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Emergencies related to HIV infection and treatment (part 2)

Urgences associe és a ̀ l’infection par le VIH et traitement(2e partie)

Amit Chandra a ,*, Jacqueline Firth b, Abid Sheikh a , Premal Patel c

a University of Botswana School of Medicine, Pvt. Bag 00713, Gaborone, Botswanab Botswana-UPenn Partnership, P.O. Box AC 157 ACH, Gaborone, Botswanac University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, USA

Received 12 February 2013; revised 29 March 2013; accepted 3 April 2013Available online 21 May 2013

KEYWORDS

HIV;AIDS;ARV;CMV;VZV;IRIS

Abstract HIV is a leading cause of mortality in resource limited settings, and HIV associated med-ical emergencies are common emergency department presentations in high-prevalence settings. HIVattacks the body’s immune system, making infected individuals susceptible to severe infections of multiple organ systems including the respiratory tract, ocular structures, and central nervous sys-tem. HIV infected individuals also suffer from unique patterns of cardiac disease, gastrointestinaldisturbances, and haematologic and oncologic conditions. Anti-retroviral therapy itself is also asso-ciated with numerous side effects, many of which can be life-threatening. Diagnosis and manage-ment of HIV infected patients require knowledge of the disease’s pathology and the lifethreatening complications associated with it. Part 2 of this article reviews haematologic/oncologic,ocular, gastrointestinal, and treatment complications.

ª 2013 Production and hosting by Elsevier on behalf of African Federation for Emergency Medicine.

* Corresponding author.E-mail addresses: [email protected] (A. Chandra),

[email protected] (J. Firth), [email protected](A. Sheikh), [email protected] (P. Patel).Peer review under responsibility of African Federation for EmergencyMedicine.

Production and hosting by Elsevier

African Journal of Emergency Medicine (2013) 3, 197–202

African Federation for Emergency Medicine

African Journal of Emergency Medicine

www.afjem.comwww.sciencedirect.com

2211-419X ª 2013 Production and hosting by Elsevier on behalf of African Federation for Emergency Medicine.http://dx.doi.org/10.1016/j.afjem.2013.04.001

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KEYWORDS

HIV;AIDS;ARV;CMV;VZV;IRIS

Abstract Le VIH est l’une des principales causes de mortalite ́dans les environnements caracte ŕise śpar des ressources limité es, et les urgences mé dicales associé es au VIH sont des motifs courants deconsultation dans les services d’urgence dans les zones a ̀forte pre v́alence. Le VIH attaque le syste m̀eimmunitaire, rendant les individus infecte ś plus susceptibles de contracter de graves infections demultiples organes, tels que les voies respiratoires, les structures oculaires et le syste m̀e nerveux cen-tral. Les personnes se ŕopositives souffrent e ǵalement de types de maladies cardiaques uniques, detroubles gastro-intestinaux et de troubles he ḿatologiques et oncologiques. La the ŕapie antire t́rovi-

rale est elle-mê me associe é a ̀nombre d’effets secondaires, dont beaucoup peuvent s’ave ŕer mortels.Le diagnostic et la prise en charge des patients se ŕopositifs ne ćessitent une bonne connaissance de lapathologie de la maladie et des complications mortelles qui y sont associe és. La deuxie m̀e partie decet article se penche sur les complications he ḿatologiques/oncologiques, oculaires, gastro-intesti-nales et associe és au traitement.

ª 2013 Production and hosting by Elsevier on behalf of African Federation for Emergency Medicine.

African relevance

HIV is a major cause of mortality in Sub-Saharan Africa. Patients with HIV associated emergencies often present to

African emergency departments with acute illnesses. Patients may be naive to their own infection, their CD4count, or their specic HAART regimen, so cliniciansrequire a broad knowledge base to manage thesepresentations.

As HAART becomes more widely available across the con-tinent, complications of treatment will become an increas-ingly common issue.

Introduction

Part one of this series discussed the pathophysiology of HIVand associated respiratory, cardiac, psychiatric, and neuro-

logic complications. The paper highlighted a variety of opportunistic infections (OI) and the challenges of tuberculosis(TB) treatment. Part two continues from here and describeshaematologic/oncologic, ocular, gastrointestinal, and treat-ment complications.

Haematologic/oncologic

HIV infected patients may present to the emergency centre(EC) due to symptoms associated with haematologic andoncologic diseases related to their HIV infection. While themost common reason for presentation within this category issevere anaemia, both thrombosis and symptoms related tomalignancies, either known or previously undiagnosed, alsooccur with regularity.

