Herpes simplex virus (HSV) Manifestations of primary infection: \212Systemic infection: Fe ver, sore throat, and lymphadenopathy may pass unnoticed. If immunocompromised, it may be l ife-threatening with fever, lymphadenopathy, pneumonitis, and hepatitis. \212Gingivostomatitis: Ulcers filled with yellow slough appear in the mouth. \212Herpetic whitlow: A breach in the skin allows the virus to enter the finger, causing a vesicle to form. This often affects children \200\231s nurses. \212Traumatic herpes (herpes gladiatorum): Vesicles develop at any site where HSV is ground into the skin by brute force. \212Eczema herpeticum: H SV infection of eczematous skin; usually in children. \212Herpes simplex meningitis: This is uncommon and usually self-lim- iting (typically HSV -2 in women during a primary attack). May be recur- rent. CSF PCR is test of choice. \212Genital herpes: At least 50 million people in America are infected. HSV-2 is most comm on and more likely to be recurrent. Most people do not know they have genital HSV, but stil l shed virus intermittently. Classic lesions are painful, may appear as ulcers or grouped v esicles and papules, develop around anus and penis (with pain, fever, and dysuria) palms , feet, or throat. Recurrent infection is generally less symptomatic than primary infection . Diagnosis: Classic lesions are frequently absent. Obtain PCR or culture of skin lesions. Negative test does not rule out infection. HSV \200\2232 antibodies are highly sensitive an d specific. Tzanck smear is not reliable. Treatment: Give analgesia and one of the regimens in Table 14.22 for acute, recurrent, and suppressive therapy. Suppressive therapy may impr ove quality of life and decrease transmission in discordant couples. \212HSV keratitis: Co rneal dendritic ulcers. Avoid steroids. Trifluridine eye drops, 1 drop q2h up to 9 \227 /d \227 21 d. Usually HSV1. Virus spreads centrip- Herpes simplex encephalitis: etally (e.g., from cranial nerve ganglia, to frontal and temporal lob es). Suspect this if there are fevers, seizures, headaches, odd behavior, dyspha- sia, hemi paresis, or coma or subacute brainstem encephalitis, meningitis, or myelitis. Diagnosis: Ur gent PCR on CSF sample (CT/magnetic reso- nance imaging (MRI) and electroencephalogram (EEG ) may show tem- poral lobe changes but are nonspecific and unreliable; brain biopsy rarely required). Seek expert help: Consider admitting to ICU; careful fluid balance is important to minimize cerebral edema. Poor predictors are age >30, delay in starting acyclovir >4 d, altered consciousness. Prompt acyclovir (e.g., 10 mg/kg/8 h IV for 14 \200\22321 d) decreas es mortality to 8% (untreated mortality 70%). \212 Table 14.22 Genital herpes treatment 558 Acute 400 mg/8 h or 200 mg/4 \200\2235 h \227 7 \200\22310 d 250 mg/8 h \227 7 \200\22310 d Recurrent 400 mg/8 h, 800 mg/12 h \227 5 d, 800 mg/8 h \227 2d 125 mg/12 h \227 5 d, 500 mg \227 1 then 250 mg/12 h \227 2 d, 1 g/12 h \227 1 d 500 mg/12 h \227 3 d or 1 g/d \227 5 d Suppression 400 mg bid Acyclovir Famciclovir 250 mg bid Valacyclovir 1 g/12 h \227 7 \200\22310 d 0.5 \200\2231 g/d Severe disease: Acyclovir 10 mg/kg q8h IV Acyclovir resistance: Foscarnet 120 \200\223200 m g/d iv or topical cidofovir gel 1% applied daily \227 5 d \212 HSV lying dormant in ganglion cells may be reactivated Recurrent HSV: by illness, immunosup pression, menstruation, or even sunlight. Cold sores (perioral vesicles) are one manifestat ion. Acyclovir cream is not recommended. s e s a e s i d Infectious mononucleosis This is a common disease of young adults that may pass unnoticed o r cause acute illness. Spread is thought to be by saliva or droplet. The incubation period is uncertain, but may be 4 \200\2235 wks. EBV is the cause of classic mono- nucleosis, but other viruses (e.g., HIV, CMV) can cause a similar syndrome. EBV preferentially infects B-l ymphocytes. There follows a proliferation of T-cells (the \200\234atypical \200\235 mononu clear cells), which are cytotoxic to EBV- infected cells. The latter are \200\234immortali zed \200\235 by EBV infection and can, very rarely, proliferate to form a picture indisting uishable from immunoblastic lymphoma in immunodeficient individuals (whose suppressor T-cel ls fail to check multiplication of these B-cells). Symptoms and signs include sore throat, fever, anorexia, malaise, lymphadenopathy, palatal petechiae, splenomegaly, hepatitis, and hemolytic anemia. Occasionally, there is encephalitis, myocarditis, pericarditis, or neurop athy. Rashes may occur, particularly if the patient is given ampicillin. Differential diagn osis Streptococcal sore throat (may coexist), CMV, viral hepatitis, HIV seroconversion illn ess, adenovirus, toxoplasmosis, leukemia, diphtheria, drug reaction (e.g., phenytoin). Inve stigations Blood \201 lm shows lymphocytosis (up to 20% of WBC) and atypical lymphocytes (large, irregular nuclei). Such cells may be seen