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INFECTIOUS DISEASE Let us know what you
THE SEPSIS SYNDROME: DIFFERENTIAL DIAGNOSIS OF THE
The syndrome of fever, malaise, myalgias, and other constitutional
complaints is common in medical practice. When localizing symptoms and
physical findings are few and there is no rash, patients are often presumed to
have a “flu-like illness” or “viral syndrome.” Some, however, have treatable
life-threatening disease. Examples include septicemia due to S. aureus or
aerobic gram-negative rods, septic abortion, endocarditis, and Rocky
Mountain spotted fever (figure 1,2,3). The clinician’s task is to determine
which patients require close observation, special laboratory studies, and
empiric antimicrobial therapy.
Microorganisms have diverse effects on human cells and tissues, but the
concept of a “final common pathway” leading to refractory shock continues
to evolve. At the molecular level, researchers focus especially on a large
number of cytokines (peptide hormones that act on cells) released in response
to various insults. The best-studied interaction involves the endotoxin
molecule (specifically, the lipid A moiety of a complex lipopolysaccharide)
of gram-negative bacteria and human mononuclear cells, but it is now clear
that gram-positive bacteria and other types of microorganisms cause shock
by similar mechanisms.
Certain definitions facilitate our understanding of what happens during acute
Sepsis denotes clinical evidence of infection plus a host response:
fever (temperature > 38°C) or hypothermia (temperature < 36°C),
tachycardia (heart rate > 90 beats/minute), tachypnea (respiratory rate
> 20 breaths/minute or PaC02 < 32 mm Hg, and both quantitative and
qualitative changes in circulating white blood cells (WBC > 12,000
cells/mm3 or < 4,000 cells/mm3 or > 10% immature (band) forms)
Sepsis syndrome denotes sepsis plus evidence of impaired organ
perfusion. Evidence of impaired organ perfusion in the primary care
setting includes altered mental status, decreased urine output, and low
oxygen saturation by pulse oximetry. Lactic acidosis may also be
Severe sepsis denotes sepsis associated with organ dysfunction,
hypoperfusion, or hypotension. Hypoperfusion abnormalities include
oliguria and altered mental status. Hypotension is defined as systolic
blood pressure < 90 mmHg or a falloff > 40 mmHg from baseline in
the absence of other causes of hypotension.
Septic shock is defined as sepsis with hypotension despite adequate
fluid resuscitation, along with perfusion abnormalities such as lactic
acidosis, oliguria, or acute alteration in mental status.
Many clinicians still use the older term septicemia, which denotes the
presence of microorganisms in the blood (as confirmed by culture) plus
clinical evidence of sepsis. The concept of a systemic inflammatory response
syndrome expresses the notion that the body responds in certain ways to a
wide variety of insults. Thus, for example, shock with acute respiratory
distress syndrome and renal failure can result from conditions as diverse as
Rocky Mountain spotted fever and acute hemorrhagic pancreatitis.
Staphylococcal septicemia not infrequently presents as an undifferentiated
'flu-like illness, and this presentation can be especially treacherous when
influenza A is prevalent in a community. The illness often begins abruptly
with chills and generalized “aching all over” which is sometimes localized to
the joints. Physical examination is often unrevealing. Endocarditis is
relatively common in patients with community-acquired staphylococcal
septicemia (10% or more of cases). Other patients have occult abscesses or
osteomyelitis. Patients with S. aureus bacteremia can progress rapidly
through the stages of sepsis, sepsis syndrome, severe sepsis, septic shock,
and refractory septic shock.
Skin lesions in sepsis can arise by at least 5 mechanisms:
Disseminated intravascular coagulation and coagulopathy - for
example, in sepsis due to gram-negative and gram-positive bacteria.
Invasion of blood vessel walls - for example, in ecthyma
gangrenosum, Rocky Mountain spotted fever, meningococcemia,
disseminated candidiasis, Aspergillus infection, and mucormycosis.
Immune complex formation with vasculitis―for example,
endocarditis, disseminated gonococcal disease, typhoid fever, and
meningococcemia (later phases).
Embolism―for example, endocarditis and, rarely, mycotic aneurysm.
Toxin formation―for example, toxic shock syndrome, scarlet fever,
Ecthyma gangrenosum is especially important to recognize, since it provides
an early clue to severe infection caused by Pseudomonas aeruginosa and,
less commonly, to other bacteria and fungi. The characteristic skin lesion of
ecthyma gangrenosum, seen in 1% to 6% of patients with Pseudomonas
septicemia, is usually encountered in severely immunocompromised persons,
especially patients undergoing chemotherapy for cancer. However, ecthyma
gangrenosum and pseudomonal sepsis occasionally occurs in previously
healthy infants and children.
