When an exhaustive search for infection is negative occult malignancy is the usual cause of prolonged unidentified fevers.

It should be pointed out, however, that some patients recover completely with no cause identified and others recur and still defy diagnosis. Extrapulmonary TB needs to be considered in patients with prolonged fevers that defy identification.

INFECTIONS OF SPECIFIC SITES

Urinary Tract and Kidney

Lower urinary tract infections (cystitis) are associated with frequency and dysuria, but not fever; fever indicates pyelonephritis.

Acute pyelonephritis may take 72 hours to respond to antibiotics, but in general is not a serious disease particularly in young women. The usual organisms are gastrointestinal (GI) bacteria commonly Escherichia coli, or Klebsiella.

Repeated attacks of pyelonephritis require evaluation for structural urinary tract abnormalities.

In men pyelonephritis suggests obstruction, usually, prostatic hypertrophy.

A positive urine culture for Staphylococcus aureus signifies staphylococcal bacteremia and has the same significance as a positive blood culture.

Although staph may secondarily infect the kidneys, a positive urine culture for should not be ascribed to primary kidney infection.

Sterile pyuria raises the question of genitourinary TB.

The renal collecting system is not an uncommon site of extrapulmonary TB. Hematuria is also common in genitourinary TB, and calcifications may be noted in the collecting system on x-ray.

Liver

Hepatic abscesses are of two principal types: pyogenic and amoebic; pleuritis or invasion of the right lower thoracic pleural space strongly suggests an amoebic etiology.

Traditionally difficult to diagnose and an important cause of undiagnosed febrile illness, advanced imaging techniques have made recognition of liver abscess relatively easy, although early in the course of disease these techniques may not be diagnostic. Elevation of the right hemidiaphragm on chest x-ray may suggest the diagnosis.

Pyogenic abscesses are usually a consequence of a septic focus in the abdomen or the biliary system. Anaerobic organisms are frequently involved.

Amoebic abscess is a consequence of colonic infection, principally in the cecum, and may follow a bout of amoebic hepatitis.

Portal drainage of the cecum preferentially delivers blood to the posterior aspect of the right lobe explaining the predominant location of amoebic abscesses in the right lobe posteriorly. Secondary infection of amoebic abscesses with pyogenic anaerobic bacteria is not unusual. Prompt catheter drainage is required in addition to appropriate antibiotic treatment.

Ascending cholangitis, a suppurative complication of biliary tract obstruction, is associated with rapidly progressive jaundice.

Biliary stones in the common bile duct are the most common cause, but strictures and carcinomas (ampullary, pancreatic, and cholangiocarcinoma) may be complicated by cholangitis as well. Cholangitis is said to be “ascending” because the biliary tract, usually sterile, is infected by invading organisms from the gut in the presence of obstruction. The responsible organisms are usually gut flora, aerobic gram-negative rods, especially E. coli and Klebsiella. The constellation of right upper quadrant pain, fever, and jaundice (Charcot’s triad) suggests the diagnosis, but the key is rapidly progressive jaundice. Anaerobic organisms, usual in hepatic abscesses, are not common in biliary infections.

Acute viral hepatitis is associated with malaise, anorexia, nausea, low-grade fever, icteric skin and eyes, dark urine, and right upper quadrant tenderness. The WBC is never elevated (usually 7,000) and the differential reveals 50% polys and 50% mononuclear cells.

In smokers a loss of taste for cigarettes may be an early symptom.

Hepatitis A virus (HAV) occurs in point source epidemics involving fecal contamination of water or shellfish and may (rarely) cause severe injury with hepatic failure requiring a liver transplant; it is a not a cause of chronic liver disease. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are blood-borne infections usually acquired from contaminated blood products or needles or through sexual contact. HBV and HCV may result in chronic infection and cirrhosis as well as hepatocellular carcinoma. Collapse of the normal hepatic portal architecture with necrosis that bridges the portal triads predicts the subsequent development of cirrhosis.

The immunologic response to HBV and especially HCV may result in mixed essential cryoglobulinemia.

Vaccination has significantly reduced the incidence of HAV and HBV.

Epstein–Barr virus (EBV) and cytomegalovirus (CMV) may also cause hepatitis.

These infections characteristically cause a mild hepatitis, although CMV infections may be prolonged even in immunocompetent patients.

Spine and Epidural Space

Back pain and fever strongly suggest the diagnosis of spinal epidural abscess.