in many viral infections (e.g., CMV, HIV, parvovirus, dengue fever), toxoplasmosis, leukemia, lymphomas, drug hypersensitivity, and lead poisoning. Serological tests are listed in Table 14.23: Treatment Avoid alcohol and tr auma to LUQ. Steroids are rarely recommended for severe symptoms. Ampicillin and amoxicilli n should not be given for sore throat if mononucleosis is suspected as they may cause a sev ere rash in those with acute EBV infection. Complications Depression, fatigue, and lethargy , which may persist for months. Also, mononucleosis can be associated with thrombocytopenia , ruptured spleen, splenic hemorrhage, upper airways obstruction (may need observation in I CU), secondary infection, pneumonitis, aseptic meningitis, Guillain \200\223Barr syndrom e, renal failure, lymphoma, and autoimmune hemolytic anemia. All are rare. s u o i t c e f n I 559 Table 14.23 Serological tests for mononucleosis Test Heterophil antibody (e.g., monospot) Viral capsid antigen (VCA) Comment Becomes + with acute infection and persists for 4 \200\22312 wks. False + possible in hepatitis, lymphoma, leukemia, SLE Become + with acute infection IgM: Persists 4 \200 \2236 wks IgG: Persists for life Become + with acute infection, persists for 3 \200\2236 mo nths or longer (lifelong in 20%) Becomes + 2 \200\2234 months after disease onset and persi sts for life. Early-antigen IgG Antibody to EBV nuclear antigen (EBNA) Other EBV-associated diseases Burkitt \200\231s lymphoma in Africa and nasopharyngeal carci noma in Asia. EBV positive large cell (B-cell) lymphomas occasionally appear in the immunoc ompromised (e.g., post- transplantation lymphoproliferative disorder). The EBV genome has a lso been found in the Reed \200\223Sternberg cell of Hodgkin \200\231s lymphoma. Oral hairy leukoplakia is caused by EBV and may respond to antivirals such as acyclovir and valacyclo vir. Cytomegalovirus CMV may be acquired by direct contact, blood transfusion, or organ transpla ntation. After acute infection, CMV becomes latent, but the infection may reactivate at tim es of stress or immunocompromise. If immunocompetent, primary infection is usually asymptom atic but acute hepatitis may occur. In solid organ transplant patients, CMV infection may b e acquired from the transplanted graft as primary infection or reactivate from the recipien t \200\231s own CMV. CMV disease after solid organ or post bone marrow transplantation: CMV syndrome (fever, myalgias, bone marrow sup- pression) > pneumonitis > colitis > hepatitis > retinitis. In AIDS: Retinitis > colitis > esophagitis > CNS disease. (Here, > means \200 \234is more common than. \200\235) Diagnosis of acute CMV infection is occasionally difficu lt; growth of the virus is slow and there may be prolonged CMV excretion from a distant sou rce of infection. For CMV disease in transplant recipients CMV PCR (including quantitative tests) of blood/CSF/bronchoalveolar lavage are becoming widely available. CMV retinitis is diagnosed by fundus exam in atypical host; no lab tests are necessary. Extensive CMV involv ement of GI tract or lung can be present even with negative serum PCR. Histopathology (lung , gut, etc.) shows typical inclusions. Treatment is stratified by scenario : Mainstay of th erapy in nonimmunocompromised patients is supportive. In transplant and HIV patients, treat ment is with ganciclovir IV or valganciclovir PO. In eye disease, direct antiviral injectio ns and intraocular implants are used as well. Main toxicity of systemic therapy is leukopen ia. Dose must be adjusted for renal dysfunction. Treatment is individualized. In invasive d isease, try to reduce immunosuppression. If feasible, treat infection for at least 2 wks af ter resolution of viremia and symptoms. After completion of therapy, secondary prophylaxis for 1 \200\2233 months or longer should be considered. 560 s e s a e s i d Table 14.24 Cytomegalovirus treatment Scenario Acute CMV infec- tion: Normal host Asymptomatic Antiviral Treatment (for normal GFR) None s u o i t c e f n I Valganciclovir 900 mg/12 h PO CMV viremia: Transplant CMV syndrome: Transplant Valganciclovir 900 mg/12 h PO or ganciclovir 5 mg/kg/12 h IV GI: Transplant, HIV Ganciclovir 5 mg/kg/12 IV, can switch to PO valganciclovir when stable Lung: Transplant Ganciclovir 5 mg/kg/12 IV, consider CMV Ig 100 \200\223150 mg/kg thrice weekly, can switch to PO valganciclovir when stable CNS: Transplant, Ganciclovir 5 mg/kg/12 IV HIV Retinitis: HIV, transplant Valganciclovir 900 mg/12 h PO or ganciclovir 5 mg/kg /12 h IV. Duration guided by eye exam. In severe disease, intraocular antiviral injec tion Ganciclovir 7.5 \200\22310 mg/kg/12 h IV, Foscarnet 60 mg/kg/8 h or 90 mg/kg/12 h, cid ofovir 5 mg/ kg/wk \227 2, then every other week. Consider CMV Ig. Ganciclovir- resistant infec- tion (test for UL97 and UL54 mutations) Nonspecific upper respiratory tract infections (common cold) >200 viruses are potentially r