# 05 - 127 Approach to the Acutely Ill Infected Febrile Patient

### 127 Approach to the Acutely Ill Infected Febrile Patient

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pathogen surveillance system. Nat Rev Genet 19:9, 2018.
Grubaugh ND et al: Tracking virus outbreaks in the twenty-first century. 
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variant in southern Africa. Nature 603:679, 2022.
Tamar F. Barlam  

Approach to the Acutely 

Ill Infected Febrile Patient
The physician treating the acutely ill febrile patient must be able to 
recognize infections that require emergent attention. If such infec­
tions are not adequately evaluated and treated at initial presenta­
tion, the opportunity to alter an adverse outcome may be lost. In 
this chapter, the clinical presentations of and approach to patients 
with infectious disease emergencies are discussed. These infec­
tious processes and their treatments are discussed in detail in other 
chapters.
APPROACH TO THE PATIENT
Acute Febrile Illness
Before the history is elicited and a physical examination is per­
formed, an immediate assessment of the patient’s general appear­
ance can yield valuable information. The perceptive physician’s 
subjective sense that a patient is septic or toxic often proves accu­
rate. Visible agitation or anxiety in a febrile patient can be a harbin­
ger of critical illness. 
HISTORY
Presenting symptoms are frequently nonspecific. Detailed ques­
tions should be asked about the onset and duration of symptoms 
and about changes in severity or rate of progression over time. 
Host factors, such as extremes of age and comorbid conditions, 
may increase the risk of infection with certain organisms or of a 
more fulminant course than is usually seen. Lack of splenic func­
tion, alcoholism with significant liver disease, IV drug use, HIV 
infection, diabetes, malignancy, morbid obesity, organ transplan­
tation, and chemotherapy all predispose to specific infections and 
frequently to increased severity. The patient should be questioned 
about factors that might help identify a nidus for invasive infec­
tion, such as recent upper respiratory tract infections, influenza, 
or varicella; prior trauma; disruption of cutaneous barriers due 
to lacerations, burns, surgery, body piercing, or decubiti; and the 
presence of foreign bodies or prosthetic devices. Travel, presence 
during a natural disaster such as a hurricane or tsunami, contact 
with pets or other animals, or activities that might result in tick 
or mosquito exposure can lead to diagnoses that would not other­
wise be considered. Recent dietary intake, medication use, social 
or occupational contact with ill individuals, vaccination history, 
recent sexual contacts, and menstrual history may be relevant. 
Pregnancy might increase the risk and severity of some illnesses, 
such as influenza or COVID-19, or increase the risk of significant 
morbidity for the fetus, as in Listeria or Zika virus infection. A 

detailed review of systems should include any neurologic signs 
or sensorium alterations, rashes or skin lesions, and focal pain or 
tenderness. 
PHYSICAL EXAMINATION
A complete physical examination should be performed, with spe­
cial attention to several areas that are sometimes given short 
shrift in routine examinations such as assessment of the patient’s 
general appearance and a detailed skin, soft tissue, and neurologic 
evaluation.
The patient may appear either anxious and agitated or lethargic 
and apathetic. Fever is usually present, although elderly patients 
and compromised hosts (e.g., patients who are uremic or cir­
rhotic and those who are taking glucocorticoids or nonsteroidal 
anti-inflammatory drugs) may be afebrile despite serious under­
lying infection. Critically ill patients may be hypothermic, with 
a high risk of organ failure and mortality. Mortality at 30 days 
decreases with increasing temperature at presentation. Measure­
ment of blood pressure, heart rate, and respiratory rate and oxy­
gen saturation helps determine the degree of hemodynamic and 
metabolic compromise.
The etiologic diagnosis may become evident in the context 
of a thorough skin examination (Chap. 21). Petechial rashes are 
typically seen with meningococcemia or Rocky Mountain spotted 
fever (RMSF; see Fig. A1-16); erythroderma is associated with 
toxic shock syndrome (TSS). On soft tissue and muscle examina­
tion, areas of erythema or duskiness, edema, and tenderness may 
indicate underlying necrotizing fasciitis, myositis, or myonecrosis. 
The neurologic examination must include a careful assessment of 
mental status for signs of early encephalopathy. Evidence of nuchal 
rigidity or focal neurologic findings should be sought. 
CHAPTER 127
DIAGNOSTIC WORKUP
After a quick clinical assessment, diagnostic material should be 
obtained rapidly and antibiotic and supportive treatment begun. 
Blood (for cultures; baseline complete blood count with differential; 
measurement of serum electrolytes, blood urea nitrogen, serum 
creatinine, and serum glucose; liver function tests and serum lac­
tate; and d-dimer) can be obtained at the time an IV line is placed 
and before antibiotics are administered. Three sets of blood cultures 
should be performed for patients with possible acute endocarditis. 
Blood smears from patients at risk for severe parasitic disease, 
such as malaria or babesiosis (Chaps. 231, 232, and A2), must be 
examined for the diagnosis and quantitation of parasitemia. Blood 
smears may also be diagnostic in ehrlichiosis and anaplasmosis. 
Testing of a nasopharyngeal sample for COVID-19 or influenza 
may be indicated.
Approach to the Acutely Ill Infected Febrile Patient 
Patients with possible meningitis should have cerebrospinal 
fluid (CSF) obtained before the initiation of antibiotic therapy. 
Focal findings, depressed mental status, or papilledema should be 
evaluated by brain imaging prior to lumbar puncture, which, in this 
setting, could initiate herniation. Antibiotics should be administered 
before imaging but after blood for cultures has been drawn. If CSF 
cultures are negative, blood cultures will provide the diagnosis in 
50–70% of cases. Molecular diagnostic techniques (e.g., broadrange 16S rRNA gene polymerase chain reaction testing for bacte­
rial meningitis pathogens) are of increasing importance in the rapid 
diagnosis of life-threatening infections.
CT or MRI may be necessary to evaluate focal processes that 
require urgent surgical intervention. Other diagnostic procedures, 
such as wound cultures, should not delay the initiation of treatment 
for more than minutes. Once emergent evaluation, diagnostic pro­
cedures, and (if appropriate) surgical consultation (see below) have 
been completed, other laboratory tests can be conducted. Appropri­
ate radiography; CT and/or MRI imaging; urinalysis; measurement 
of the erythrocyte sedimentation rate, C-reactive protein, and/or 
procalcitonin; and transthoracic or transesophageal echocardiogra­
phy all may prove important.