An epidural collection of pus that threatens spinal cord compression, spinal epidural abscess should be ruled out in every case of back pain that presents with fever. MRI is the preferred imaging modality.

S. aureus is the infecting organism in two-thirds to three-fourths of cases with spinal epidural abscess.

Hematogenous dissemination is the usual method of infection, although spread from contiguous infection in a vertebrae or disc also occurs. Skin or soft tissue infection is thought to be the usual portal of entry, although in a significant portion of cases no site can be identified.

Other organisms responsible for epidural abscess include streptococci, particularly group B strep, gram-negative rods, nocardia, fungi, and mycobacterium TB.

Lumbar puncture is contraindicated because of the possibility of spread of the infecting organism. The thoracolumbar spine is the most common area involved. Elderly men are most commonly affected and diabetes increases the susceptibility. Tenderness to palpation is usually, but not always, present.

Signs of cord compression (leg weakness, incontinence, and a sensory level) indicate the need for immediate decompression of the epidural abscess by laminectomy and debridement.

The administration of antibiotics should begin as soon as the diagnosis is established by MRI and operative intervention is needed at the first sign of cord compression.

Vertebral osteomyelitis and discitis present with fever and back pain.

The pathogenesis of vertebral and disc infection is similar to spinal epidural abscess, and S. aureus is the common infecting bacteria. Unlike epidural abscess antibiotics are sufficient for treatment and surgical debridement is not required unless the imaging or clinical findings suggest cord compression.

Tuberculous involvement of the spine frequently involves adjacent vertebrae and the intervening disc space.

A psoas abscess may complicate tuberculous or pyogenic infection of the spine or epidural space. A positive “psoas sign” may be useful diagnostically.

Extension of the hip with the leg straight, in the lateral position with the involved side up, tests for a psoas sign; the latter is positive when pain is elicited as the leg is extended at the hip. It is also useful in detecting retrocecal appendicitis as the inflamed appendix abuts the psoas muscle.

Pharyngitis

Group A streptococci and EBV (infectious mononucleosis) both cause acute pharyngitis, tender cervical lymphadenopathy, and fever; they may be difficult to distinguish on the basis of physical examination, but can easily be differentiated by associated clinical and laboratory features. Both infections may occasionally coexist.

Both strep and mono may have extensive exudate, tonsillar enlargement, and very erythematous pharyngeal mucosa. Mono frequently has palatal petechiae and an edematous uvula.

Vomiting is common with strep throat. Splenomegaly is common with mono.

CBC with differential easily distinguishes the two: strep throat has a leukocytosis with granulocyte predominance; mono has normal or elevated WBC with many mononuclear cells including (frequently) atypical lymphocytes (Downey cells) which are cytotoxic T cells directed against infected B lymphocytes.

The “monospot” test, successor to the Paul–Bunnell heterophile agglutinin test, is quite specific for mono, but lacks sensitivity especially early in the course of the disease and is negative in the month-long incubation period. It must be kept in mind that strep and mono may coexist, so a low threshold for a strep screen in patients with mono is a reasonable idea.

If ampicillin (or amoxicillin) is given to a patient with mono it is almost certain that a rash will develop; such a rash, however, does not necessarily indicate drug allergy.

The hepatitis associated with EBV in immunocompetent patients is characteristically mild and not associated with chronic liver disease.

Lung Abscess

There are several different types of lung abscess; the common feature is necrosis of pulmonary parenchyma caused by microbial infection.

The major causes of pulmonary infection with necrosis are: 1) aspiration of oropharyngeal (particularly dental) flora; 2) suppuration and necrosis in an area of acute bacterial pneumonia; 3) secondary infection in a necrotic area of lung as a complication of bronchogenic carcinoma, collagen vascular disease (particularly Wegener’s granulomatosis), or pulmonary embolus with infarction; and 4) metastatic infection from hematogenous dissemination of an infectious process in another region of the body.

The classic lung abscess is in an indolent anaerobic infection from aspiration of mouth flora. Alcoholic stupor is an important predisposing factor.

Symptoms develop over weeks to months; the patient is chronically ill with fever, cough, and the production of purulent fetid sputum. The feculent smell is indicative of anaerobic infection, especially anaerobic streptococci.

Clubbing may be present in patients with lung abscess.

