 2008;8:539–43

Common AIDS-associated opportunistic

infections

CD4 (T-helper) lymphocyte count is the most important indicator ofimmunocompetence of a HIV-infected invididual

P. jiroveci is the most common life-threatening infection in patients with AIDS

Toxoplasmosis is an important cause of focal brain lesions

Cryptococcosis is the cause of the most common life-threatening meningitis in AIDS

Key Points

KEY WORDS: CD4 count, cryptococcosis, pneumocystis, toxoplasmosis

Fig 1. Sequence of opportunistic infections during natural history of HIV infection.

Herpes zoster

Herpes simplex

Tuberculosis

Oral candida

Kaposi sarcoma

Pneumocystis pneumonia

Declining cell-mediated immunity

ToxoplasmaMycobacterium-avium intracellulare

Cryptosporidium

PCP usually presents as a diffuse pul-monary infiltrate associated with fever,chest tightness, cough and breathlessness.A typical diffuse pulmonary infiltrate ofPCP is shown in Fig 2.

Some patients may complain ofwheeze.6 It is important not to discountsymptoms in patients even with a normalchest radiograph as 5–14% of patientssubsequently found to have respiratorydisease had a normal chest radiograph atpresentation.7 Severe cases of PCP fre-quently show extensive consolidationwith air bronchograms and 5–10% showatypical features, including cysticchanges, localised upper zone changesand miliary pattern, hilar and media-stinal lymphadenopathy and pleuraleffusion.

Diagnosis

PCP is most readily diagnosed byinduced sputum examination. The yieldranges from 70–95%, although the sensi-tivity is reduced by 20% if patients are onprophylaxis.8 Almost all cases of PCP canbe diagnosed by bronchoalveolar lavage;transbronchial and open lung biopsiesare rarely necessary. Giemsa, toluidineblue O, methenamine silver, Gram’s stainand immunofluorescent monoclonalantibody techniques are commonly usedfor diagnostic staining.

Treatment

High dose co-trimoxazole (trimetho-prim-sulfamethoxazole (TMP-SMX))given for 21 days is the treatment ofchoice for PCP. The standard dosageused in patients with advanced HIV dis-ease was 20 mg/kg/day of TMP plus100 mg/kg/day of SMX given eitherorally or intravenously (divided every6 or 8 hours daily). Subsequent reportsdescribed similar efficacy and a lowerfrequency of adverse reactions with adosage of 15 mg/kg/day of TMP and75 mg/kg/day of SMX for 14–21 days.This has become the standard dosingregimen for acute PCP in adults.

Side effects are common and may occurin up to 50–80% of patients with HIV.9

Hypersensitivity reactions, bone marrowsuppression and hepatotoxicity are well

recognised. Clindamycin with pri-maquine, parenteral pentamidine, trime-trexate and atovaquone are alternatives.Adjunctive therapy with corticosteroidshas been shown to be of benefit if admin-istered in the early stages of PCP for thosewith moderate to severe disease.10

HIV-infected patients with CD4counts below 200 cells/µl or who havesurvived an episode of PCP shouldreceive prophylaxis against PCP. In gen-eral, TMP-SMX (1 double-strengthtablet daily or 3 times weekly) should bethe first choice of prophylaxis forpatients without a prior history ofadverse reactions to that drug combina-tion. Dapsone, dapsone-pyrimethamineand atovaquone are suitable alternativesfor patients unable to take TMP-SMX forprophylaxis. Aerosolised pentamidine(300 mg every 4 weeks via the RespirgardII nebuliser or equivalent) is an alterna-tive for those who do not tolerate the oralregimens.

Toxoplasmosis

Toxoplasma gondii is an obligate intracel-lular protozoan of worldwide distribu-tion. Feline animals are the definitivehosts for the parasite and human infec-tion occurs usually as a result of inges-tion of ether food contaminated with catfaeces or undercooked meat from aninfected animal.