esponsible. Rhinoviruses are the main culprits (dozens of strains). Other viruses include p arainfluenza, respiratory syn- cytial virus (RSV), adenovirus, and influenza. Illness usual ly includes a self- limiting nasal discharge (which becomes mucopurulent over a few days), sore throat, watery eyes, mild body aches, and headache. Symptoms last average of 7 \200 \22311 d. Influenza is the most important (see below), but other viruses (e.g., RSV, parain fluenza, and adenovirus) can cause devastating ill- ness in immunocompromised patients. Inc ubation 1 \200\2234 d. Complications Sinusitis, lower respiratory tract infection. Treatmen t Avoid smoking or second-hand smoke; humidifier may help with coughing; ice chips or throa t lozenges for sore throat; ibuprofen, acetaminophen for low-grade fevers and pain. First-g eneration anti- histamines and decongestants may also help with symptoms. 561 Influenza This is a very important viral respiratory infection because of its frequency and complication rate, particularly in the elderly and in those with underly- ing medical cond itions. Influenza is responsible for 20,000 deaths/year in the United States. Compared to seasonal influenza, when pandemic strains evolve, mortality may be significantly higher an d/or new groups may be par- ticularly vulnerable. The virus (RNA orthomyxovirus) has three types (A, B, C). Only types A and B cause significant morbidity in humans. Subtyping (for t ype A) is by hemagglutinin (H) and neuraminidase (N) characteris- tics. Frequent mutations give strains with new antigenic properties. Minor changes (antigenic drift) and especially major changes (antigenic shift) can place whole areas at risk. World Health Organization (W HO) classification specifies: Type/host origin/geographic origin/strain number/year of isol a- tion/subtype (e.g., A/Swine/Taiwan/2/87/[H3, N2]). Spread is by droplets or hands. Incub ation period: 1 \200\2234 d. Infectivity : 1 d before to 7 d after symptoms start. Immunity : Those attacked by one strain are immune to that strain only. Convalescence : May be slow . Symptoms Fever, headache, malaise, myalgias, nausea, vomiting, and conjunctivitis/eye pai n (even photophobia). Tests Only test if result will change management or infection control practices. PCR of nasopharyngeal aspirates is highly sensitive and specific. Other tests h ave limitations. These include rapid flu tests (<60% sensitive), immunofluorescence (requir es lab expertise), and culture (results not available in timely fashion). Complications Bro nchitis 20%, pneumonia (especially S. pneumoniae and S. aureus ), sinusitis, otitis media, encephalitis, pericarditis, and Reye \200\231s syndrome (coma, increased LFTs; may be assoc iated with ASA use). Treatment With mild disease, recommend rest at home until afebrile >24 hours. Symptom relief with acetaminophen may help. Antiviral therapy should be considered in all patients diagnosed within 48 h of symptom onset and those requiring hospitalization. Also consider therapy in those with immunosuppression, underlying illnesses (e.g., sickle cell, cancer, pulmonary, renal, heart, neurological, diabetes mellitus), residents of long- term care facilities, and age >65. If severe pneumonia, most authorities recommend rapid t ransfer to ICU as sepsis and hypoxia may rapidly progress to circulatory collapse and death . Antiviral: Oseltamivir 75 mg PO bid for 5 d eases symptoms if started within 48 h of onse t of symptoms. Amantadine and rimantadine are only effective against influenza type A virus . Zanamivir (an inhaled neuraminidase 562 Table 14.25 Influenza treatments Medication Oseltamivir Dose Treatment: 75 mg/12 h \227 5 d, prophylaxis: 75 mg/d Spectrum A, B Toxicity GI, neuropsy- chiatric Zanamivir Treatment: Two 5 mg inhalations/12 h \227 5d. Prophylaxis: Two inhalations/d A, B Bronchospasm Rimantadine/ amantadine Treatment or prophy- laxis: 200 mg/d or 100 mg/12 h \227 5 d A, but GI, neuropsy- chiatric resistance in H3N2 inhibitor) and oseltamivir are active against influenza types A and B. Note : Inhalation is not an ideal route if elderly or prone to bronchospasm. May also cause oropharyngeal edema . Prevention Seasonal in \202 uenza (trivalent) vaccination: Inactivated virus (injected) and live attenuated virus (intranasal). It is prepared from current serotypes and takes <2 wks to work. Indications: Inactivated virus: All persons 6 months. Particularly importan t for health care workers with patient contact, household contacts of high-risk persons, pe rsons 50 yrs, pregnant women (second- and third-trimester), residents of long-term care facilities, and patients with high-risk comorbidity (e.g., neurologic disorders; morbid obe sity; diabetes; chronic lung, heart, or renal disease; immunosuppression; hemoglobinopathie s). Dose: 0.5 ml SC (once). Side effects ( SE ): Mild pain or swelling (17%). Fever, headac hes, and malaise are reported in 10%. Live attenuated