Chest x-ray shows a cavity with an air fluid level. Treatment is a prolonged course (months) of antibiotics with effective anaerobic coverage. Surgical drainage is not required for two reasons: 1) communication with the airway permits discharge of the contents; and 2) the compliance of lung tissue avoids the buildup of pressure within the cavity and permits adequate antibiotic penetration.

Lung abscess in an edentulous patient is uncommon and should raise the suspicion of superinfection in an underlying carcinoma.

Abscess formation in an area of bacterial pneumonia is most common with staphylococci, but Klebsiella, certain serotypes of pneumococci, and nocardia are other potential causes.

Bowel Infections

The causes of infectious gastroenteritis are legion and include pathogens of bacterial, viral, and protozoan origin.

Fecal–oral transmission and contaminated food and water account for the spread of most bowel infections.

Attention to hygiene (hand washing and wearing underpants) lessens the spread of GI infections among hospitalized patients.

Viral Gastroenteritis

Viral gastroenteritis causes vomiting and nonbloody diarrhea, is usually mild, and is almost always short lived; it is the most common infectious disease of the gut. Norovirus is the most common etiologic agent among the viruses that cause gastroenteritis.

The illness lasts 1 to 2 days although some severe norovirus infections may last longer. Norovirus derives its name from an outbreak in Norwalk, Ohio; it was found to be filterable, and therefore nonbacterial, and referred to as the “Norwalk agent” before the virus was identified.

BACTERIAL GASTROENTERITIS

Campylobacter, certain subtypes of E. Coli, Salmonella, and Shigella, all gram-negative rods, are the most common bacterial pathogens causing gastroenteritis. Diagnosis is established by culturing the organism from the stool. Clostridium difficile and S. aureus, gram-positive organisms, produce toxins that inflame the bowel and cause diarrhea.

Salmonella

Salmonella infection in humans produces a spectrum of GI disease that varies from acute gastroenteritis at one end to enteric fever at the other.

Salmonella enteritis at one extreme may cause an afebrile, nonbloody, self-limited diarrheal disease; at the other a serious invasive infection of the small and large bowel with fever, toxicity, and with local (and distal) complications. In reality, the distinction between the benign enteritis and enteric fever is usually blurred; the disease caused by salmonella in humans represents a continuous spectrum from mild gastroenteritis to severe enteric fever.

Unlike other Salmonella species, which are endemic in warm- and cold-blooded animals, S. Typhi is an obligate human pathogen. Typhoid fever is contracted from infected patients or chronic carriers.

Typhoid fever is the prototypical enteric fever. Although uncommon in the United States at present, typhoid is common worldwide and should be suspected in patients with febrile illnesses returning from areas where the infection is endemic (parts of Southeast Asia, the Middle East, Africa, and Latin America).

Unlike typhoid fever which is rare in the United States, Salmonella enteritis is a common form of food-borne illness (“food poisoning”).

The severity of the disease varies greatly but many cases are characterized by fever, abdominal pain, and diarrhea which may be bloody. Improperly handled poultry is a common source of infection with non-S. typhi strains. Outbreaks of varying size may occur from a contaminated source at a social event. Stool cultures are positive and blood cultures may be positive as well. The systemic manifestations reflect the impact of endotoxin release and are most marked in the enteric fever form of the infection.

The presence of fever, blood, and leukocytes in the stool indicates invasive disease requiring treatment with antibiotics.

Invasive salmonella infections are frequently associated with bacteremia and should be treated with the appropriate antibiotic, ceftriaxone. The contention that antibiotics should be avoided in cases of (non-S. typhi) salmonella enteritis because treatment may result in a prolonged carrier state is a faux pearl, often cited by infectious disease specialists. It makes no sense since nontyphoid strains of salmonella are not associated with prolonged carriage, and typhoid fever, which may be, is always treated with antibiotics.

Typhoid fever is not associated with diarrhea in the early phases of the disease.

Fever and abdominal pain dominate the clinical picture of early typhoid fever; splenomegaly and a characteristic rash (rose spots) may be present along with leukopenia and bradycardia (despite fever). Intestinal perforation is a feared complication since the organisms heavily infect the Peyer’s patches in the ileum. The patient should be kept NPO until the symptoms resolve and then the reintroduction of feeding should be slow and cautious. (Alexander the Great is said to have died of intestinal perforation in Babylon on his return from India, apparently because he was fed too early – chicken – in the recovery phase of an illness that was very likely typhoid fever).

Salmonella bacteremia (non–S. typhi strains) has a predilection for secondarily infecting atheromatous arteries.