Development of cell-mediated immu-

nity after acute infection with T. gondiiresults in control but not eradication ofthe infection. The ensuing chronic orlatent phase of infection is characterisedby the persistence of the organism in tis-sues of the infected individual (primarilybrain, skeletal muscle, and heart). Indeed,T. gondii is one of the most commoncauses of chronic infection with an intra-cellular organism in humans. A chroni-cally infected individual who developsdefects in cell-mediated immunity is atrisk for reactivation of the infection.Toxoplasmosis in this setting manifestsprimarily as toxoplasmic encephalitis.This disease is an important cause of focalbrain lesions in HIV-infected patients(Fig 3).11

Clinical features

Characteristically, TE has a subacuteonset with focal neurological abnormali-ties, frequently accompanied by head-ache, altered mental status and fever. Themost common focal neurological signsare motor weakness and speech distur-bances. Patients can also present withseizures, cranial nerve abnormalities,visual field defects, sensory disturbances,cerebellar dysfunction, meningismus,movement disorders and neuropsychi-atric manifestations. Toxoplasmosis rarelypresents as a rapidly fatal form of diffuseencephalitis. Diffuse TE should be consid-ered in patients with anti-Toxoplasma


540 Clinical Medicine Vol 8 No 5 October 2008


Fig 2. Chest X-rayshowing typical diffusepulmonary infiltrate ofPneumocystis cariniipneumonia.




gondii immunoglobulin G antibodies andCD4 T-cell counts below 100/µl, whopresent with unexplained neurologicaldisease.

HIV-infected patients may developextracerebral toxoplasmosis with orwithout concomitant encephalitis.Ocular and pulmonary disease are themost common presentations in patientswith extracerebral toxoplasmosis.Patients with chorioretinitis present withblurred vision, scotoma, pain or photo-phobia. Ophthalmological examinationreveals multifocal, bilateral lesions typi-cally more confluent, thick and opaquethan those caused by cytomegalovirus(CMV). Vitritis may be accompanied byanterior uveitis. T. gondii is a much lesscommon cause of chorioretinitis in HIV-infected patients than CMV.

The clinical presentation of patientswith pulmonary toxoplasmosis may bedifficult to distinguish from PCP.12 Ahighly lethal syndrome of disseminatedtoxoplasmosis comprising fever andsepsis-like syndrome with hypotension,

disseminated intravascular coagulation,elevated lactic dehydrogenase and pul-monary infiltrates has been described inHIV-infected patients.

Diagnosis

T. gondii infection is detected by serolog-ical studies. Disease caused by the para-site (toxoplasmosis) can be diagnosed bydemonstration of tachyzoites in tissuebiopsies or cytological preparations ofbody fluids, isolation of T. gondii frombody fluids or blood, or amplification ofparasite DNA in body fluids or blood bypolymerase chain reaction.

Treatment

Pyrimethamine (a dihydrofolate reduc-tase inhibitor) is considered the corner-stone in the treatment of toxoplasmosis.In combination with sulfadiazine (adihydrofolate synthase inhibitor) it is thestandard regimen for treatment of TE.Patients receiving pyrimethamine should

also be given folinic acid to preventhaematological adverse effects.

The combination of pyrimethamineand clindamycin is as effective aspyrimethamine and sulfadiazine duringthe acute phase of therapy,13 althoughrash and diarrhoea are common adverseeffects. A randomised, prospective studyreported that TMP-SMX is as effective aspyrimethamine plus sulfadiazine for thetreatment of TE.14

From limited data it appears that AIDSpatients with extracerebral toxoplas-mosis respond to pyrimethamine pluseither sulfadiazine or clindamycin. Themortality rate in patients with pul-monary or disseminated toxoplasmosismay be higher than in those with TEalone. Patients with AIDS-associatedtoxoplasmosis should therefore be placedon a maintenance regimen on comple-tion of the acute phase of treatment.Maintenance therapy typically consists ofthe same drugs used for primary therapybut at lower dosages.

Cryptococcus

Cryptococcus neoformans is an encapsu-lated, round-to-oval yeast measuring4–6 microns with a surrounding polysac-charide capsule ranging in size from 1 to>30 microns when cultivated in the lab-oratory. In its natural environment, it issmaller and poorly encapsulated.

Cryptococcosis is the cause of the mostcommon life-threatening meningitis inAIDS. Early in the epidemic about 5–8%of patients with AIDS developed crypto-coccal infection. The incidence of cryp-tococcosis, along with other OIs, hasdecreased where effective antiretroviraltreatment (ART) is available.15 In fact,the decrease in new cases may havestarted before the advent of HAART;other data suggest a decline in incidenceassociated with the more frequent use ofazole antifungals.16

Clinical features

Meningoencephalitis is the most frequentmanifestation of cryptococcosis in HIV-infected individuals. It typically presentsas a subacute process characterised byheadache, fever and, less often, alteredFig 3. Focal brain lesion of toxoplasmosis.

mental status, but presentations charac-teristic of either acute or chronic menin-gitis can occur. Cranial nerve palsies andpapilloedema are the most commonocular manifestations in patients withcryptococcal central nervous system(CNS) invasion. Complications of CNSinfection include hydrocephalus, motoror sensory deficits, cerebellar dysfunction,seizures and dementia. Focal disease israrely described. Intracerebral granulo-mata, referred to as cryptococcomas, maybe seen occasionally on computed tomog-raphy or magnetic resonance imaging.