Anaemia

Anaemia in HIV infected persons may be due to the infectionitself, anaemia of chronic disease associated with HIVinfection, bone marrow inltration or suppression by HIV orOIs (especially TB), or due to the medications used to treatthe infection and p revent OIs, particularly zidovudine (AZT)and cotrimoxazole. 1 While determination of the actual causeof the anaemia is generally pursued outside of the EC, the ini-tial laboratory tests should be sent from the EC, particularly if

the patient’s anaemia warrants transfusion, as the diagnosticworkup must be postponed for at least three months aftertransfusion to ensure accuracy. Important tests to be sent priorto transfusion include full blood count, reticulocyte count, ironstudies, serum B12 and folate levels, and tests for haemolysis

including LDH, peripheral smear, haptoglobin and bilirubinlevels. Coagulation proles should be sent in cases of bleedingleading to anaemia, and creatinine and blood urea levels maybe useful in indicating renal dysfunction which may have led toor contributed to chronic anaemia. Criteria for transfusion inHIV patients are the same as those for uninfected patients, andO negative blood should be used if blood matching the pa-tient’s blood type is not available. Other cytopaenias may bepresent with or without anaemia and may also be due toHIV infection. Particular attention should be paid to patientswith thrombocytopenia, as both idiopathic thrombocytopenicpurpura and thrombotic thrombocytopenic purpura are morecommon in HIV-infected persons, and have high rates of mor-bidity and mortality; a peripheral smear should be sent imme-diately to evaluate for schistocy tes (RBC fragments) if either of these conditions are suspected. 2

Thrombosis (deep venous thrombosis/pulmonary embolism)

Although the mechanism is not yet well understood, it hasbeen demonstrated that HIV patients are four-times morelikely to develop deep venous thrombosis compared with unin-fected persons of the same age and gender. 3 HIV-infected pa-tients are also 43% more likely to develop a pulmonaryembolism. 4 Thrombotic potential has been found to increasein direct relationship with opportunistic infections, malignan-cies, AIDS-related nephropathy and auto-immune hae molytic

anaemia and in inverse relationship to the CD4 count.5

Con-sideration of the interaction between warfarin and proteaseinhibitors (PI) and non-nucleoside reverse transcriptase inhib-itors (NNRTI) must be considered for HIV-infected patientsbeing treated for thrombosis.

AIDS-related malignancies

There are ve AIDS-dening malignancies, all of which havebeen found to be largely virally-mediated: invasive cervicalcancer (HPV), Kaposi’s sarcoma (HHV-8), Burkitt’sLymphoma (EBV), Immunoblastic lympho ma (EBV andHHV-8), and primary CNS lymphoma (EBV). 6,7 Many other

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malignancies show higher rates in HIV-infected persons. 8 Theintroduction of HAART therapy in most of Sub-Saharan Afri-ca has presumably reduced the rates of many AIDS-relatedmalignancies, however, some re ports indicate the rates of lym-phoma have actually increased. 2 Although HIV-related malig-nancies are far less common than OIs in most of Sub-SaharanAfrica, signicant lymphadenopathy and weight loss withoutrespiratory symptoms, elevated LDH or unexplained cytopae-

nias, or ring-enhancing lesions on CT scan should prompt athorough evaluation of malignancy in addition to evaluationand potential treatment for OIs. 1 EC clinicians must alwaysinclude malignancy on their differential for any HIV-infectedperson and ensure that patients who are discharged from theEC receive appropriate follow up for symptoms concerningfor malignancy.

Ocular

The clinical presentation of an acute red eye in an HIV positivepatient should raise suspicions for two sight threatening infec-tions: cytomegalovirus (CMV) retinitis and Varicella ZosterVirus (VZV) ophthalmicus.

Cytomegalovirus

Chronic infection by CMV, also known as Human Herpesvirus 5, is common in the general population, but can leadto life threatening infections when the immune system is com-promised. CMV retinitis causes permanent damage to the ret-ina and is associated with low CD4 count. It presents withsymptoms of oaters, light ashes, and decreased visual acu-ity. 9 The infection can lead to retinal detachment and blind-ness, and often spreads from o ne eye to the other whendiagnosis and therapy is delayed. 10 The diagnosis is made byhistory and fundoscopy, which reveals disc oedema and areas

of ischaemia and haemorrhage, often referred to as a ‘‘pizzapie’’ appearance. In patients with atypical lesions or an uncleardiagnosis, DNA polymerase chain reaction (PCR) can be per-formed on vitreous uid. Treatment involves systemic antivi-rals (e.g., valganciclovir or ganciclovir) and ophthalmologicconsultation for possible intravitreal antiviral injection orintraocular antiviral implants (ganciclovir) and retinal repair.HAART should be initiated after commencing antiviral treat-ment. In resource limited settings with poor access to ophthal-mologists, primary care providers can be trained to detectCMV and perform intravitreal injections. 11 Immune recoverywith HAART is critical to managing ocular CMV, althoughit can initia lly worsen inammation and lead to immune recov-ery uveitis. 12,10