Metastatic infection may involve existing abdominal aneurysms or cause mycotic aneurysms.

Relapsing salmonella bacteremia or persistently positive blood cultures should raise suspicion of an endovascular site of infection.

Campylobacter

The most common cause of bacterial gastroenteritis in adults, infection with Campylobacter jejuni causes an acute diarrheal syndrome that may be bloody, and that may be followed by reactive arthritis (Reiter’s syndrome) or an immune-mediated polyradiculoneuropathy (Guillain–Barre syndrome).

The clinical features of campylobacter infection and the factors that predispose to infection are similar to those of salmonella gastroenteritis. There is an animal reservoir of campylobacter and undercooked poultry is a common source of infection.

The association with Guillain–Barre is likely an example of “molecular mimicry” with antibodies to campylobacter antigens cross-reacting to epitopes on myelin.

Shigella

Shigellosis, also known as bacillary dysentery, is an infection of the distal colon and rectum. The major features reflect the distal localization of the lesions: urgency, tenesmus, scant bloody diarrhea, and cramping abdominal pain.

The pathogenesis involves direct mucosal invasion and production of Shiga toxin which damages the mucosal colonic epithelium. Rectal swab should be performed as well as stool culture as this enhances the likelihood of culturing the organism.

Pathogenic Escherichia coli

Long known as normal gut flora, over the last several decades it has become increasingly recognized that some E. coli subtypes possess substantial pathogenetic potential; these are now recognized as an important cause of bacterial enterocolitis.

The clinical manifestations of E. coli enterocolitis depend upon the virulence factors acquired by the particular subtype. The only subtype that can be identified in routine clinical practice is O157, the strain that produces Shiga toxin.

Shiga producing strains of E. coli, particularly, 0157:H7 have been strongly implicated in the pathogenesis of the hemolytic uremic syndrome (HUS). These strains are known as enterohemorrhagic E. coli as they produce severe bloody diarrhea.

Enterotoxigenic E. coli are not invasive but cause a watery nonbloody diarrhea; they are a prominent cause of “traveler’s diarrhea.” The toxins elaborated stimulate intestinal secretion by an adenylate cyclase/cyclic AMP mechanism and are distinct from the Shiga toxins that are associated with severe invasive disease. Enteroinvasive strains of E. coli cause a more severe colitis akin to those caused by Shigella.

Clostridium difficile (C. diff)

Certain strains of these anaerobic, spore-forming, gram-positive rods elaborate toxins that cause diarrhea and, occasionally, severe colitis with pseudomembrane formation. C. diff is not invasive and strains that do not produce the toxins do not cause disease. Antibiotics potentiate colonization of the colon with C. diff which is the major cause of antibiotic-associated diarrhea.

C. diff classically causes colitis in hospitalized patients on antibiotics. Despite the fact that the infection is not invasive fever, abdominal pain and leukocytosis are frequently noted.

The diagnosis is established not by culture but by demonstration of the C. diff toxin in the stool.

Clindamycin was the first antibiotic implicated in C. diff colitis and remains an important cause but it is now recognized that a wide variety of antibiotics including the fluoroquinolones and the beta-lactams are commonly implicated.

Cancer chemotherapy predisposes as well.

Along with antibiotic usage hospitalization was previously considered a prerequisite for C. diff diarrhea; it is now recognized that many patients acquire the disease in the community, some without a history of antibiotic usage.

Occasional cases are quite severe and unresponsive to treatment. In these patients colectomy was a last resort but recently fecal transplants to restore normal bowel flora have shown promise.

Staphylococcal Enterotoxin Enteritis

S. aureus produces an exotoxin (enterotoxin B) which is an important cause of “food poisoning.”

Staphylococcal food poisoning begins 1 to 8 hours after eating contaminated food and is characterized by vomiting and diarrhea, both often explosive. The symptoms are short lived, usually ending in less than 12 hours.

The pathogenesis involves the ingestion of preformed toxin generated by staphylococci multiplying in improperly refrigerated food, classically mayonnaise in chicken or tuna salad in hot weather, and at picnics.

Staphylococcal enterotoxin B is also the cause of some nonmenstrual staphylococcal toxic shock syndromes.

SPECIFIC INFECTIOUS AGENTS

Gonococci (GC)

Disseminated gonococcal infection presents as a febrile polyarticular tendinitis often associated with characteristic skin lesions (vesicular lesions which become pustules – few in number and most commonly occurring on the extremities).