influenza vaccine: Indicated for immu nocompetent persons aged 5 \200\22349 yrs. Do not use in immunosuppressed patients or their close contacts; persons with asthma, chronic underlying illnesses, and pregnant women. Ant iviral prophy- laxis: Consider using in high-risk patients when influenza is circulating un til vaccine becomes effective (about 2 wks). s e s a e s i d s u o i t c e f n I Poliomyelitis Poliovirus is highly contagious, although only 4 \200\2238% of patients devel op any illness from the infection and <1% become paralyzed (usually lower extremities). Spr ead is by droplets or fecal \200\223oral. Polio has been eliminated from the Americas, Euro pe, and the Western Pacific. Polio remains endemic in India, Pakistan, Afghanistan, and Nig eria. The patient 7 d incubation, then a flu-like prodrome, leading to a \200\234pre- para lytic \200\235 stage: Fever, tachycardia, headache, vomiting, neck stiffness, and unilatera l tremor. In <50% of patients, this progresses to the paralytic stage: Myalgias, lower moto r neuron signs, and respiratory failure. Tests: CSF: WBC elevation, polymorphs then lymphoc ytes, otherwise normal; paired sera (14 d apart); throat swab and stool culture identify vi rus. Natural history: 5 \200\22310% of those with paralysis die. There may be delayed progr ession of paralysis. Risk factors for severe paralysis: Adulthood, pregnancy, post-tonsille ctomy, muscle fatigue/trauma during incubation period. Prophylaxis: Vaccination. Toxoplasmosis The protozoan Toxoplasma gondii infects via gut, lung, or broken skin. Cats ( the primary host) excrete oocysts, but the ingestion of poorly cooked infected meat by huma ns may be as important as contact with cat feces. In humans, the oocysts release trophozoit es, which migrate widely, with a predilection for eye, brain, and muscle. Toxoplasmosis occ urs worldwide, but is common in the tropics. Infection is life-long. HIV may reactivate it. Note : Rats are also sources of infection. The patient In any patient with granulomatous u veitis or necrotizing retinitis, think of toxoplasmosis. Most infections are asymptomatic. Symptomatic acquired toxoplasmosis resembles infectious mononucleosis and is usually self-l imiting. Eye infection , usually congenital, presents with posterior uveitis, often in the second-decade of life, and may cause cataract. In the immunocompromised (e.g., aids): Encep halitis with CD4 <100, ring enhancing lesion(s) on MRI, and positive IgG serology; clinical symptoms include focal neurological signs, stroke, or seizures. Tests Acute infection is c onfirmed by a fourfold rise in antibody titer over 4 wks or specific IgM. Parasite isolatio n is difficult but easily seen on 563 histopathology; lymph node or CNS biopsy may be diagnostic. Cerebral CT may show characteri stic multiple ring-shaped contrast-enhancing lesions in compromised hosts, especially those with AIDS. Treatment Often none is needed: Seek expert advice. If the eye is involved, or in the immunocompromised, pyrimethamine 200 mg PO \227 1, then 50 \200\22375 mg PO qd plus sulfadiazine 1 \200\2231.5 g PO q6h plus leucovorin 10 \200\22325 mg po qd \227 \200\234 6wks, then pyrimethamine 25 \200\22350 mg PO qd + sulfadiazine 500 \200\223 1,000 mg PO qi d + leucovorin 10 \200\22325 mg PO qd. If pregnant, get expert help. Alternatives: Pyrimeth amine + leucovorin + either clindamycin or atovaquone or TMP/SMX. Viral hepatitis Hepatitis A virus (HAV) RNA virus. Spread: Fecal \200\223oral, often in tra vel- ers or institutions. Most infections occur in childhood. Incubation: 2 \200\2236 wks. Symptoms: Prodrome symptoms include fever, malaise, anorexia, nausea, and arthralgias. Jaun dice develops hepatomegaly, splenomegaly, and adenopathy. Tests: Serum transaminases ris e 21 \200\22342 d after exposure. IgM rises from day 25 and signifies recent infection. IgG remains detectable for life. Treatment: Supportive. Avoid alcohol. Prevention: Immunizatio n with HAV vaccine is a pillar of prevention. It is indicated for travelers to endemic area s, anyone exposed to hepatitis A, close contacts of adoptees from endemic areas, men who ha ve sex with men (MSM), illicit drug users, and patients with chronic liver disease. Passive immunization with normal human immunoglobulin (0.02 ml/kg IM) gives <3 months \200\231 imm unity to those at risk. Use passive immunization in unvaccinated persons >40 who were expos ed to hepatitis A (as soon as possible) or who must travel in next 2 wks and are at risk fo r severe disease (older, chronic liver disease). Prognosis: Usually self-limiting. Fulminan t hepatitis occurs rarely. Chronic liver disease does not occur, but 10 \200\22315% develop relapse of symptoms in first 6 months after acute illness. Hepatitis B virus (HBV) DNA vir us. Spread: Blood products, injection drug use, sexual intercourse, and vertical transmissi on. Risk groups: Health workers, hemophiliacs, hemodialysis, unprotected