Varicella zoster ophthalmicus

VZV, also known as Human Herpes Virus 3, is the causativeagent of chickenpox (varicella), after which it remains dormantin the peripheral nervous system. Later in life, it can cause aviral reactivation syndrome along a particular dermatomecommonly referred to as zoster or shingles. These episodescan be precipitated by physiologic stress or an immunocom-promised state, and are sometimes preceded by a viral syn-drome prodrome. VZV ophthalmicus occurs when thereactivation involves the nasociliary branch of the rst (oph-thalmic) division of the fth cranial (trigeminal) nerve, and

accounts for 10–25% of all zoster cases. 13 The conditioncauses lesions on the cornea, anterior uveitis, and eventuallycorneal scarring and retinal necrosis. Long-term complicationsoccur in about 50% of patie nt s with this condition and includechronic pain and blindness. 14 The disease should be suspectedin all patients presenting with acute red eye with or withoutshingles of the face, especially when associated with Hutchin-son’s sign: vesicular rash on the tip of the nose (also innervated

by the nasociliary branch). HIV infection and Hutchinson’ssign are each associated with higher rates of post infectionocular complications. 15 Diagnosis is conrmed by thevisualization of dentritic lesions on the cornea when viewedwith uorescein stain. Treatment includes analgesia, eye lubri-cation, and immediate initiation of systemic antivirals (e.g.,acyclovir). Patients should be referred for urgent ophthalmo-logic evaluation where available.

Gastrointestinal

Diarrhoea and dysphagia are common gastrointestinal tra ctsymptoms of HIV positive patients presenting to ECs. 16

Abdominal pain in the setting of a low CD4 count or new anti-retroviral regimens should raise suspicion for colitis, enteritis,hepatitis, TB abdomen, or pancreatitis.

Causes of diarrhoea include HAART side effects (e.g., pro-tease inhibitors), common bacterial pathogenic strains, Myco-bacter ium avium-intracellulare , Cryptosporidia , Isospora , andCMV. 17 A denitive diagnosis may depend on stool micros-copy and culture results or colonoscopy with biopsy whereavailable. Special stains may be required to identify certaindiarrheal pathogens on microscopy. Treatment involves rehy-dration and supportive care. In cases where acute bacterialdiarrhoea is suspected, associated with fever, abdominal pain,and bloody stool, treatment should include a third generationcephalosporin or a uoroquinolone. For chronic diarrhoea,

empiric antibiotics, e.g., metronidazole or a sulphonamide,can be considered depending on the local prevalence of causa-tive pathogens. HAART initiation can lead to the resolution of certain types of HIV-associated chronic diarrhoea.

Oesophageal symptoms, retrosternal odynophagia, anddysphagia are commonly associated with candidal esophagitis,a common AIDS dening illness. CMV, HSV, and aphthousulcers can also cause similar symptoms, associated with ulcer-ating lesions along the oesophagus, and should be consideredif the disease does not respond to uconazole therapy. Endos-copy and barium swallow evaluation may also be needed torule out oesophageal malignancies like Kapos i’s sarcoma,non-Hodgkin’s lymphoma, and adenocarcinoma. 18

Complications of treatment

The devastating course of HIV infection can only be haltedwith effective HAART. Various classes of HAART haveemerged targeting multiple enzymes, proteins and receptorsintegral to the HIV life cycle. In resource-limited settings,HAART regimens are commonly composed of two nucleosidereverse transcriptase inhibitors (NRTIs) paired with a non-nucleoside reverse transcriptase inhibitor (NNRTI) (1st line)or a protease inhibitor (PI) (2nd line).

Major short-term complications of HAART are related tothe drug class and particular drug itself. Table 1 outlines com-mon HAART abbreviations and adverse drug events. Adverse

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drug reactions (ADR) appear worldwide to complicate 11– 36% of patients r eceiving HAART often occurring withinthe rst 6 months. 19 A few HAART side effects warrantprompt diagnosis to avoid unnecessary morbidity andmortality.