This is the bacteremic phase of the disease.

The bacteremic phase of disseminated gonococcal infection may be followed by the development of typical septic arthritis in one or two large joints.

Arthrocentesis at this latter stage reveals large numbers of polys and it may be possible to culture the organism from the joint fluid.

Disseminated GC is much more common in women and typically occurs in the perimenstrual period or in early pregnancy when the normal endometrial barrier to dissemination is compromised.

The asymptomatic carrier state, the reservoir for dissemination, is not uncommon in women but does not occur in men.

In the early phase of the disseminated form of GC the response to intravenous antibiotics is prompt with rapid resolution of fever and tendinitis.

The rapid response to therapy helps secure the diagnosis.

Meningococci

Acute infections with the meningococcus, meningococcemia, and meningococcal meningitis, are well known serious diseases, endemic in sub-Saharan Africa and frequently occurring in epidemics in the United States, particularly in overcrowded areas and among military recruits.

Chronic meningococcemia is a rare disease characterized by recurrent bouts of fever, headache, chills, arthralgias, anorexia, occasionally diarrhea or vomiting, and an erythematous maculopapular or petechial eruption on the extremities and occasionally on the trunk.

Chronic meningococcemia is a curious disease since meningococcemia is almost always acute and fulminant with shock, disseminated intravascular coagulation, a petechial eruption that evolves into purplish ecchymosis, and, not uncommonly, adrenal hemorrhage which contributes to the shock (Waterhouse–Friedrichsen syndrome). The typical acute presentation is a consequence of endotoxin release which results in a thrombohemorrhagic state (DIC) reminiscent of a general Schwartzman reaction. Meningococcal meningitis is frequently associated. It is not known why some patients have a chronic form of the disease nor why chronic nasopharyngeal carriage of meningococci does not more frequently result in acute disease. Chronic meningococcemia, however, may devolve into the acute septicemic form or meningitis, so recognition and treatment are critical.

The typical case of chronic meningococcemia presents to the emergency room with fever, rash, headache, malaise, and anorexia. There is frequently a history of similar episodes in the recent past.

Absent localizing signs the patient is sent home for outpatient follow–up, but because the patient does not appear well and is febrile blood cultures are drawn. When these are returned positive for pleomorphic gram negative diplococci, to the alarm of the ER staff, the patient is called back, admitted and appropriate treatment initiated.

Staphylococcal Infections

Staphylococcal bacteremia is the proximate cause of infection of the joints and the heart valves as well as the vertebrae and epidural space.

The portal of entry for the bacteremia is thought to be the skin or soft tissue but often no nidus of infection is detected. The bacteremia itself may be associated with diarrhea perhaps related to a staphylococcal toxin. Urine culture may be positive for Staph as the bacteria are filtered in the kidney. Prompt treatment is necessary to prevent multiple long term complications.

Staphylococci are an important cause of acute bacterial endocarditis which is frequently associated with rapid valve destruction, embolization, and congestive failure.

Prompt surgical intervention is usually required. Interestingly, prognosis appears to be better in intravenous drug abusers where the portal of entry is contaminated needles, rather than in patients without a drug history.

Toxic shock syndrome, a serious complication of staphylococcal infection, is due to the elaboration of a toxin which causes fever, diffuse erythema, hypotension, and in severe cases, multi-organ system failure.

First recognized in menstruating women using super absorbent tampons it is now recognized that staphylococcal infection at different sites may be responsible for elaborating the toxin that is responsible for the syndrome. Cases may follow influenza with staphylococcal superinfection, childbirth, or sinus infection, as well as vaginal infection associated with tampon use. Intensive treatment of the hypotension and eradicating the source of the infection are the therapeutic goals.

Streptococcal toxic shock, secondary to a related toxin elaborated in group A β-hemolytic strep infections, is more serious than classic staphylococcal toxic shock syndrome, is more commonly associated with renal failure, and a higher mortality rate.

The common portal of entry is skin infection or necrotizing fasciitis.

Syphilis (Lues)

Sexually transmitted, this spirochetal disease begins with the characteristic painless firm ulceration on the penis or cervix. If untreated secondary lues appears 2 weeks to 3 months after the primary infection.

It is important to recognize secondary syphilis since in many cases a history of primary infection is absent and the secondary phase is highly infectious.