Abnormal cerebrospinal fluid (CSF)findings such as pleocytosis, low glucoseand high protein concentrations are seenin approximately 40% of patients withAIDS-related cryptococcal meningitis(CM). A low CSF white cell count(<20 cells/µl) is associated with a poorprognosis.

Although pulmonary cryptococcosis isdiagnosed less frequently than meningitisin patients with AIDS, the lung is mostlikely the portal of entry. Cryptococcalpneumonia may be either asymptomaticor symptomatic, with or without evidenceof dissemination. It is unclear whetherdisseminated disease represents a progres-sion or reactivation of pulmonary diseasebecause many patients have no evidenceof pulmonary involvement at the time ofdiagnosis of disseminated disease.

Diagnosis

Diagnosis is confirmed by isolation ofcryptococcus from a sterile body site byeither histopathological analysis or detec-tion of cryptococcal capsular antigen(CrAg). CrAg in the serum usually isindicative of systemic disease and corre-lates with fungal burden. A localisedcryptococcal infection, such as pul-monary cryptococcosis without lymphnode involvement, is not usually associ-ated with a positive serum CrAg; a posi-tive result warrants a search fordisseminated disease. CrAg in the CSF isproduced locally in the subarachnoidspace by the invading yeast and does notrepresent either active or passive diffu-sion from the serum into the CNS.Detection of CrAg in either serum or CSFhas >95% sensitivity and specificity in

the diagnosis of true invasive crypto-coccal infection.

The India ink stain that outlines thepolysaccharide capsule is positive ondirect examination of the CSF in approx-imately 50% of normal hosts with CMand in more than 80% of patients withAIDS (Fig 4). Encapsulated yeasts seenon Alcian blue, mucicarmine or Gomorimethenamine silver stains are diagnosticof cryptococcus. Other stains such asFontana-Masson and periodic acid-Schiff reveal yeast cells but are notspecific for cryptococcus.17

Treatment

The recommended first-line therapy forAIDS patients with CM is based on theresults of the Mycology Study Group(MSG)/AIDS Clinical Trial Group(ACTG) clinical trial: intravenous ampho-tericin B (0.7 mg/kg per day) plus iv flucy-tosine (100 mg/kg/day) for two weeks,followed by oral fluconazole (400 mgdaily) for eight weeks of consolidationtherapy and 200 mg daily for maintenancetherapy.18

The relapse rates for CM in non-AIDSand AIDS patients are 15–25% and lessthan 50%, respectively. Prior to theintroduction of HAART, patients withAIDS-associated CM had to continue

chronic suppressive therapy for the restof their life. Repeat lumbar punctures(LPs) should be performed after twoweeks of therapy; they may also be con-sidered after completion of therapy andat any time there is clinical evidence tosuggest relapse. CSF pleocytosis may per-sist for up to six months after successfultreatment, but most patients should havenormal CSF findings by one-year post-treatment.

Raised intracranial pressure occurs inmore than 50% of cases and may compli-cate the management. The opening pres-sure should always be recorded at LP andif this exceeds 20 cm of water, LP shouldbe repeated daily to reduce it to below20 cm. Insertion of a lumbar drain maybe required occasionally.

The US Public Health Service/Infectious Diseases Society of Americaguidelines recommend discontinuationof secondary prophylaxis if patients:

• successfully complete a course ofinitial therapy for cryptococcosis

• remain asymptomatic with respectto signs and symptoms ofcryptococcosis

• have a sustained increase(>6 months) in their CD4 counts toover 100–200 cells/µl on ART.

Prophylaxis should be restarted if theCD4 count declines to below 100–200cells/µl.19

References

1 Dybul M, Fauci AS, Bartlett JG et al. Panelon Clinical Practices for Treatment of HIV.Guidelines for using antiretroviral agentsamong HIV-infected adults andadolescents. Ann Intern Med 2002;137(5 Pt 2):381–433.

2 Masur H, Ognibene FP, Yarchoan R et al.CD4 counts as predictors of opportunisticpneumonias in human immunodeficiencyvirus (HIV) infection. Ann Intern Med1989;111:223–31.