sex, MSM, and IV d rug users (IVDU). HBV is Endemic in the Far East, Africa, and Mediterranean. Incubation: 6 wks to 6 months. Clinical features: Resemble hepatitis A, but extrahepatic manifestations a re more common (e.g., arthralgias, urticaria). Tests: Serological markers (see Table 14.26) ; HBsAg (surface antigen) is present from 1 to 6 months after exposure. HBsAg (e antigen) i s present for 1 \200\2233 months after the acute illness and implies high infectivity. Th e persistence of HBsAg for >6 months defines carrier status and occurs in 5 \200\22310% of infections (chronic infection). Antibodies to HBcAg (anti- HBc) imply past infection; antib odies to HBSAG (ANTI-HBS) alone imply vaccination. HBV PCR allows monitoring of response to therapy. See Table 14.26. Vaccination is recommended for all unvaccinated adolescents, adu lts who wish to prevent hep B infection, and especially in adults at high risk for infectio n (e.g., health care workers, those in correctional facilities, MSM, persons at risk for ST Ds and those with HIV). Passive immunization (specific anti-HBV immunoglobulin) may be give n to nonimmune contacts after high-risk exposure. Treatment: Supportive. Avoid alcohol. Abo ut 5 \200\2236% with acute HBV infection develop chronic HBV, define by persistence of HBsA g >6 months. Chronic HBV may respond to interferon- or antivirals (e.g., adefovir, tenof ovir, lamivudine or entecavir). Unlike HCV, cure is rare, so the goal of therapy is convers ion to e Ag negativity (most likely with viral interferon) or reduction in viral load and r ates of disease progression. Immunize sexual contacts. Complications: Fulminant hepatic fai lure (rare); relapse; prolonged cholestasis; chronic hepatitis (5 \200\22310%); cirrhosis; hepatocellular carcinoma (HCC: 10-fold increased risk if 564 s e s a e s i d Table 14.26 Hepatitis B serology HBsAg Anti-HBc (IgG + IgM) - Anti-HBc (IgM) Anti-HBs Comment + Vaccination or past infection Recovered from past s u o i t c e f n I + + infection Acute infection Resolving infection Chronic infection False-positive, + - + - + + + + + + - - - - acute, chronic or past infection Sexually Transmitted Diseases Treatment Guidelines, 2010. MMWR December 17, 2010;59(RR \200 \22312). HBsAg positive, 60-fold increased risk if both HBsAg and HBsAg positive); glomerulonephriti s; cryoglobulinemia. Hepatitis C virus (HCV) RNA virus. Spread: Blood, IVDU, sexual (not an efficient mode of transfer), unknown (40%). Early infection is often mild or asymptomatic. Incubation: HCV RNA is detectable at 1 \200\2233 wks, anti-HCV at 8 \200\2239 wks. Clinica l features: Most (70 \200\22385%) develop chronic infection; 60 \200\22370% of patients hav e evidence of chronic liver disease, LFT (typically AST: ALT <1 until cirrhosis, 15 \200 \22320% get cirrhosis within 20 yrs; a few also get hepatocellular cancer. Tests: Anti-HCV by enzyme immunoassay (EIA), enzyme-linked immunosorbent assay (ELISA), enhanced chemilumin escence assay, and recombinant immunoblot assay; PCR for diagnosis and monitoring disease p rogression; genotype and liver biopsy for prognosis and to guide therapeutic decisions. See Table 14.27. Treatment: This is a rapidly evolving field. Treatment considerations: Treat adults with all of the following criteria: Age >18, + HCV RNA, liver biopsy that shows chro nic hepatitis and significant fibrosis, compensated liver dis- ease and no contraindication s (see below). Consider treatment in those with acute infection, biopsy that shows mild or no fibrosis, renal disease, liver transplant, decompensated cirrhosis, and HIV co-infection . Regimens: Pegylated interferon- \222 + ribavirin are used in chronic infection. For geno type 1, chronic HCV, the addition of a protease inhibitor (bo- ceprevir or telaprevir) has been supported by recent studies and is now 565 Table 14.27 Hepatitis C serology Anti-HCV - - PCR - + Interpretation No infection Early infection, chronic infection in immu- nosuppressed state + + + Acute or resolved infection Chronic infection Diagnosis, Management, and Treatment of Hepatitis C: An Update. Hepatology. 2009:49(4): 133 5 \200\2231374. the standard. IL28B genotype testing of patients can provide important pre- treatment infor mation regarding response to antiviral therapy. The goal of treatment, unlike in HBV, is cu re as indicated by sustained viral suppression defined as no detectable HCV at 6 months aft er treatment. Factors associ- ated with favorable response to IFN/ribavirin: HCV genotype o ther than 1, lower viral load, white race, female sex, and age <40, weight <85 kg, HIV nega tive, and IL28B genotype Contraindications: Major depression (not controlled), solid organ transplant (except liver), severe concomitant medical illness, autoimmune hepatitis, untrea ted thyroid disease, pregnancy, age <2, inability to comply with long- treatment course, wo men of childbearing potential unwilling to use con- traception. Hepatitis