TREATMENT
The Acutely Ill Patient
In the acutely ill patient, empirical antibiotic therapy for presumed 
bacterial or fungal infection is critical and should be administered 
without undue delay in addition to fluid resuscitation and vasopres­
sor support as needed. Increased prevalence of antibiotic resistance 
in community-acquired bacteria must be considered when antibiot­
ics are selected. Table 127-1 lists first-line empirical regimens for 
infections considered in this chapter. In addition to the rapid initia­
tion of antibiotic therapy, several of these infections require urgent 
surgical attention. Neurosurgical evaluation for subdural empyema, 
otolaryngologic surgery for possible mucormycosis, and cardiotho­
racic surgery for critically ill patients with acute endocarditis are as 
important as antibiotic therapy. For infections such as necrotizing 
fasciitis and clostridial myonecrosis, rapid surgical intervention 
supersedes other diagnostic or therapeutic maneuvers.
Adjunctive treatments may reduce morbidity and mortality rates 
and include dexamethasone for bacterial meningitis or IV immu­
noglobulin for TSS. Adjunctive therapies should usually be initiated 
within the first hours of treatment; however, dexamethasone for 
bacterial meningitis must be given before or at the time of the first 
dose of antibiotic. Glucocorticoids may also be harmful—e.g., when 
given in the setting of cerebral malaria or viral hepatitis.
SPECIFIC PRESENTATIONS
The infections considered below according to common clinical pre­
sentation can have rapidly catastrophic outcomes, and their immediate 
recognition and treatment can be life-saving.
PART 5
Infectious Diseases
■
■SEPSIS WITHOUT AN OBVIOUS FOCUS OF 
PRIMARY INFECTION
Patients initially have a brief prodrome of nonspecific symptoms and 
signs that progresses quickly to hemodynamic instability with hypoten­
sion, tachycardia, tachypnea, respiratory distress, and altered mental 
status. Disseminated intravascular coagulation (DIC) with clinical 
evidence of a hemorrhagic diathesis is a poor prognostic sign.
Septic Shock (See also Chap. 315) 
Patients with bacteremia 
leading to septic shock may have a primary site of infection (e.g., 
pneumonia, pyelonephritis, or cholangitis) that is not evident initially. 
Elderly patients who may have atypical presentations and often have 
comorbid conditions, hosts compromised by malignancy and neutro­
penia, and patients who have recently undergone a surgical procedure 
or hospitalization are at increased risk for an adverse outcome. Gramnegative bacteremia with organisms such as Pseudomonas aeruginosa 
or Escherichia coli and gram-positive infection with organisms such 
as Staphylococcus aureus (including methicillin-resistant S. aureus 
[MRSA]) or group A streptococci can present as intractable hypo­
tension and multiorgan failure. Treatment can usually be initiated 
empirically on the basis of the presentation, host factors (Chap. 315), 
and local patterns of bacterial resistance. Outcomes are worse when 
antimicrobial treatment is delayed or when the responsible pathogen 
ultimately proves not to be susceptible to the initial regimen. The 
increasing prevalence of multidrug-resistant organisms makes this 
especially relevant. Broad-spectrum antimicrobial agents are therefore 
recommended and should be instituted rapidly, preferably within the 
first hours after presentation with septic shock. Pharmacodynamics 
are altered in sepsis due to increased volume of distribution and renal 
clearance, so it is important to adequately dose antimicrobials. Risk fac­
tors for fungal infection should be assessed, as the incidence of fungal 
septic shock is increasing. Nonbacterial causes of shock, such as den­
gue virus infection, should be considered in endemic areas. Glucocor­
ticoids are often considered for patients with severe sepsis who do not 
respond to fluid resuscitation and vasopressor therapy, but conclusive 
evidence for efficacy in this setting is lacking.
Overwhelming Infection in Asplenic Patients (See also 
Chap. 315) 
Patients without splenic function are at risk for 

overwhelming bacterial sepsis compared with the general population. 
The median interval between splenectomy and sepsis is 4–6 years, with 
a range of 1–19 years. Almost 50% or more of these infections occur 
within the first l or 2 years, but the increased risk persists throughout 
life. Encapsulated bacteria cause the majority of infections. Strepto­
coccus pneumoniae is the most common isolate, causing 40–70% of 
cases. Children less than 5 years of age are at 15 times higher risk of 
invasive pneumococcal disease than adults, who are more likely to have 
antibody to these organisms. The risk of infection with Haemophilus 
influenzae or Neisseria meningitidis also is greater in patients without 
splenic function, but reported cases are declining. Severe clinical mani­
festations of infections due to other organisms, such as E. coli, S. aureus, 
Bordetella holmesii, Capnocytophaga, Babesia, and Plasmodium species, 
have been described.
Babesiosis (See also Chap. 232) 
A history of recent travel to 
endemic areas raises the possibility of infection with Babesia. Cases are 
increasing in the United States, particularly in the Northeast. Between 
1 and 4 weeks after a tick bite, the patient experiences chills, fatigue, 
anorexia, myalgia, arthralgia, shortness of breath, nausea, and neuro­
logic symptoms such as headache, confusion, delirium or impaired 
consciousness; ecchymosis and/or petechiae are occasionally seen. 
The tick that most commonly transmits Babesia, Ixodes scapularis, 
also transmits Borrelia burgdorferi (the agent of Lyme disease) and 
Anaplasma; co-infection can occur and may result in more severe 
disease. Infection with the European species Babesia divergens is more 
frequently fulminant than that due to the U.S. species Babesia microti. 
B. divergens causes a febrile syndrome with hemolysis, jaundice, hemo­
globinemia, and renal failure and is associated with a mortality rate as 
high as 40%. Severe babesiosis is especially common in asplenic hosts 
but does occur in hosts with normal splenic function, particularly 
those >60 years of age and those with underlying immunosuppres­
sive conditions such as HIV infection or malignancy. Complications 
include renal failure, acute respiratory failure, heart failure, DIC, and 
splenic rupture.
Other Sepsis Syndromes 
Tularemia (Chap. 175) has been 
reported in every U.S. state except Hawaii. This disease is associated 
with wild rabbit, tick, horse-fly, and tabanid fly contact. It can be 
transmitted by arthropod bite, handling of infected animal carcasses, 
consumption of contaminated food and water, or inhalation. The 
typhoidal form can be associated with gram-negative septic shock and 
a mortality rate of >30%, especially in patients with underlying comor­
bid or immunosuppressive conditions. Plague occurs infrequently in 
the United States (Chap. 176), primarily after contact with ground 
squirrels, prairie dogs, or chipmunks, but is endemic in other parts of 
the world; >90% of all cases occur in Africa with Madagascar especially 
affected. The septic form is particularly rare and is associated with 
shock, multiorgan failure, and a 30% mortality rate. Pneumonic plague 
is rapidly progressive and fatal without treatment. These infections 
should be considered in the appropriate epidemiologic setting. The 
Centers for Disease Control and Prevention (CDC) lists Francisella 
tularensis and Yersinia pestis (the agents of tularemia and plague, 
respectively) along with Bacillus anthracis (the agent of anthrax) as 
important organisms that might be used for bioterrorism (Chap. S4).
■
■SEPSIS WITH SKIN MANIFESTATIONS 

(SEE ALSO CHAP. 21)
Sepsis can be associated with diverse skin findings. In one study, almost 
18% of patients with severe sepsis had secondary skin findings, such as 
purpura, petechiae, or ecchymoses. Maculopapular rashes may reflect 
early meningococcal or rickettsial disease but are usually associated 
with nonemergent infections. Exanthems are usually viral. Primary 
HIV infection commonly presents with a rash that is typically maculo­
papular and involves the upper part of the body but can spread to the 
palms and soles. The patient is usually febrile and can have lymphade­
nopathy, severe headache, dysphagia, diarrhea, myalgias, and arthral­
gias. Recognition of this syndrome provides an opportunity to prevent 
transmission and to institute early treatment.