The initial skin lesions of ecthyma gangrenosum are erythematous to
purpuric macules, hemorrhagic vesicles, bullae, or nodules. They rapidly
progress to a painless, indurated ulcer with a central necrotic black eschar
and surrounding erythema. The most common sites of distribution are the
axillae and anogenital regions. Diagnosis is confirmed by blood and tissue
cultures. Histologic examination and culture of punch biopsy specimens
obtained from patients with sepsis and skin lesions is often invaluable.
Suspicion of ecthyma gangrenosum and pseudomonal septicemia mandates
hospitalization. Mortality remains high (30% to 70%) even with aggressive
STAPHYLOCOCCAL AND STREPTOCOCCAL TOXIC SHOCK
The staphylococcal and streptococcal toxic shock syndromes now rank
Figure prominently among the causes of sudden onset of non-hemorrhagic shock in
This patient displayed previously healthy patients. These syndromes are caused by strains of group
marked desquamation A streptococci (S. pyogenes) and S. aureus that produce unique toxins. These
of right thumb and
toxins function as superantigens; that is, they cause T-lymphocytes to
palm due to Toxic
produce and release massive quantities of cytokines that result in widespread
tissue damage, resulting in shock and multiple organ system failure.
TSS manifests itself
with a sudden onset Staphylococcal toxic shock syndrome came to the attention of the general
of fever, chills,
public as a disease affecting young women during menstruation. Some non-
menstrual cases have been associated with rhinoplasty and other surgical
muscle pains and
procedures in which nasal packing or Teflon® stints are used to close off
and mucous spaces. Other non-menstrual cases are associated with sites of staphylococcal
membrane, colonization and disease, such as skin infections, decubitus ulcers, or
require type-specific antibody for successful phagocytosis by leukocytes.
Streptococcus pneumoniae accounts for 50% to 90% of infections and about
60% of deaths in asplenic patients. Haemophilus influenzae may account for
nearly one-third of the mortality. Neisseria meningitidis is also important.
The syndrome has also been associated with a wide variety of gram-positive
and gram-negative bacteria. I have seen a fatal case due to Salmonella
enteritidis as the initial manifestation of HIV infection in an asplenic patient.
Unusual but well-publicized causes include Capnocytophaga canimorsus
after dog bites, and Babesia microti (babesiosis).
Most patients experience a short prodrome of non-specific symptoms. These
may include chills, headache, malaise, and symptoms pointing to the
abdomen such as nausea, vomiting, diarrhea, and abdominal pain. Symptoms
of pneumonia (cough, chest pain) and meningitis may also be present. The
short prodrome is followed by symptoms and signs of severe sepsis. Vital
signs often reveal fever, tachycardia, hypotension, and tachypnea. The
patient may appear anxious, delirious, or stuporous. Rapid deterioration is the
rule rather than the exception.
This syndrome should be suspected whenever an asplenic person develops
symptoms and signs of an infectious illness. Symptoms suggesting “viral
syndrome” or “gastroenteritis” should not cause postponement of aggressive
treatment. Empiric therapy takes priority over diagnostic deliberation.
Microorganisms are often seen on examination of a random peripheral blood
smear, which implies truly massive bacteremia (>106 organisms/mL). The
yield is increased by examining the buffy coat. Studies to be done in most
cases include blood cultures, complete blood count and electrolyte panel,
urine culture, sputum culture, chest x-ray, and lumbar puncture for analysis
and culture of the CSF.
Meningococcemia with or without meningitis is one of the few infections
diseases capable of killing a previously-healthy person within hours. It
mainly affects children, adolescents, and young adults but can occur at any
age. The initial symptoms are non-specific, and the diagnosis is frequently
Neisseria meningitidis is a normal colonizer of the human upper respiratory
tract, its only known reservoir. To cause invasive disease, the organisms
must first penetrate the respiratory mucosa, a process facilitated by viral or
mycoplasmal respiratory tract infection or by cigarette smoking (including
exposure of young children to passive smoke). Once in the bloodstream, the
organisms must evade the serum bactericidal system in order to multiply and
cause disease. Most, if not all, of the disease manifestations are now
understood as the host response to endotoxin, manifested mainly by release
of cytokines and other inflammatory mediators by monocytes, macrophages,
and endothelial cells. The end-stage result consists of shock, disseminated
intravascular coagulation, and multiple organ system failure.