D virus (HDV) Inc omplete RNA virus exists only with HBV. Spread: Coinfection or superinfection with HBV. Cli nical features: Increased risk of acute hepatic failure and cirrhosis. Tests: Anti-HDV anti body. Treatment: Interferon- has limited success in treatment of HDV infection. Hepatiti s E virus (HEV) RNA virus similar to HAV. Commonly occurs in areas with poor sanitation (e. g., parts of India) and associated with high mortality in pregnancy. Diagnosis: Serology. D ifferential diagnosis Acute hepatitis: Alcohol, drugs, toxins, EBV, CMV, leptospirosis, mal aria, Q fever, syphilis, yellow fever. Chronic hepatitis: Alcohol, drugs, autoimmune hepati tis, Wilson \200\231s disease. Human immunodeficiency virus/AIDS Worldwide, there are 34 million people living with HIV. In 2010, there were 2.7 million new infections and 1.8 million deaths. Two-thirds of cases and deaths are in sub-Saharan Africa. In the United States, there are 1.8 million people living with HIV (about 20% undiagnosed) and 50,000 new cases each year. Most are in MSM. A frican Americans are disproportion- ately affected. HIV \200\2231 (a retrovirus) is respons ible for most cases worldwide. HIV \200\2232 is a related virus and produces a similar illn ess, perhaps with a longer latent period. Transmission The global experience is primarily b y sexual contact (84%), and infected blood or blood products, IV drug abuse, or perinatally . In the United States, about 60% of new infections are in MSM and 10% in IVDU. Aggressive screening of pregnant women and modern blood banking processes has all but eliminated perin atal and blood product transmission of HIV in developed countries. Immunology HIV binds, vi a its gp120 envelope glycoprotein, to CD4 receptors on helper T-lymphocytes, monocytes, mac rophages, and neural cells. CD4 cells migrate to the lymphoid tissue, where the virus repli cates producing billions of new virions. These are released, and, in turn, infect new CD4 c ells. As the infection progresses, depletion or impaired function of CD4 cells predisposes to the development of immune dysfunction. Virology HIV is a double-stranded RNA retrovirus. After entry into the cell, the viral reverse transcriptase enzyme (hence retrovirus) makes a DNA copy of the RNA genome. The viral integrase enzyme then integrates this into the hos t DNA. The core viral proteins are initially synthesized as large polypeptides that are cle aved by the viral protease enzyme into the enzymes and building blocks of the virus. The co mpleted virions are then released from the cell by characteristic budding. The number of ci rculating viruses (viral load) predicts progression to AIDS. Stages of HIV infection Acute infection is often asymptomatic. Seroconversion may be accompanied by a 1 \200\2232 wk illn ess 2 \200\2236 wks after 566 HIV infection: Fever, malaise, myalgias, pharyngitis, maculopapular rash, or meningoencepha litis (rare). Patients in these early stages of HIV are very contagious due to high levels of virus in serum and genital fluids. A period of asymptomatic infection follows, although one-third of patients will have persistent generalized lymphadenopathy (PGL) , defined as n odes >1cm diameter at multiple extrainguinal sites, persisting for 3 months. There may b e opportunistic infections prior to AIDS, such as tuberculosis, pneumococcal pneumonia, ora l Candida , oral hairy leuko- plakia, herpes zoster. AIDS is a stage in HIV infection chara cterized by the presence of an indicator disease or a CD4 count <200/mm 3 . AIDS prognosis If untreated, death in 20 months, longer by an average of 15 yrs (or more) if treated with current regimens. Diagnosis is based on detecting anti-HIV antibodies in serum. A positive screening test (e.g., EIA/ELISA, chemiluminescent immunoassays, rapid assays) must be conf irmed with a Western blot, indirect immunofluorescent assay, or a nucleic acid test (e.g., HIV \200\2231 RNA). Rapid assays are point-of- care tests that can detect antibodies to HIV in <1 h. Negative tests are generally definitive, except in cases of acute infection. Acut e infection can be difficult to diagnose. When suspected, check an HIV antibody screening a ssay and HIV RNA \200\2231. In cases where there is virological evidence of infection, sero logy should be checked in a few weeks to confirm infection. Efforts should be made to remov e hurdles to testing. Prevention About 40% of transmissions occur during early acute infect ion, prior to seroconversion. This makes detection of acute infection for counseling and co nsideration of early treatment a high priority. Partner notification, safer sex practices, and avoidance of sharing needles are important. Postexposure prophylaxis with combination a ntiretroviral therapy for occupational and sexual exposure should be offered. Screening of blood products, transplanted organs, universal precautions, and use of disposable equipment are important