TABLE 127-1  Empirical Treatment for Common Infectious Disease Emergenciesa
CLINICAL SYNDROME
POSSIBLE ETIOLOGIES
TREATMENT
COMMENTS
SEE CHAP(S)
Sepsis without a Clear Focus
Septic shock
Pseudomonas spp., gramnegative enteric bacilli, 
Staphylococcus spp., 
Streptococcus spp.
Vancomycin (15 mg/kg q12h)b
plus either
Piperacillin/tazobactam (4.5 g) 
q8h via extended infusion (EI)c 
or cefepime (2 g) q8h via EI
Overwhelming postsplenectomy sepsis
Streptococcus 
pneumoniae, Haemophilus 
influenzae, Neisseria 
meningitidis
Ceftriaxone (2 g q12h) plus 
vancomycin (15 mg/kg q12h)b
If a β-lactam–sensitive strain is identified, vancomycin can 
be discontinued and a narrower-spectrum agent, such as 
penicillin, considered based on susceptibility testing.
Babesiosis
Babesia microti (U.S.), 

B. divergens (Europe)
Atovaquone (750 mg q12h) plus 
azithromycin (500 mg q24h)
Sepsis with Skin Findings
Meningococcemia
N. meningitidis
Ceftriaxone (2 g q12h) or 
penicillin (4 mU q4h)
Rocky Mountain 
spotted fever (RMSF)
Rickettsia rickettsii
Doxycycline (100 mg bid)
If both meningococcemia and RMSF are being considered, 
use ceftriaxone (2 g q12h) plus doxycycline (100 mg bid). If 
RMSF is diagnosed, ceftriaxone can be discontinued.
Purpura fulminans
S. pneumoniae, H. 
influenzae, N. meningitidis
Ceftriaxone (2 g q12h) plus 
vancomycin (15 mg/kg q12h)b
If a β-lactam-sensitive strain is identified, vancomycin can be 
discontinued.
Erythroderma: toxic 
shock syndrome
Group A Streptococcus, 
Staphylococcus aureus
Vancomycin (15 mg/kg q12h)b 
plus clindamycin (600 mg q8h)
Sepsis with Soft Tissue Findings
Necrotizing fasciitis
Group A Streptococcus, 
mixed aerobic/anaerobic 
flora
Vancomycin (15 mg/kg q12h)b 
plus piperacillin/tazobactam 
(4.5 q q8h via EI)c plus 
clindamycin (600 mg q8h)
Clostridial 
myonecrosis
Clostridium perfringens
Penicillin (2 mU q4h) plus 
clindamycin (600 mg q8h)
Neurologic Infections
Bacterial meningitis
S. pneumoniae, 

N. meningitidis
Ceftriaxone (2 g q12h) plus 
vancomycin (15 mg/kg q12h)b
If a β-lactam–sensitive strain is identified, vancomycin can be 
discontinued. If the patient is >50 years old or has comorbid 
disease, add ampicillin (2 g q4h) for Listeria coverage. 
Dexamethasone (10 mg q6h for 4 days) started before, or at 
the time of, the first dose of antibiotic improves outcome in 
adults with meningitis (especially pneumococcal).
Brain abscess, 
suppurative 
intracranial infections
Streptococcus spp., 
Staphylococcus spp., 
anaerobes, gram-negative 
bacilli
Vancomycin (15 mg/kg q12h)b 
plus metronidazole (500 mg q8h) 
plus ceftriaxone (2 g q12h)
Cerebral malaria
Plasmodium falciparum
Artesunate (2.4 mg/kg IV at 0, 
12, and 24 h; then once daily)
Spinal epidural 
abscess
Staphylococcus spp., 
gram-negative bacilli
Vancomycin (15 mg/kg q12h)b 
plus either
Piperacillin/tazobactam (4.5 g 
q8h via EI) or cefepime (2 g q8h 
via EI)c
Focal Infections
Acute bacterial 
endocarditis
Ceftriaxone (2 g q12h) or 
cefepime (2 g q8h via EI)c plus 
vancomycin (15 mg/kg q12h)b
S. aureus, β-hemolytic 
streptococci, HACEK 
group,e Neisseria spp., 

S. pneumoniae
aThese empirical regimens include coverage for gram-positive pathogens that are resistant to β-lactam antibiotics. Local resistance patterns should be considered and may 
alter the need for empirical vancomycin or for expanded coverage for antibiotic-resistant gram-negative pathogens. bA vancomycin loading dose of 20–25 mg/kg can be 
considered in critically ill patients. Dosing must be adjusted based on pharmacokinetic/pharmacodynamic monitoring. Daptomycin (10 mg/kg once daily) can be considered 
in place of vancomycin as alternate coverage for β-lactam resistant gram-positive organisms. Data for use in central nervous system infections are limited but emerging. 
cEI, extended infusion. β-Lactam antibiotics may exhibit unpredictable pharmacodynamics in sepsis. Prolonged or continuous infusions are often used. dThe optimal 
dose of IV immunoglobulin has not been determined, but the median dose in observational studies is 2 g/kg (total dose administered for 1–5 days). eHaemophilus spp., 
Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae.

Empirical therapy should be tailored to local resistance 
patterns. Carbapenem or aminoglycoside antibiotics should 
be considered for empirical therapy when rates of multidrugresistant gram-negative organisms are high or for patients 
with risk factors for resistant organisms. Adjust treatment 
when culture data become available.
152, 153, 166, 
170, 315

Clindamycin (600 mg q8h) plus quinine (650 mg q8h) can be 
used in severe disease not responding to atovaquone and 
azithromycin. Treatment with doxycycline (100 mg bid) for 
potential co-infection with Borrelia burgdorferi or Anaplasma 
spp. may be prudent.
229, 232
Ceftriaxone eradicates nasopharyngeal carriage of the 
organism. Close contacts require chemoprophylaxis with 
rifampin (600 mg q12h for 2 days) or ciprofloxacin (a single 
dose, 500 mg).

151, 160, 162, 

CHAPTER 127
If a penicillin- or oxacillin-sensitive strain is isolated, these 
agents are superior to vancomycin (penicillin, 2 mU q4h; or 
oxacillin, 2 g IV q4h). The site of toxigenic bacteria should be 
debrided; IV immunoglobulin can be used in severe cases.d
152, 153
Urgent surgical evaluation is critical. Empirical therapy should 
be tailored to local resistance patterns. For mixed aerobic/
anaerobic infections, clindamycin can be discontinued. Adjust 
treatment when culture data become available.
134, 152, 153
Approach to the Acutely Ill Infected Febrile Patient 
Urgent surgical evaluation is critical.