The typical patient presents with a rash, malaise, lymphadenopathy, sometimes with fever and arthralgias. Skin lesions (and occasionally mucosal lesions) are the key to the diagnosis but these may be variable in appearance. Violaceous to brown depending on the region of the body and the complexion of the patient, these maculopapular, squamous, occasionally scaling lesions may appear on the trunk or the extremities or on the palms and soles.

Location of luetic lesions on the palms and soles is highly suspicious and usually the key to the diagnosis.

A high index of suspicion is required.

The secondary luetic lesions are swarming with spirochetes and hence very infectious, especially the moist lesions on mucosal surfaces.

Every patient with a sexually transmitted disease should have a serologic test for syphilis.

Treatment of secondary syphilis with penicillin may result in the Jarisch–Herxheimer reaction, a consequence of the rapid killing of large numbers of organisms with the release of proinflammatory cytokines.

Fever, chills, hypotension, and apprehension may be severe necessitating intravenous fluids and in some cases glucocorticoids.

Luetic aortitis, a form of tertiary syphilis, occurring years after the initial infection, involves the ascending aorta; aneurysmal dilatation is the consequence which may be associated with aortic regurgitation.

Aortic regurgitation in luetic aneurysm is best heard over the right precordium at the second intercostal space and is associated with a “booming” (tambour) aortic closure sound.

Luetic aneurysms are not associated with aortic dissection since the medial inflammation prevents separation of the wall components.

The aneurysms may, however, be quite large.

Tabes dorsalis is a luetic myelopathy, a tertiary form of neurosyphilis involving the posterior columns of the spinal cord.

It is associated with parasthesias (shooting “lightning” pains) and extensive loss of proprioception. It may be associated with destructive arthritis of the knee (Charcot joint).

Herpes Zoster

It is well recognized that “shingles” (dermatomal zoster) results from reactivation of the previously dormant varicella zoster virus in the dorsal root ganglia of sensory nerves.

After the childhood exanthem chickenpox the varicella zoster virus lies dormant in the dorsal root ganglia of sensory nerves. Waning immunity, as occurs with aging, the use of immunosuppressive drugs, or diseases which compromise the immune system, is associated with reactivation of the latent infection. A curious observation, largely unexplained, is that an attack of zoster in adults sometimes follows exposure to a child with chickenpox. How can this be since zoster is the reactivation of a dormant infection? Perhaps re-exposure via the respiratory tree attracts varicella antibodies to the portal of entry, thus freeing up virus previously pinned down in the dorsal root ganglia, thereby permitting emergence along the sensory nerves.

Zoster begins with pain in a dermatomal distribution followed in 2 to 3 days by erythematous macules that vesiculate, become pustular, and impetiginize.

Early treatment with antiviral agents may abort the usual progression.

Fever and a cerebrospinal fluid pleocytosis (with or without aseptic meningitis) may occur with zoster.

An episode of zoster does not require work up for an underlying malignancy beyond history, physical examination, and age-appropriate screening.

Involvement of the geniculate ganglion of the facial (VII cranial) nerve results in the Ramsay Hunt syndrome (herpes zoster oticus): pain in the ear followed by typical lesions in the external auditory canal, and, frequently, facial paresis.

The facial paralysis has a worse prognosis for recovery than the usual case of Bell’s palsy. Loss of taste over the anterior two-thirds of the tongue may be associated.

Zoster ophthalmicus occurs with involvement of the first (ophthalmic) division of the V cranial nerve.

Pain often begins at the tip of the nose. Pain and inflammation of the anterior structures of the eye may threaten vision and necessitate prompt treatment.

Tzanck smear is useful in identifying zoster or herpes simplex in vesicular lesions: multinucleate giant cells are present in scrapings from the base of vesicles.

Herpes Simplex Virus (HSV)

In addition to the well-known fever blister (herpes labialis) herpes simplex causes mucocutaneous stomatitis, herpes genitalis, encephalitis, aseptic meningitis, keratitis, Bell’s palsy, erythema multiform (Stevens–Johnson syndrome), an uncommon finger infection (herpetic whitlow), and rarely, a widely disseminated vaccinia-like rash known as Kaposi’s varicelliform eruption.

Herpes labialis, the fever blister or “cold sore,” is the footprint of prior HSV type 1 infection, representing reactivation of a latent HSV-1 infection.

Typically located on the border of the upper or lower lip it may rarely involve the hard palate or gums.

Primary HSV-1 infection occurs in children or young adults and may result in a severe but self-limited erosive ulceration of the gingiva, pharynx, and buccal mucosa.