infection control measures. Antiretroviral therapy for mother and infant ( cesarean section) and bottle-feeding are a means of preventing vertical transmission. Anti retroviral therapy may also have a role in reducing horizontal transmission. Complications of HIV infection All patients with a new diagnosis of HIV should be screened for TB and be tested for Toxoplasma , CMV, hepatitis B/C, and syphilis serology, to identify past or curr ent infections that may develop as immunosuppression progresses. All AIDS-defining diagnose s are seen almost exclusively with a CD4 count <200/mm 3 and some (disseminated MAC and CMV ) are seen only with a CD4 count of <50. Pulmonary: Pneumocystis jiroveci pneumonia (PCP) r emains an important life-threatening opportunistic infection in AIDS. The disease evolves o ver days to weeks with dyspnea, dry cough, fever, and chest pain. Diagnosis: Stains of resp iratory specimen for P. jiroveci . Treatment: High-dose TMP/ SMX IV or PO, trimethoprim-dap sone PO, primaquine-clindamycin PO, atovaquone PO, or pentamidine by slow IV for 3 wks. Ste roids are benefi- cial if severe hypoxemia (pO 2 <70). Primary prophylaxis (e.g., TMP/SMX o r dapsone PO) is indicated while CD4 count <200. Secondary prophylaxis is the same and cont inued after first attack until CD4 count >200 for >3 months. Other pathogens include M. tub erculosis ; M. avium intracellulare (MAI); fungi ( Aspergillus , Cryptococcus, Histoplasma ); parasites (toxoplas- mosis, cryptosporidiosis, Isospora), viruses (HSV, CMV, JC virus). Also: Kaposi \200\231s sarcoma, lymphoma, lymphoid interstitial pneumonitis, and non- speci fic pneumonitis. Community-acquired pneumonia, especially due to S. pneumoniae, is a major problem in HIV/AIDS patients. s e s a e s i d s u o i t c e f n I 567 GI tract: Candidiasis, HSV or aphthous ulcers, or tumors may cause oral pain. Oral candida is treated with nystatin suspension/pastilles or clotrima- zole lozenges. Esophageal involv ement causes dysphagia retrosternal dis- comfort. Fluconazole is the mainstay of therapy . For resistant cases, other azoles (e.g., itraconazole, voriconazole, posaconazole), the e chinocandins (e.g., micafungin, caspofungin, anidulafungin) can be useful. HSV and CMV also cause esophageal ulceration, which may be difficult to differentiate from Candida by bariu m studies. EGD with biopsy facilitates diagnosis. Anorexia and weight loss are common in HI V infection. Elevated LFT and hepatomegaly are common; causes include drugs, viral hepatiti s, AIDS scle- rosing cholangitis, or mai . Disseminated mai causes fever, night sweats, mal aise, anorexia, weight loss, abdominal pain, diarrhea, hepatomegaly, and anemia. Diagnosis: Blood cultures, but requires 7 \200\22314 d for growth; biopsies (lymph node, liver, colon , bone marrow). Treatment is with ethambutol + clarithromycin rifabutin/rifampicin (see Table 14.28). Primary prophylaxis: E.g., azithromycin 1,200 mg weekly, while CD4 <100. Salm onella, C. difficile , and viruses often cause acute diarrhea. Chronic diarrhea may be caus ed by bacteria (MAI), protozoa ( Cryptosporidium , Microsporidium, Isospora belli, Cy- clos pora ), viruses (CMV, adenovirus), or meds esp. LPV/r and NFV. Perianal disease may be due to recurrent HSV ulceration, GC, Chlamydia (including LGV in MSM), perianal warts, and squa mous cell carcinoma (rare). Kaposi \200\231s sarcoma and lymphomas can also affect the gut. Neurological: Acute HIV is associated with transient meningoencephalitis, myelopathy, and peripheral neuropathy. Chronic HIV is associated with sev- eral CNS syndromes: Most common are HIV-associated dementia (HAD) attributed to HIV, toxoplasmosis encephalitis, cryptococc al meningitis, TB meningitis, CNS lymphoma, HIV-related meningitis, CMV encephalitis, pro- gressive multifocal leukoencephalopathy (PML), neurosyphilis, listeriosis, vacuolar myelopa thy, and peripheral neuropathy. T. gondii is an important CNS pathogen in AIDS, presenting with focal symptoms/signs. CT/MRI shows ring-shaped contrast enhancing lesions. Treatment i s pyrimethamine (and folinic acid) + sulfadiazine or clindamycin for 6 months. Treatment sh ould continue until CD4 >100 \227 3 \200\2236 months. Primary prophylaxis (e.g., TMP/SMX P O) is indicated in patients with serum antitoxoplasma IgG and CD4 <100. Cryptococcus neofor mans is a major cause of meningitis in HIV. It causes insidious meningitis, often without n eck stiffness. Diagnosis: CSF cryptococcal antigen. Treatment is initially with amphoterici n IV + flu- cytosine, then fluconazole for long-term treatment. Careful monitoring and mana gement of CSF pressure is crucial in cryptococcosis. Secondary pro- phylaxis with fluconazo le is needed until CD4 is >100 \200\223200 for 6 months. Tumors affecting the CNS includ e primary cerebral lymphoma, B-cell non- Hodgkin \200\231s lymphoma. CSF EBV PCR can assist with diagnosis. JC virus PCR may be useful in distinguishing lymphoma from PML. Eye: CMV r etinitis may present with floaters, scotoma, and visual field de- fects or decreased acuity . Funduscopy shows characteristic appearance. Treatment is with valganciclovir PO, ganciclo vir IV, ganciclovir intraocular device + valganciclovir PO. Alternatives are foscarnet, cid ofovir. Treat- ment has traditionally been lifelong, but trials suggest that therapy may be stopped in some patients when CD4 >150 after HAART. Other HIV-associ- ated eye diseases in clude VZV-associated progressive outer retinal necrosis (PORN), ocular syphilis, dry eyes, and uveitis due to immune reconstitution or medications (e.g., rifabutin). 