Urgent surgical evaluation is critical. If a penicillin- or 
oxacillin-sensitive strain is isolated, these agents are superior 
to vancomycin (penicillin, 4 mU q4h; or oxacillin, 2 g q4h).

Avoid glucocorticoids. Until IV artesunate is available, 
treatment can be initiated with oral artemether-lumefantrine. 
Atovaquone-proguanil, quinine, and mefloquine are other 
options.
229, 231

Surgical evaluation is essential. If a β-lactam–sensitive 
strain is isolated, oxacillin, 2 g q4h or cefazolin 2 gm IV q8h is 
superior to vancomycin.
Adjust treatment when culture data become available. 
Evaluation by cardiology and cardiothoracic surgery is 
essential.

Petechial rashes caused by viruses are seldom associated with 
hypotension or a toxic appearance, although there can be exceptions 
(e.g., severe measles or arboviral infection). Petechial rashes limited 
to the distribution of the superior vena cava are rarely associated with 
severe disease. In other settings, petechial rashes require more urgent 
attention.

Meningococcemia (See also Chap. 160) 
Almost three-quarters 
of patients with N. meningitidis bacteremia have a rash. Meningococ­
cemia most often affects young children (i.e., those 6 months to 
5 years old). In sub-Saharan Africa, the high prevalence of serogroup 
A meningococcal disease has been a threat to public health for more 
than a century. Thousands of deaths occur annually in this area, which 
is known as the “meningitis belt,” and large epidemic waves occur 
approximately every 8–12 years. In the setting of aggressive vaccination 
programs against serogroup A, disease due to other serogroups, such 
as serogroups C, W135, and X, are increasing. Outside Africa, out­
breaks for the past 50 years reported in the United States and Europe 
are caused primarily by serogroup C (approximately 60%) followed by 
serogroup B (29%). In the United States, sporadic cases and outbreaks 
occur in day-care centers, schools (grade school through college, 
particularly among college freshmen living in residential halls), and 
army barracks. Outbreaks have also been described in people expe­
riencing homelessness. People with underlying comorbidities, such as 
cancer, renal or liver disease, or solid organ transplant recipients, are at 
increased risk. Household contacts of index cases are at 400–800 times 
greater risk of disease than the general population. Patients may have 
fever, headache, nausea, vomiting, myalgias, changes in mental status, 
and meningismus. However, the rapidly progressive form of disease 
is not usually associated with meningitis. The rash is initially pink, 
blanching, and maculopapular, appearing on the trunk and extremi­
ties, but then becomes hemorrhagic, forming petechiae. Petechiae are 
first seen at the ankles, wrists, axillae, mucosal surfaces, and palpebral 
and bulbar conjunctiva, with subsequent spread on the lower extremi­
ties and to the trunk. A cluster of petechiae may be seen at pressure 
points—e.g., where a blood pressure cuff has been inflated. In rapidly 
progressive meningococcemia (10–20% of cases), the petechial rash 
quickly becomes purpuric (see Fig. A1-41), and patients develop DIC, 
multiorgan failure, and shock; 50–60% of these patients die, and survi­
vors often require extensive debridement or amputation of gangrenous 
extremities. Hypotension with petechiae for <12 h is associated with 
significant mortality. Cyanosis, coma, oliguria, metabolic acidosis, and 
elevated partial thromboplastin time also are associated with a fatal 
outcome. Antibiotics given in the office by the primary care provider 
before hospital evaluation and admission may improve prognosis; this 
observation suggests that early initiation of treatment may be lifesaving. Members of the patient’s household and other persons with 
close contact should receive antibiotic prophylaxis with ciprofloxacin, 
rifampin, or ceftriaxone. Meningococcal conjugate vaccines are protec­
tive against serogroups A, C, Y, and W135 and are recommended for 
children 11–12 years of age with a booster dose at 16 years of age, and 
for other high-risk patients. Vaccines active against serogroup B are 
recommended for high-risk individuals ≥10 years of age and may be 
appropriate for teens and young adults (16 through 23 years of age).
PART 5
Infectious Diseases
Rocky Mountain Spotted Fever and Other Rickettsial Dis­
eases (See also Chap. 192) 
RMSF is a tickborne disease that 
occurs throughout North and South America. It is caused primarily 
by Rickettsia rickettsii but can be caused by other rickettsiae (e.g., R. 
parkeri, R. akari). Up to 40% of patients do not report a history of 
a tick bite, but a history of travel or outdoor activity (e.g., camping 
in tick-infested areas) can often be ascertained. For the first 3 days, 
headache, fever, malaise, myalgias, nausea, vomiting, and anorexia are 
documented. By day 3, half of patients have skin findings. Blanching 
macules develop initially on the wrists and ankles and then spread over 
the legs and trunk. The lesions become hemorrhagic and are frequently 
petechial. The rash spreads to palms and soles later in the course. The 
centripetal spread is a classic feature of RMSF but occurs in a minority 
of patients. Moreover, 10–15% of patients with RMSF never develop 