Host defense against invasive meningococcal disease depends mainly on
serum bactericidal activity, which requires complement and serogroup-
specific antibody. The highest attack rates occur in patients with impaired
serum bactericidal activity. Sporadic meningococcal disease occurs most
frequently in young children who have yet to develop antibodies against N.
meningitidis. In one study, 90% of cases occurred in children less than two
years of age. Patients with deficiencies of the late-acting complement
components (C5 to C9) form another high-risk group. Although this
condition is uncommon, up to 60% of patients with such complement
deficiencies will have at least one episode of invasive meningococcal disease
during their lifetimes, and up to one-half of individuals with such episodes
will have a second episode. (These patients are also predisposed to
gonococcal bacteremia as a complication of gonorrhea.) Also predisposing to
meningococcal disease are asplenia (see above), immunoglobulin deficiency,
and acquired complement deficiencies (for example, in systemic lupus
erythematosus, end-stage liver disease, the nephrotic syndrome, and protein-
The mean age of meningococcal disease in the general population is about 3
years; however, the mean age for the first episode of meningococcal disease
in persons with deficiency of late-acting complement components is about 17
years. There is often a prodromal upper respiratory tract infection. There
follows a flu-like illness with fever, chills, malaise, generalized aching
(myalgias, arthralgias), headache, nausea, and vomiting. Some patients
develop meningococcemia with rapid progression to shock; others develop
meningitis with or without meningococcemia.
Initial symptoms are often subtle. For this reason, I recommend “the buddy
check” for persons who might have early meningococcal disease but in
whom the index of suspicion is insufficiently high to recommend
hospitalization. Petechial rash, which eventually occurs in up to 60% of
patients and which becomes purpuric in severe cases, is the telltale finding.
The petechiae usually begin on the distal parts of the extremities (ankles and
wrists), the axillary folds, or in places exposed to pressure as by the elastic
straps of underwear. Later, petechiae spread to the trunk and can involve the
conjunctivae. The palms, soles, and face are usually spared. The rash is
sometimes macular or maculopapular rather than petechial.
Untreated meningococcemia with shock is nearly 100% fatal. Expressions of
the disease with a better prognosis include chronic meningococcemia with
rash and arthritis (resembling the gonococcal arthritis-dermatitis syndrome)
and occult, self-limited bacteremia in children.
VIBRIO VULNIFICUS INFECTION
Vibrio vulnificus is an invasive, marine, gram-negative bacillus found in
warm seawater. It has been isolated from the Gulf of Mexico, the Pacific and
micrograph (SEM) of
Atlantic oceans, and the waters of Hawaii, Utah, and Massachusetts. The
organism is found in oysters, crabs, clams, and mussels. Most cases (>90%)
have been associated with ingestion of oysters within 1 to 3 days of clinical
Vibrio vulnificus is a presentation. Cirrhosis is the major risk factor to Vibrio vulnificus
bacterium in the same
septicemia. Other predisposing factors include iron overload states (for
family as those that
example, hemochromatosis or hemolytic anemia), immunosuppressive drug
cause cholera. It
therapy, HIV disease, chronic renal failure, and malignancy.
normally lives in
warm seawater and is
part of a group of Symptoms begin abruptly with chills and fever, often followed by
vibrios that are called
hypotension. The typical skin lesions usually appear within 36 hours of the
initial symptoms. Most patients will give a history of ingesting raw shellfish
they require salt. V.
within the previous week. The characteristic skin findings are large bullae
vulnificus can cause
filled with hemorrhagic fluid. Other associated skin manifestations include
disease in those who
eat contaminated necrotic ulcers, necrotizing fasciitis, vasculitis, pustules, petechiae, purpura,
seafood or have an
generalized papules or macules, gangrene, urticaria, and an erythema
open wound that is
multiforme-like rash. The skin lesions are usually on the extremities,
especially the lower extremities. Sepsis develops rapidly; thus, early
recognition is essential.
ingestion of V.
Localized wound infections may also occur after direct exposure of soft
vulnificus can cause
tissue to Vibrio vulnificus through new or preexisting wounds after
submersion in seawater. Local cellulitis and pain are followed quickly by
and abdominal pain.
fever, bullous lesions with vasculitis, and later frank tissue necrosis.
immunocompromised Necrotizing fasciitis due to V. vulnificus differs from necrotizing fasciitis due
to Streptococcus pyogenes in that it is more likely to occur during the
those with chronic
summer months, is more likely to be associated with edema and
liver disease, V.
subcutaneous hemorrhage, but is less likely to be associated with superficial
vulnificus can infect
necrosis of the skin.
causing a severe and
Vibrio infection must be diagnosed clinically to expedite initiation of
therapy. Blood and wound cultures confirm the diagnosis. In septicemia,
by fever and chills,
blood cultures are positive in 97% of patients. The mortality of patients with
pressure (septic Vibrio vulnificus septicemia is greater than 50% and increases to greater than
shock), and blistering 90% if septic shock occurs. Vibrio vulnificus now accounts for about 90% of
skin lesions. V.
deaths due to seafood in the United States.
infections are fatal
about 50% of the
ROCKY MOUNTAIN SPOTTED FEVER
Rocky Mountain spotted fever is a generalized infection of the vascular
endothelium caused by Rickettsia rickettsiae and transmitted by ticks. The
name is misleading, since the disease no longer occurs mainly in the Rocky
Mountains and the telltale rash is often absent especially when the patient is
first seen (quot;Rocky Mountain spotless feverquot;). Failure to suspect and treat this
tick-borne illness can have disastrous consequences.