Hepatotoxicity

Though the patterns and denitions of hepato-toxity differ, se-vere elevations in ALT (>5x upper limits of normal) are seenin up to 14% of individuals on HAART and are fu rther com-plicated with concurrent HBV or HCV infection. 20 The spec-trum of disease can range from asymptomatic elevations inLFTS to fulminant liver failure. HAART most associated withhepatotoxicity are 1st generation NNRTIs (NVP, EFV),NRTIs (ABC, d4T, ddI), PIs (DRV, LPV, ATV, etc.) thoughalmost all antiretroviral agents carry the potential to causehepatotoxicity in varying degrees. In resource-limited settings,hepatotoxicity is most commonly caused by the use of NVP.NVP induced hepatotoxicity can result in symptomatic hepati-tis in 2.5–11% of recipients with 50% of cases presenting with

a hypersensitivity reaction.21

Severe liver toxicity with subse-quent liver failure has been reported. Atazanavir can causean indirect hyperbilirubinaemia though it rarely leads to drugdiscontinuation. D4T and ddI can cause steatohepatitis.

Nephrotoxicity

Renal failure, whether acute or chronic, has various aetiologiesin the context of HIV. Though the exact mechanism is unclear,HIV-associated nephropathy (HIVAN) has been frequentlydescribed in patients with AIDS, most commonly those notreceiving HAART. Characteristics of HIVAN include nephri-tic range proteinuria, large echogenic kidneys on ultrasound

and detectable plasma HIV. HAART is the mainstay of treat-ment. However, HAART itself can also have nephrotoxiceffects.

The majority of nephrotoxicity has been associated withIDV, TDF and more recently, ATV. Those with prior renalimpairment are generally at higher risk. Given widespreaduse, TDF related nephrotoxicity will be commonly encoun-tered in clinical practice. TDF can cause damage to the renaltubules and glomerulus causing a diversity of injury from Fan-coni’s syndrome to acute renal failure. IDV induced nephro-toxicity can be caused by nephrolithiasis, tubulointerstitialnephritis or acu te renal failure; nephrolithiasis can also becaused by ATV. 21

Though only a few ARVs can directly cause nephrotoxicity,many more require renal dosing in patients with diminishedGFR. A decrease in renal function should be monitored care-fully with prompt evaluation of aetiology and renal dosing of medications where applicable.

Pancreatitis

Pancreatitis is a rare complication of the NRTIs d4T and ddI(especially when used in combination) and all PIs. NRTI-associated panc reatitis can occur alone or in conjunction withlactic acidosis. 22 Though ARVs are most commonlyimplicated, administration of cotrimoxazole has also beenassociated with pancreatitis, albeit in rare cases. 23 Patientscommonly present with symptoms of epigastric abdominalpain, nausea, vomiting and inability to tolerate food. Lipaseis commonly elevated. Amylase is non-specic and elevationscan also be caused by non-pancreatic mechanisms. Inaddition to prompt discontinuation of HAART, treatmentincludes supportive care with intravenous uids, nothing bymouth and pain control. 24

Table 1 Common anti-retrovirals by class and toxicities. 21,26,28,29

Anti-retrovirals Abbreviation Severe adverse events

NRTIsAbacavir ABC Hypersensitivity reactionDidanosine ddI Lactic acidosis, Hepatitis, PancreatitisEmtricitabine or Lamivudine FTC 3TC Hepatitis B exacerbation on discontinuation 3TC: red cell aplasiaStavudine D4T Lactic acidosis, Hepatitis, Pancreatitis, Neuromuscular weaknessTenofovir TDF Renal failure, Hepatitis B exacerbation upon discontinuationZidovudine AZT Anaemia, Neutropenia, Lactic acidosisNNRTIsEfavirenz EFV Rash, Stevens-Johnson Syndrome, Hepatotoxicity, NeuropsychiatricNevirapine NVP Rash, Stevens–Johnson syndrome, Hypersensitivity reaction, HepatotoxicityEtravirine ETF RashPIs*Ritonavir RTV or rAtazanavir ATV 1st degree AV Block, Nephrolithiasis, Unconjugated HyperbilirubinaemiaDarunavir DRV Stevens–Johnson syndrome, Erythema multiforme, HepatotoxicityFosamprenavir FPVIndinavir IDV NephrolithiasisLopinavir/r LPV/rSaquinavir SQVTipranavir TPV Cerebral haemorrhage, HepatotoxicityIntegrase InhibitorRaltegravir RAL Rash

*All PIs can cause hypertriglyceridaemia and pancreatitis. All boosted PIs have the potential to cause conduction delays.