a rash. The patient can be hypotensive and develop noncardiogenic 
pulmonary edema, confusion, lethargy, and encephalitis progressing to 
coma. The CSF contains 10–100 cells/μL, usually with a predominance 
of mononuclear cells. The CSF glucose level is often normal; the pro­
tein concentration may be slightly elevated. Renal and hepatic injury 
as well as bleeding secondary to vascular damage are noted. Delayed 
recognition and treatment are associated with a greater risk of death; 
mortality rates are 20–35% if treatment is delayed or not prescribed 
compared with ~4% when treated with doxycycline within 5 days of 
onset. Native Americans, Alaskan natives, Pacific Islanders, children 
5–9 years of age, adults >70 years old, and persons with underlying 
immunosuppression are at increased risk of death as well.
Other rickettsial diseases cause significant morbidity and mortality 
worldwide. Mediterranean spotted fever caused by Rickettsia conorii is 
found in Africa, southwestern and south-central Asia, and southern 
Europe. Patients have fever, flu-like symptoms, and an inoculation 
eschar at the site of the tick bite. A maculopapular rash develops within 
1–7 days, involving the palms and soles but sparing the face. Elderly 
patients or those with diabetes, alcoholism, uremia, or congestive 
heart failure are at risk for severe disease characterized by neurologic 
involvement, respiratory distress, and gangrene of the digits or purpura 
fulminans. Mortality rates associated with this severe form of disease 
approach 50% without treatment, but a single day of doxycycline is 
associated with much improved outcomes. Epidemic typhus, caused 
by Rickettsia prowazekii, is transmitted in louse-infested environments 
and emerges in conditions of extreme poverty, war, refugee camps, 
and natural disaster. Patients experience a sudden onset of high fevers, 
severe headache, cough, myalgias, and abdominal pain. A maculo­
papular rash develops (primarily on the trunk) in more than half of 
patients and can progress to petechiae and purpura. Serious signs 
include delirium, coma, seizures, noncardiogenic pulmonary edema, 
skin necrosis, and peripheral gangrene. Mortality rates approached 
60% in the preantibiotic era and continue to exceed 10–15% in con­
temporary outbreaks. Scrub typhus, caused by Orientia tsutsugamushi 
(a separate genus in the family Rickettsiaceae), is transmitted by larval 
mites or chiggers and is one of the most common infections in south­
eastern Asia and the western Pacific. The organism is found in areas of 
heavy scrub vegetation (e.g., along riverbanks) and most common in 
rural areas among farming communities. Patients may have an inocula­
tion eschar and may develop a maculopapular rash, lymphadenopathy, 
and dyspnea. Severe cases progress to pneumonia, meningoencepha­
litis, myocarditis, DIC, and renal failure. Mortality rates range from 
1% to 70% and vary by location, increasing age, myocarditis, delirium, 
pneumonitis, or signs of hemorrhage.
If recognized in a timely fashion, rickettsial disease is very respon­
sive to tetracycline-based treatment. Doxycycline (100 mg twice daily 
for 1–14 days) is the treatment of choice for both adults and children. 
Combination therapy with doxycycline and azithromycin reduces 
complications and death in patients with severe scrub typhus.
Purpura Fulminans (See also Chaps. 160 and 315) 
Purpura 
fulminans is the cutaneous manifestation of DIC and presents as large 
ecchymotic areas and hemorrhagic bullae. Progression of petechiae to 
purpura, ecchymoses, and gangrene is associated with congestive heart 
failure, septic shock, acute renal failure, acidosis, hypoxia, hypotension, 
and death. Purpura fulminans has been associated primarily with 
N. meningitidis but, in splenectomized patients, may be associated with 
S. pneumoniae, H. influenzae, and S. aureus.
Ecthyma Gangrenosum 
Septic shock caused by P. aeruginosa or, 
less often, Aeromonas hydrophila or other gram-negative organisms, 
can be associated with ecthyma gangrenosum (see Figs. 170-1 and 
A1-34): hemorrhagic vesicles surrounded by a rim of erythema with 
central necrosis and ulceration, most frequently located on the legs and 
trunk. Echthyma gangrenosum is most common among patients with 
neutropenia, extensive burns, and hypogammaglobulinemia.
Other Infections Associated with Rash 
Vibrio vulnificus and 
other noncholera Vibrio bacteremic infections (Chap. 173) can cause 
focal skin lesions and overwhelming sepsis in hosts with chronic liver

disease, heavy alcohol consumption, iron storage disorders, diabe­
tes, renal insufficiency, hematologic disease, or malignancy or other 
immunocompromising conditions. More than 95% of the cases are 
in the subtropical Pacific and Atlantic Oceans coastal regions in the 
Northern Hemisphere. After ingestion of contaminated raw shellfish 
(typically oysters from the Gulf Coast in U.S. cases), there is a sudden 
onset of malaise, chills, fever, and hypotension. The patient develops 
bullous or hemorrhagic skin lesions, usually on the lower extremities, 
and 75% of patients have leg pain. The mortality rate can be as high as 
35–60%, particularly when the patient presents with hypotension and 
septicemia. Outcomes are improved when patients are treated with 
fluoroquinolones with or without cephalosporins or with tetracyclinecontaining regimens. Other infections, caused by agents such as 
Aeromonas, Klebsiella, and E. coli, can cause hemorrhagic bullae and 
death due to overwhelming sepsis in cirrhotic patients. Capnocytoph­
aga canimorsus can cause septic shock in asplenic or cirrhotic patients. 
Infection typically follows a dog bite. Serovars A–C appear more 
virulent, constituting 92% of human infections but only 7.6% of canine 
isolates. Patients present with fever, chills, myalgia, vomiting, diarrhea, 
dyspnea, confusion, and headache. Findings can include an exan­
them or erythema multiforme (see Figs. 59-9 and A1-24A), cyanotic 
mottling or peripheral cyanosis, petechiae, and ecchymosis. About 
one-third of patients with sepsis develop septic shock, and 11–30% of 
patients with this fulminant form die of overwhelming sepsis and DIC. 
Survivors may require amputation because of gangrene.
Erythroderma 
TSS (Chaps. 152 and 153) is usually associated 
with erythroderma. The patient presents with fever, malaise, myalgias, 
nausea, vomiting, diarrhea, and confusion. There is a sunburn-type 
rash that may be subtle and patchy but is usually diffuse and is found 
on the face, trunk, and extremities. Erythroderma, which desquamates 
after 1–2 weeks, is more common in Staphylococcus-associated than 
in Streptococcus-associated TSS. Hypotension develops rapidly—often 
within hours—after the onset of symptoms. Early renal failure may 
precede hypotension and distinguishes this syndrome from other sep­
tic shock syndromes. There may be no indication of a primary focal 
infection, although possible cutaneous or mucosal portals of entry for 
the organism can be ascertained through a careful history. Coloniza­
tion rather than overt infection of the vagina or a postoperative wound, 
for example, is typical with staphylococcal TSS, and the mucosal areas 
appear hyperemic but not infected. Streptococcal TSS is more often 
associated with skin or soft tissue infection (including necrotizing 
fasciitis), and patients are more likely to be bacteremic. TSS caused by 
Clostridium sordellii is associated with childbirth or with skin injec­
tion of black-tar heroin. The diagnosis of TSS is defined by the clini­
cal criteria of fever, rash, hypotension, and multiorgan involvement, 
although fever is typically absent when TSS is caused by C. sordellii. 
The mortality rate is 5% for menstruation-associated TSS, 10–15% 
for nonmenstrual TSS, 30–70% for streptococcal TSS, and up to 90% 
for obstetric C. sordellii TSS. Clindamycin improves outcomes when 
included in the treatment regimen. The use of IV immunoglobulin is 
associated with improved survival in some studies, in conjunction with 
clindamycin therapy.
Viral Hemorrhagic Fevers 
Viral hemorrhagic fevers (Chaps. 215 
and 216) are zoonotic illnesses caused by viruses that reside in either 
animal reservoirs or arthropod vectors. These diseases occur world­
wide and are restricted to areas where the host species live. They are 
caused by four major groups of viruses: Arenaviridae (e.g., Lassa fever 
in Africa), Bunyaviridae (e.g., Rift Valley fever in Africa; hantavirus 
hemorrhagic fever with renal syndrome in Asia; and Crimean-Congo 
hemorrhagic fever, which has an extensive geographic distribution), 
Filoviridae (e.g., Ebola and Marburg virus infections in Africa), and 
Flaviviridae (e.g., yellow fever in Africa and South America and dengue 
in Asia, Africa, and the Americas). Lassa fever and Ebola and Marburg 
virus infections are also transmitted from person to person. The vec­
tors for most viral fevers are found in rural areas; dengue and yellow 
fever are important exceptions. After a prodrome of fever, myalgias, 
and malaise, patients develop evidence of vascular damage, petechiae, 

and local hemorrhage. Shock, multifocal hemorrhaging, and neuro­
logic signs (e.g., seizures or coma) predict a poor prognosis. Dengue 
(Chap. 215) is the most common arboviral disease worldwide. More 
than 100–400 million cases occur each year, ~25% of which are 
symptomatic with at least 12,000–20,000 deaths. Patients have a triad 
of symptoms: hemorrhagic manifestations, evidence of plasma leak­
age, and platelet counts of <100,000/μL. Mortality rates are 10–20%. 
If dengue shock syndrome develops, which is associated with severe 
hepatitis and neurologic involvement, mortality rates can reach 40%. 
Ebola infection has been associated with outbreaks with high mortality 
rates. From 1976 to 2022, 35 outbreaks were reported with an average 
case fatality rate of approximately 50%. Symptoms can appear 2–21 
days after exposure, but most patients become ill within 9 days. The 
patient first presents with fatigue, fever, headache, and muscle pains, 
and the illness can progress to multiorgan failure and hemorrhaging. 
Careful volume-replacement therapy to maintain blood pressure and 
intravascular volume is key to survival in these infections.