568 What every doctor should know about HIV An expert should manage patients with HIV infection . HIV in developed countries is primary management of antiretroviral drugs and their toxici ties and controlling HIV viral load \200\224not opportunistic infections. Preventing HIV spread Screen patients for high-risk behavior and reduce barriers to safer s ex: Pro- mote lifelong safer sex, barrier contraception, and reduction in the num- ber of p artners. Videos followed by interactive discussions are one way to double the use of condom s. Another way is the 100% condom program involving distribution of condoms to brothels, wi th enforcement programs enabling monitoring and encouraging condom use at any sex establish ment. Such programs are estimated to have prevented 2 million HIV infections in Thailand. T esting enhances counseling, partner notification, and early treat- ment. Warn everyone abou t the dangers of sexual tourism/promiscuity. Tell drug users not to share needles. Use need le exchange programs. Vigorous control of other STIs can reduce HIV incidence. Strengthen a wareness of clinics for STIs. Encourage pregnant women to have HIV tests. (Cesarean section s and HAART during pregnancy can prevent vertical transmission). All HIV-infected persons s hould have partner notification. Think about acute seroconversion: The clinical features ar e similar to infec- tious mononucleosis; perform tests if there are unusual signs; e.g., or al can- didiasis, recurrent shingles, leucopenia, or CNS signs (antibody tests may be negat ive, but HIV RNA levels are elevated in early infection). As always, take a thorough histor y. If you do identify acute seroconversion illness, get expert help promptly. Counseling to prevent HIV transmission is critical. Occupational exposure and needle-stick injury Seroco nversion rates are 0.4% for HIV, 30% for hepatitis B, if HBeAg positive and recipient is u nvaccinated, and 1.9% for hepatitis C. Wash wound well; do not suck or immerse in bleach. N ote name, address, and clinical details of source patient. Report incident to Occupational Health and fill out an accident form. Rapid HIV test should be performed on source if HIV s tatus is unknown. Informed consent in a source patient is sometimes required for HIV serol- ogy. Also test source for HBV (HBsAg) and HCV (anti-HCV). Immunize (active and passive) ag ainst hepatitis B at once, if needed. Counsel injured person that HIV risk <0.5% if source is HIV positive and test recipient at baseline 3, 6, 12 months (seroconversion may take t his long). Weigh risks, which are based on the viral load in the source patient and the sev erity of injury to the health care worker, volume of blood on instru- ment, and depth of in jury. Higher risk exposures include source patients with symptomatic HIV, acute seroconvers ion, and viral load >1,500 and deeper injuries with needles that have hollow bores, were us ed in an artery or vein and/or have visible blood. Higher risk exposures should be treated with three or more antiretroviral drugs. Lower risk exposures include source patients who a re asymptomatic and have a viral load <1,500 and superficial injuries with solid needles/in struments. These may be treated with a two- drug regimen. Mucus membrane or nonintact skin exposure carries a lower risk. If fluid volume is high and source patient is high risk, use three or more drugs. Otherwise consider two drugs, or none in the case of low-risk source patient and low fluid volume exposure. HIV test counseling: If in doubt, get help from an H IV care center. Routine tests in the recipient are HIV serology at baseline, 6 wks, 3 month s, and 6 months. Viral load to detect acute infection should not be done unless symptomatic . Routine tests in the donor are rapid HIV serology, anti-HCV, and HBsAg if these have not been done previously. For assistance in testing and selection of therapy, health care worke rs can call PEPline at 888 \200\223448 \200\2234911. s e s a e s i d s u o i t c e f n I 569 Table 14.28 Prophylaxis and treatment of opportunistic infections Infection Pneumocystis jiroveci (PCP) Prophylaxis TMP/SMX DS/d, TMP/ Indication Start: CD4<200, oropha- ryngeal candidiasis, h/o PCP SMX SS/d, TMP/SMX DS/thrice weekly Dapsone 100 mg/d, Stop: CD4 count >200