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Lactic acidosis

Lactic acidosis is a known side effect of NRTIs, especially withd4T and ddi though others (AZT, 3TC = TDF) are capable toa lesser degree. 25 In resource-limited settings where d4T is stillwidely used, lactic acidosis should be suspected with non-specic symptoms which can include abdominal pain, nausea,vomiting, fatigue, dyspnoea, and recent weight loss. Symptomsmay occur months to years after starting NRTIs. The criteriaused to diagnose lactic acidosis are shown in Table 2 . If ABGand measurement of lactate are not possible, an anion gap maybe suggestive in the right clinical context. Lab ndings of in-creased CK, LDH, lipase and LFTs are supportive of the diag-nosis. Clinicians must maintain a high index of susp icion forthe condition as mortality can be as high as 60%. 25,20 Progres-sion to liver failure can also occur. Since signs and symptomscan mimic clinical features of sepsis, empiric management mayalso include obtaining cultures and administering broad spec-trum antibiotics. The mainstay of treatment of lactic acidosis isdiscontinuation of all HAART and supportive care withaggressive uid resuscitation. Evidence is limited for the rou-tine use of sodium bicarbonate or vitamin co-factors. Uponclinical resolution, HAART can be reinitiated with ABC orTDF in combination w ith 3TC or FTC; D4T, DDI, andAZT should be avoided. 24

Anaemia

The NRTI, AZT, is known to cause macrocytic anae mia, usu-ally developing in the rst 6 months of treatment. 24 In onestudy, up to 20% of patients on AZT-containing regimensdevelo ped anaemia though lower rates have been reported else-where. 24 Signs and symptoms of symptomatic anaemia includepallor, fatigue, generalized weakness, orthostatic hypotension,shortness of breath and chest pain. Symptomatic patientsshould be transfused. AZT should be discontinued and chan-ged to an alternate NRTI.

Hypersensitivity reactions

Abacavir hypersensitivity reaction (AHR) is a systemic re-sponse to the NRTI, ABC. Though the HLA B5701 allele is

associated with AHR, gene testing is not commonly performedin resource-limited settings. Moreover, the prevalence of B5701 appears to be 250 cells/mm 3 in womenand >400 cells/mm 3 in men are at higher risk. NVP-relatedhypersensitivity can be associated with constitutional symp-

toms, fever, rash, and hepatitis.24

Rash is among the mostcommon side effects by users of NVP. Steven’s Johnson’sSyndrome (SJS) and Toxic epidermal necrolysis (TEN) arepotentially lethal dermatologic toxicities manifested by blis-ters, bullae, sloughing of the skin and/or mucus membraneinvolvement. Mainstay of treatment depends on cessation of NVP, and management as burns with supportive care.

Immune reconstitution inammatory syndrome

HAART initiation promptly leads to a fall in HIV viral loadand higher CD4 cell numbers and function. This initial immuneresponse can lead to paradoxical clinical worsening referred toas IRIS and has been noted in 10–32% of patients initiatingHAART. 27 The underlying pathogenesis appears to be a dy s-regulated immune response to antigens and/or pathogens. 26

IRIS can present as a ‘‘paradoxical’’ exacerbation of a known,pre-existing OI or ‘‘unmasking’’ of a newly diagnosed OI.Though there is no universal consensus on the denition of IRIS, any clinical worsening not attributable to drug toxicityshould raise suspicion. IRIS is frequently attributed to myco-bacterium infections and fungal infections, particularly tuber-culosis and cryptococcus respectively though any pathogencan be implicated. IRIS involving the CNS can be life threaten-ing and fatal. In addition to treating the underlying OI, IRIStherapy consists of NSAIDs and in severe cases, steroids. 26

HAART can usually be safely continued with rare exceptions. 27

Conclusion

The prevalence of specic HIV related presentations to acutecare facilities is not well known. HIV infected patients canpresent with diseases common in the uninfected population,and they can present with a variety of HIV associated condi-tions. The situation is complicated by the fact that many of these patients may not know their HIV status. Subacute orchronic conditions associated with HIV infection, and notdiagnosed or managed in a timely fashion by primary care ser-vices, can progress to life threatening situations. An HIV asso-ciated emergency should therefore be a strong consideration

for any critically ill patient, especially in high prevalenceregions.Clinicians working in ECs should have a broad knowledge

of HIV, its effects on host immune systems, and common HIVassociated diseases. In high prevalence regions, bedside rapidHIV testing can aid in diagnosis and management of criticallyill patients.

Acknowledgment

The authors would like to acknowledge the input of Dr. Mat-thew Dacso.

Table 2 Criteria for lactic acidosis. 26

Lactate > 2 mmol/LpH < 7.35HCO 3 < 20 mmol/L

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