Other viral illnesses with rash, such as measles, can be associated 
with significant mortality rates, especially in patients who develop 
organ complications such as pneumonia, pancreatitis or encephalitis. 
Measles continues to be responsible for more than 100,000 deaths per 
year worldwide, and to cause outbreaks in populations with low vac­
cination rates.
■
■SEPSIS WITH A SOFT TISSUE/MUSCLE 

PRIMARY FOCUS
See also Chap. 134.
Necrotizing Fasciitis 
This infection is characterized by extensive 
necrosis of the subcutaneous tissue and fascia. It may arise at a site of 
minimal trauma or surgical incision and may also be associated with 
recent varicella, childbirth, or muscle strain. Diabetes mellitus, IV drug 
use, chronic liver or renal disease, and malignancy are associated risk 
factors. The most common causes of necrotizing fasciitis are group A 
streptococci alone (Chap. 153) and a mixed facultative and anaerobic 
flora (Chap. 134). The incidence of group A streptococcal necrotizing 
fasciitis has been increasing for the past quarter-century; surveillance 
in the United States links 13% of the cases to active IV drug use or 
homelessness. Physical findings are initially minimal except for soft 
tissue edema and mild erythema compared with the severity of pain 
and the degree of fever. The infected area is red, hot, shiny, swollen, and 
exquisitely tender. In untreated infection, the overlying skin develops 
blue-gray patches after 36 h, and cutaneous bullae and necrosis develop 
after 3–5 days. Necrotizing fasciitis due to a mixed flora, but not that 
due to group A streptococci, can be associated with gas production. 
Without treatment, pain decreases because of thrombosis of the small 
blood vessels and destruction of the peripheral nerves—an ominous 
sign. The mortality rate is 11–34% overall and increases when in 
association with TSS. With surgery, outcomes are significantly better. 
Necrotizing fasciitis may also be due to Clostridium perfringens 
(Chap. 159); in this condition, the patient is extremely toxic and the 
mortality rate is high. Within 48 h, rapid tissue invasion and systemic tox­
icity associated with hemolysis and death ensue. The distinction between 
this entity and clostridial myonecrosis is made by muscle biopsy.
CHAPTER 127
Approach to the Acutely Ill Infected Febrile Patient 
Clostridial Myonecrosis (See also Chap. 159) 
Myonecrosis 
is often associated with trauma or surgery but can develop spontane­
ously. The incubation period is usually 12–24 h long, and massive 
necrotizing gangrene develops within hours of onset. Systemic toxicity, 
shock, and death can occur within 12 h. The patient’s pain and toxic 
appearance are out of proportion to physical findings. On examina­
tion, the patient is febrile, apathetic, tachycardic, and tachypneic and 
may express a feeling of impending doom. Hypotension and renal 
failure develop later, and hyperalertness is evident preterminally. The 
skin over the affected area is bronze-brown, mottled, and edematous. 
Bullous lesions with serosanguineous drainage and a mousy or sweet 
odor can develop. Crepitus can occur secondary to gas production in 
muscle tissue. The mortality rate is >65% for spontaneous myonecrosis, 
which is often associated with Clostridium septicum or C. tertium and 
underlying malignancy. The mortality rates associated with trunk and

limb infection are 63% and 12%, respectively, and any delay in surgical 
treatment increases the risk of death.

■
■NEUROLOGIC INFECTIONS WITH OR 

WITHOUT SEPTIC SHOCK
Bacterial Meningitis (See also Chap. 143) 
Bacterial meningi­
tis is one of the most common infectious disease emergencies involv­
ing the central nervous system. Although hosts with cell-mediated 
immune deficiency (including transplant recipients, diabetic patients, 
elderly patients, and cancer patients receiving certain chemotherapeu­
tic agents) are at particular risk for Listeria monocytogenes meningitis, 
most cases in adults are due to S. pneumoniae (30–60%) and N. men­
ingitidis (10–35%). The classic presentation of fever, meningismus, and 
altered mental status is seen in only one-third to one-half of patients 
and is more common in adults over 60 years of age, although the 
elderly can also present without fever or meningeal signs. Cerebral 
dysfunction is evidenced by confusion, delirium, and lethargy that can 
progress to coma. In some cases, the presentation is fulminant, with 
sepsis and brain edema; papilledema at presentation is unusual and 
suggests another diagnosis (e.g., an intracranial lesion). Focal signs, 
including cranial nerve palsies (IV, VI, VII), can be seen in 10–20% of 
cases; 50–70% of patients have bacteremia. A poor outcome is associ­
ated with coma, seizures, hypotension, a purpuric rash, a pneumococ­
cal etiology, respiratory distress, a CSF glucose level of <0.6 mmol/L 
(<10 mg/dL), a CSF protein level of >2.5 g/L, and peripheral leukope­
nia or thrombocytopenia. Rapid initiation of treatment is essential; the 
odds of an unfavorable outcome may increase by 30% for each hour 
that treatment is delayed. Dexamethasone is an adjunctive treatment 
for meningitis in adults, especially for infections caused by S. pneu­
moniae, but is not recommended for Listeria meningitis. It must be 
given before or with the first dose of antibiotics; otherwise, it is unlikely 
to improve outcomes.
PART 5
Infectious Diseases
Suppurative Intracranial Infections (See also Chap. 145) 
Sup­
purative intracranial infections present along with sepsis and hemo­
dynamic instability. Rapid recognition of the toxic patient with central 
neurologic signs is crucial to improvement of the prognosis of these 
entities. Patients with diabetes or hematologic disease may be at 
increased risk for these infections. Subdural empyema arises from the 
paranasal sinus in 60–70% of cases. Microaerophilic streptococci and 
staphylococci are the predominant etiologic organisms. The patient 
is toxic, with fever, headache, and nuchal rigidity. Of all patients, 
75% have focal signs and 6–20% die. Despite improved survival rates, 
15–44% of patients are left with permanent neurologic deficits. Septic 
cavernous sinus thrombosis follows a facial or sphenoid sinus infec­
tion; 70% of cases are due to staphylococci (including MRSA), and 
the remainder are due primarily to aerobic or anaerobic streptococci. 
Fungi have been common in some series. A unilateral or retro-orbital 
headache progresses to a toxic appearance and fever within days. 
Three-quarters of patients have unilateral periorbital edema that 
becomes bilateral and then progresses to ptosis, proptosis, ophthalmo­
plegia, and papilledema. The mortality rate is as high as 30% in older 
studies with frequent neurologic sequelae but recent reports indicate 
improved survival as high as 90%. Septic thrombosis of the superior 
sagittal sinus spreads from the ethmoid or maxillary sinuses and is 
caused by S. pneumoniae, other streptococci, and staphylococci. The 
fulminant course is characterized by headache, nausea, vomiting, rapid 
progression to confusion and coma, nuchal rigidity, and brainstem 
signs. Broad-spectrum antibiotics and early surgical intervention at 
the primary site of infection may improve outcomes. Anticoagulation 
or steroids are of uncertain benefit.
Brain Abscess (See also Chap. 145) 
Brain abscess often occurs 
without systemic signs. Almost half of patients are afebrile, and pre­
sentations are more consistent with a space-occupying lesion in the 
brain; 70% of patients have headache and/or altered mental status, 50% 
have focal neurologic signs, and 25% have papilledema. Abscesses can 
present as single or multiple lesions resulting from contiguous foci 
or hematogenous infection, such as endocarditis, or after surgery or 