3 Murray JF, Felton CP, Garay SM et al.Pulmonary complications of the acquiredimmunodeficiency syndrome. Report of aNational Heart, Lung, and Blood Instituteworkshop. N Engl J Med 1984;310:1682–8.

4 Kaplan JE, Hanson D, Dworkin MS et al.Epidemiology of human immuno-deficiency virus-associated opportunisticinfections in the United States in the era ofhighly active antiretroviral therapy. ClinInfect Dis 2000;30(Suppl 1):S5–14.


542 Clinical Medicine Vol 8 No 5 October 2008


Fig 4. India ink stain outlining thepolysaccharide capsule shows positivein 50% of normal hosts and over 80%of AIDS patients.




5 Wachter RM, Luce JM, Turner J, Volberding P, Hopewell PC.Intensive care of patients with the acquired immunodeficiencysyndrome. Outcome and changing patterns of utilization. AmRev Respir Dis 1986;134:891–6.

6 Ong EL, Hanley SP, Mandal BK. Bronchial responsiveness inAIDS patients with Pneumocystis carinii pneumonia. AIDS1992;6:1331–3.

7 Rankin JA, Collman R, Daniele RP. Acquired immunedeficiency syndrome and the lung. Chest 1988;94:155–64.

8 Homer KS, Wiley EL, Smith AL et al. Monoclonal antibody toPneumocystis carinii. Comparison with silver stain in bronchiallavage specimens. Am J Clin Pathol 1992;97:619–24.

9 Wharton JM, Coleman DL, Wofsy CB et al. Trimethoprim-sulfamethoxazole or pentamidine for Pneumocystis cariniipneumonia in the acquired immunodeficiency syndrome.A prospective randomized trial. Ann Intern Med 1986;105:37–44.

10 Bozzette SA, Sattler FR, Chiu J et al. A controlled trial of earlyadjunctive treatment with corticosteroids for Pneumocystiscarinii pneumonia in the acquired immunodeficiencysyndrome. California Collaborative Treatment Group. N Engl JMed 1990;323:1451–7.

11 Luft BJ, Remington JS. Toxoplasmic encephalitis in AIDS.Review. Clin Infect Dis 1992;15:211–22.

12 Schnapp LM, Geaghan SM, Campagna A et al. Toxoplasmagondii pneumonitis in patients infected with the humanimmunodeficiency virus. Arch Intern Med 1992;152:1073–7.

13 Dannemann B, McCutchan JA, Israelski D et al. Treatment oftoxoplasmic encephalitis in patients with AIDS. A randomizedtrial comparing pyrimethamine plus clindamycin topyrimethamine plus sulfadiazine. The California CollaborativeTreatment Group. Ann Intern Med 1992; 116:33–43.

14 Torre D, Casari S, Speranza F et al. Randomized trial oftrimethoprim-sulfamethoxazole versus pyrimethamine-sulfadiazine for therapy of toxoplasmic encephalitis in patientswith AIDS. Italian Collaborative Study Group. AntimicrobAgents Chemother 1998;42:1346–9.

15 Murphy EL, Collier AC, Kalish LA et al. Viral ActivationTransfusion Study Investigators. Highly active antiretroviraltherapy decreases mortality and morbidity in patients withadvanced HIV disease. Ann Intern Med 2001;135:17–26.

16 Hajjeh RA, Conn LA, Stephens DS et al. Cryptococcosis:population-based multistate active surveillance and risk factorsin human immunodeficiency virus-infected persons.Cryptococcal Active Surveillance Group. J Infect Dis 1999;179:449–54.

17 Saag MS, Graybill RJ, Larsen RA et al. Practice guidelines for themanagement of cryptococcal disease. Infectious Diseases Societyof America. Clin Infect Dis 2000; 30:710–8.

18 van der Horst CM, Saag MS, Cloud GA et al. Treatment ofcryptococcal meningitis associated with the acquiredimmunodeficiency syndrome. National Institute of Allergy andInfectious Diseases Mycoses Study Group and AIDS ClinicalTrials Group. N Engl J Med 1997;337:15–21.

19 Benson CA, Kaplan JE, Masur H, Pau A, Holmes KK; CDC;National Institutes of Health; Infectious Diseases Society ofAmerica. Treating opportunistic infections among HIV-infectedadults and adolescents: recommendations from CDC, theNational Institutes of Health, and the HIV MedicineAssociation/Infectious Diseases Society of America. MMWRRecomm Rep 2004;53(RR–15):1–112.

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