It is accompanied by fever and malaise.

Genital herpes is a sexually transmitted disease usually caused by HSV type 2 but may be caused by HSV-1 as well.

It is typically a painful erosive cluster of vesicles on the genitalia but may be asymptomatic. Recurrent episodes are usual, especially with HSV-2.

Herpetic encephalitis is a serious CNS infection that may represent primary or reactivation HSV-1 disease.

Temporal lobe involvement is usual and MRI frequently shows subtle signs of bleeding in this area. The virus may be detected in the CSF. Treatment should begin promptly with IV acyclovir or its congeners.

HSV is an important cause of viral “aseptic” meningitis. Recurrent aseptic meningitis, known as “Mollaret’s syndrome” is usually caused by HSV-2.

Also known as benign recurrent lymphocytic meningitis, it is self-limited but usually treated with acyclovir.

Corneal involvement (keratitis) by HSV-1 is severe and threatens vision. If suspected immediate ophthalmologic consultation is mandatory.

Herpetic whitlow is a painful erythematous, vesicular or pustular lesion of the fingertip caused by HSV-1. In immunosuppressed patients, AIDS for example, the lesion may look necrotic and resemble gangrene.

Diagnosis is important because surgery is contraindicated and the response to acyclovir rapid and impressive.

Human Herpes virus 8 (HHV-8) is the cause of Kaposi’s sarcoma.

In young HIV positive adults the lesions frequently occur about the face, upper body, and internal organs; in older non-HIV patients the legs are the most common sites of involvement.

Kaposi’s varicelliform eruption is a disseminated vesiculopustular skin infection that occurs in areas of pre-existing skin disease, most notably, atopic dermatitis. HSV is the usual cause and gives rise to the alternative name “eczema herpticum.”

This is a serious disease and may be fatal. Smallpox vaccination (vaccinia virus) may give rise to the syndrome in children with atopic dermatitis. Tzanck prep is positive but does not distinguish between HSV and zoster or vaccinia, but both are treated with acyclovir. Diagnosis is confirmed by demonstrating the herpes virus in the vesicular fluid. Other skin disease may predispose as well including pemphigus vulgaris.

CMV, a member of the herpes virus family is a well-recognized cause of disseminated opportunistic infection in immunosuppressed patients. In immunocompetent individuals it may cause a mono-like syndrome with fever, malaise, and fatigue.

In distinction to EBV pharyngitis is absent. The illness in the immunocompetent may last weeks. Liver function abnormalities reflective of hepatitis are often present with fever and a predominance of mononuclear cells in the WBC differential.

GLOBALIZATION AND INFECTIOUS DISEASE

Travel history is vital in the evaluation of patients with febrile illnesses. Knowledge of infections endemic in the regions visited by returning sick travelers or immigrants is essential.

Malaria

Endemic areas include Latin America, the Middle East, Africa, and Southeast Asia. Travelers from these areas should be asked in detail about prophylactic medications and mosquito bites.

High spiking fever, headache, and rigors in a traveler returning from an endemic area will usually turn out to be falciparum malaria.

At the onset the febrile spikes occur daily which may mislead. The history will usually reveal that prophylaxis was omitted or not administered properly including after return.

TB is a serious concern in immigrants from Southeast Asia.

Diseases that have Spread Beyond their Traditional Locales

Globalization has changed the pattern of distribution of many diseases. The recent emergence of West Nile Virus from the Middle East to become endemic in the United States and other regions is a good example. Dengue fever is another example of a tropical disease that has developed a worldwide distribution over the last half century. The recent spread of chikungunya to the western hemisphere from endemic regions in Africa and southern Asia is the latest of these diseases to spread to the United States following its initial appearance in the Caribbean. Autochthonous (indigenous) cases have been reported in Florida and more are expected as the reservoir in the animal world enlarges and the arthropod vectors spread north.

Chikungunya fever is an arbovirus infection (spread by two species of Aedes) characterized by fever, painful arthralgias and arthritis, malaise, and a maculopapular morbilliform rash.

The distinguishing feature is the severity of the joint manifestations which differentiates chikungunya from dengue fever. Another distinguishing point is the absence of leukopenia, common in dengue fever. The term chikungunya is from an African dialect that means “bent over” in reference to the stooped posture imposed by the joint pains. Hands and feet are most prominently involved. Although the illness is usually self-limited, lasting about 1 week, the joint pains may persist for long periods of time.

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