trauma. The infection progresses over several days from cerebritis to 
an abscess with a mature capsule. More than one-fourth to one-half of 
infections are polymicrobial, with an etiology consisting of aerobic bac­
teria (primarily streptococcal species) and anaerobes. Abscesses arising 
hematogenously are especially apt to rupture into the ventricular space, 
causing a sudden and severe deterioration in clinical status and a high 
mortality rate. Otherwise, mortality is low (<20%) but morbidity is 
high (30–55%). Patients presenting with stroke and a parameningeal 
infectious focus, such as sinusitis or otitis, may have a brain abscess; 
physicians must maintain a high level of suspicion. Prognosis worsens 
in patients with a fulminant course, delayed diagnosis, abscess rupture 
into the ventricles, multiple abscesses, or abnormal neurologic status 
at presentation. Patients who receive medical therapy alone, compared 
with those receiving combined medical and surgical interventions, 
have higher mortality and a greater chance of neurologic sequelae.
Cerebral Malaria (See also Chap. 231) 
This entity should be 
urgently considered for inhabitants of, or recent travelers to, areas 
endemic for malaria. Any patient with a change in mental status 
or repeated seizure in the setting of fulminant malaria has cerebral 
malaria. Fulminant malaria is caused by Plasmodium falciparum and 
is associated with temperatures of >40°C (>104°F), hypotension, 
jaundice, acute respiratory distress syndrome, and bleeding. Patients 
present with a febrile illness and lethargy or other neurologic signs, 
In adults, this nonspecific febrile illness progresses to coma over 
several days; occasionally, coma occurs within hours and death within 
24 h. Nuchal rigidity and photophobia are rare. On physical examina­
tion, symmetric encephalopathy is typical, and upper motor neuron 
dysfunction with decorticate and decerebrate posturing can be seen in 
advanced disease. Unrecognized infection results in a 20–30% mortal­
ity rate. Intravenous artesunate is associated with better outcomes. 
Children with neurologic deficit at hospital discharge, seizure recur­
rence during treatment, and/or ischemic neural injury on MRI are at 
particular risk for neurologic and mental health sequelae.
Intracranial and Spinal Epidural Abscesses (See also 

Chap. 453) 
Spinal and intracranial epidural abscesses (SEAs and 
ICEAs) can result in permanent neurologic deficits, sepsis, and death. 
At-risk patients include those with diabetes mellitus; IV drug use; chronic 
alcohol abuse; recent spinal trauma, surgery, or epidural anesthesia; 
and other comorbid conditions, such as HIV infection. Fungal epidural 
abscess and meningitis have been linked to epidural or paraspinal glu­
cocorticoid injections. In the United States and Canada, where early 
treatment of otitis and sinusitis is typical, ICEA is rare but the number 
of cases of SEA is on the rise. ICEAs typically present as fever, mental 
status changes, and neck pain, while SEAs often present as fever, local­
ized spinal tenderness, and back pain. ICEAs are typically polymicro­
bial, whereas SEAs are most often due to hematogenous seeding, with 
staphylococci the most common etiologic agent. Early diagnosis and 
treatment, which may include surgical drainage, minimize rates of 
mortality and permanent neurologic sequelae. Outcomes are worse for 
SEA due to MRSA, for infection at a higher vertebral-body level, for 
impaired neurologic status on presentation, and for dorsal rather than 
ventral abscess location. Elderly patients and persons with renal failure, 
malignancy, and other comorbidities also have less favorable outcomes.
■
■OTHER FOCAL SYNDROMES WITH A FULMINANT 
COURSE
Infection at virtually any primary focus (e.g., osteomyelitis, pneu­
monia, pyelonephritis, or cholangitis) can result in bacteremia and 
sepsis. Rapid clinical deterioration and death can be associated with 
destruction of the primary site of infection, as is seen in endocarditis 
and in infections of the oropharynx (e.g., Ludwig’s angina or epiglot­
titis, in which edema suddenly compromises the airway). TSS has been 
associated with focal infections such as septic arthritis, peritonitis, 
sinusitis, and wound infection. Lemierre’s syndrome is jugular septic 
thrombophlebitis primarily caused by Fusobacterium necrophorum, but 
it can be caused by other Fusobacterium spp., anaerobic streptococci 
and other bacteria. Lemierre’s syndrome is associated with metastatic 
infectious emboli (primarily to the lung but sometimes to the liver or

other organs) and sepsis, with mortality rates of >15%. Fusobacterium 
bloodstream infections have been associated with occult gastrointesti­
nal or genitourinary malignancy.
Rhinocerebral Mucormycosis (See also Chap. 224) 
Individ­
uals with diabetes or immunocompromising conditions such as solid 
organ transplants or hematologic malignancies are at risk for invasive 
rhinocerebral mucormycosis. Patients present with low-grade fever, 
dull sinus pain, diplopia, decreased mental status, decreased ocular 
motion, chemosis, proptosis, dusky or necrotic nasal turbinates, and 
necrotic hard-palate lesions that respect the midline. Without rapid 
recognition, surgical intervention, and antifungal therapy, the process 
continues on an inexorable invasive course, with mortality rates of 
50–85% or greater. Uncontrolled diabetes and increasing age are nega­
tive prognostic factors.
Acute Bacterial Endocarditis (See also Chap. 133) 
This 
entity presents with a much more aggressive course than subacute 
endocarditis. Bacteria such as S. aureus, S. pneumoniae, L. monocy­
togenes, Haemophilus species, and streptococci of groups A, B, and 
G attack native valves. Native-valve endocarditis caused by S. aureus 
(including MRSA strains) is increasing. Mortality rates range from 10% 
to 40%. The host may have comorbid conditions such as underlying 
malignancy, diabetes mellitus, IV drug use, or alcoholism. Rheumatic 
valvular disease remains the most prevalent risk factor in Africa but 
is much less common in the United States. The patient presents with 
fever, fatigue, and malaise <2 weeks after onset of infection. On physi­
cal examination, a changing murmur and congestive heart failure may 
be noted. Hemorrhagic macules on palms or soles (Janeway lesions) 
sometimes develop. Petechiae, Roth’s spots, splinter hemorrhages, and 
splenomegaly are unusual. Rapid valvular destruction, particularly of 
the aortic valve, results in pulmonary edema and hypotension. Myo­
cardial abscesses can form, eroding through the septum or into the 
conduction system and causing life-threatening arrhythmias or highdegree conduction block. Large friable vegetations can result in major 
arterial emboli, metastatic infection, or tissue infarction including 
stroke. Older patients with S. aureus endocarditis are especially likely 
to present with nonspecific symptoms—a circumstance that delays 
diagnosis and worsens prognosis. Rapid intervention is crucial for a 
successful outcome.
Inhalational Anthrax (See also Chap. S4) 
Inhalational 
anthrax, the most severe form of disease caused by B. anthracis, had 
not been reported in the United States for more than 25 years until 
the use of this organism as an agent of bioterrorism in 2001. Patients 
presented with malaise, fever, cough, nausea, drenching sweats, short­
ness of breath, and headache. Rhinorrhea was unusual. All patients had 
abnormal chest roentgenograms at presentation. Pulmonary infiltrates, 
mediastinal widening, and pleural effusions were the most common 
findings. Hemorrhagic meningitis was documented in 38% of these 
patients. Survival was more likely when antibiotics were given during 
the prodromal period and when multidrug regimens with at least two 
bacteriocidal antibiotic agents were used. In the absence of urgent 
intervention with antimicrobial agents and supportive care, inhala­
tional anthrax progresses rapidly to hypotension, cyanosis, and death.
Viral Respiratory Tract Illness 
Viral respiratory tract illnesses 
can cause severe disease; several new syndromes have been described 
in the past decade. For patients who present with a respiratory illness 
and a relevant exposure and travel history, these viral illnesses must be 
considered and appropriate infection control measures instituted in 
addition to supportive care.
Avian and Swine Influenza (See also Chap. 206) 
Human 
cases of avian influenza have occurred primarily in Southeast Asia, 
particularly Vietnam (H5N1) and China (H7N9). Avian influenza 
should be considered in patients with severe respiratory tract illness, 
particularly if they have been exposed to poultry. Patients present with 
high fever, an influenza-like illness, and lower respiratory tract symp­
toms; this illness can progress rapidly to bilateral pneumonia, acute 
respiratory distress syndrome, multiorgan failure, and death. Younger 

age appears to be associated with a lower risk of complications. Early 
antiviral treatment with neuraminidase inhibitors should be initiated 
along with aggressive supportive measures. Unlike avian influenza, 
whose human-to-human transmission has so far been rare and has not 
been sustained, influenza caused by a novel swine-associated A(H1N1) 
virus emerged in 2009 and caused more than 60 million cases and 
12,000 deaths in 1 year. Patients most at risk of severe disease were 
children <5 years of age, elderly persons, patients with underlying 
chronic conditions, and pregnant women. Obesity also has been identi­
fied as a risk factor for severe illness. The virus continues to circulate 
as a seasonal influenza virus, along with A(H1N1) strains. Although 
influenza cases dropped during the peak of the COVID-19 pandemic, 
they are again increasing and cause 3–5 million cases of severe illness 
and 300,000–650,000 deaths each year.

SARS, COVID-19, and MERS (See Chaps. 204 and 205) 
Novel 
betacoronaviruses have now been identified as the cause of severe acute 
respiratory syndrome (SARS, caused by SARS-CoV-1), Middle East 
respiratory syndrome (MERS, caused by MERS-CoV), and COVID-19 
(caused by SARS-CoV-2). Although the three viruses have many simi­
larities, they differ in degree of contagion and case fatality rates. SARS 
and MERS “super-spreaders” are very symptomatic and typically criti­
cally ill, hospitalized patients. This is in contrast to COVID-19 where 
patients with highly transmissible virus are often asymptomatic or have 
mild disease. SARS emerged in 2002 in China and was diagnosed in 
several countries, primarily in Asia. Possible animal reservoirs include 
bats and civets. SARS-CoV-1 is characterized by efficient human trans­
mission but relatively low mortality. The potential SARS-CoV-1 pan­
demic was controlled through identification and isolation of infected 
patients. There have been no reported cases since 2004.
CHAPTER 127
MERS likely has a bat reservoir and was first recognized in 2012 in 
Saudi Arabia. Human cases have been associated with direct and indi­
rect contact with dromedary camels. Unlike SARS and COVID-19, MERS 
exhibits inefficient human transmission but carries a high mortality 
rate. As of 2023, >2600 cases had been confirmed, most in the Arabian 
Peninsula, with 35% mortality. MERS ranges from asymptomatic infec­
tion to acute respiratory distress syndrome, multiorgan failure, and 
death. Elderly men with comorbidities appear to be at highest risk for 
poor outcomes. Despite little documented human-to-human transmis­
sion in the community, nosocomial infection must be prevented by 
adherence to strict infection control practices. MERS is currently a 
low-level public health threat and is likely to remain so unless the virus 
mutates and its transmissibility increases.
Approach to the Acutely Ill Infected Febrile Patient 
COVID-19 caused by SARS-CoV-2 resulted in a pandemic of his­
toric proportion. Originally linked to cases in China, SARS-CoV-2 
spread internationally at a rapid pace. As of December 2023, cases 
approached 773 million worldwide with almost 7 million confirmed 
deaths; the United States has reported more than 103 million cases and 
over 1.1 million deaths. Actual infection may exceed reported cases by 
8−10 fold. The primary mode of transmission of COVID-19 is through 
direct person-to-person contact via respiratory droplets; transmission 
by the airborne route or by contact with contaminated surfaces is much 
less common. Greatest risk of infection is associated with close and 
prolonged contact such as in household or congregate settings. Rates 
of secondary infection among household contacts are high: >50% in 
studies early in the pandemic.
Although ~80% of patients with symptomatic COVID-19 infection 
have mild disease such as cough, sore throat, fever, gastrointestinal 
symptoms, and taste and smell alterations, ~5% of patients develop 
respiratory failure, shock, and multiorgan system failure. Patients typi­
cally have been symptomatic for 5−7 days before progression to severe 
pneumonia and hypoxemia. Shock, often in the setting of cardiac 
injury/myocarditis, arrhythmias or cardiomyopathy, and thromboem­
bolic complications such as pulmonary emboli or stroke, can occur. 
Other manifestations include acute kidney or liver injury. Laboratory 
findings include lymphopenia, elevated lactate dehydrogenase, and 
often evidence of a cytokine-release type syndrome with elevated 
C-reactive protein, d-dimer, ferritin, and proinflammatory cytokines 
such as interleukin 6 (IL-6). Chest radiographs and CT imaging reveal