Rickettsia rickettsiae is an intracellular bacterium belonging to the
rickettsiae. Dermacentor andersoni, the Rocky Mountain wood tick,
transmits the disease in the western United States. Dermacentor variabilis,
Figure the American dog tick, transmits the disease in the South Atlantic and west
Characteristic south central regions, where the disease is now more prevalent. The painless
spotted rash of late- tick bite often goes unnoticed, and history of tick exposure may therefore be
stage Rocky lacking. The organisms pass from the skin to the bloodstream and then to
Mountain spotted vascular endothelial cells, leading to widespread tissue injury.
fever on legs of a
patient, ca. 1946
Rocky Mountain spotted fever begins as a non-specific flu-like illness with
fever, headache, and myalgia after an incubation period of 2 to 14 days
(median 7 days) after a tick bite. The headache is typically severe and often
described as the worst the patient has ever experienced. Fever eventually
exceeds 102°F in more than 90 percent of patients but may be low-grade
when the patient is first seen. Most patients have myalgia. Nausea, vomiting,
abdominal pain and tenderness, and diarrhea often direct attention to the
rash on sole of foot
Rash occurs by the end of the third day of the illness in about one-half of
patients and eventually occurs in 84% to 91% of patients. Rash is more
frequently absent in older patients and in African American patients. The
rash is typically maculopapular, petechial, or both; often central petechiae are
seen within maculopapules. It begins most frequently on the wrists and
ankles. Involvement of the palms and soles, although considered to be
classic, often appears late in the illness or not at all.
Rocky Mountain spotted fever should be suspected in any patient presenting
with a generalized flu-like illness with prominent headache in an endemic
rash on palm and
area during the late spring and summer months, when the disease is most
prevalent. A history of tick exposure should be sought, but is frequently
absent. Although the disease occurs most often in children, young adults, or
woodsmen, it should be kept in mind that anyone including the elderly can
develop the disease and that occasional cases occur throughout the year in
endemic areas. It should also be kept in mind that the disease can crop up in
unusual places, as is evident by its recent appearance in New York City.
The diagnosis is usually suggested by the characteristic rash. Confirmation is
carried out most often by retrospective serology using one or more of several
available methods. The organisms can often be demonstrated in skin biopsy
specimens in laboratories equipped for this purpose. Culture is usually not
attempted and PCR has not proved to be sufficiently sensitive.
Untreated, Rocky Mountain spotted fever has a 20% mortality rate. Mortality
is higher in older patients and among those with shorter incubation periods.
Some patients, especially African American males with glucose-6-phosphate
dehydrogenase (G6PD) deficiency, experience a fulminant course in which
death occurs within 5 days of the onset of symptoms. More commonly, death
occurs during the second week of the illness as a result of organ failure
which may reflect involvement of the CNS (encephalopathy, seizures),
kidneys (acute renal failure), and lungs (interstitial and alveolar in
summary, infiltrates, pleural effusion, noncardiogenic pulmonary edema
features of the acute respiratory distress syndrome). Fulminant purpura with
peripheral gangrene can also occur. The prognosis may be worse in older
patients and in men.
Infective endocarditis―now the preferred term to “bacterial endocarditis”
since microorganisms other than bacteria sometimes cause the disease―is
uniformly fatal without adequate treatment. Unfortunately, the diagnosis can
be masked by prior antibiotic therapy. The primary care clinician’s task is to
know when to suspect endocarditis, when to obtain blood cultures, when to
obtain special studies such as echocardiography, and when to refer patients
for hospitalization because of the suspicion of endocarditis caused by highly
destructive organisms such as S. aureus.
The term “infective endocarditis” usually refers to infection of the heart
valves, but other surfaces can be affected such as the endocardium adjacent
to a ventricular septal defect (VSD). “Endarteritis” refers to an identical
process affecting a large blood vessel, such as a patent ductus arteriosus
(PDA). In any case, pathogenesis requires two events: (1) damage to the
endothelial surface; and (2) microorganisms in the bloodstream. Formation
of platelet-fibrin thrombi on heart valves and other endothelial surfaces may
be a relatively common event in persons with pre-existing cardiac
abnormalities and can also be induced by hemodynamic stress or by the
“chunks of junk” that traverse the veins of injecting drug users.
Microorganisms whose presence in the bloodstream would usually be a
transient phenomenon (for example, after a dental procedure) find in the
bland thrombi a privileged sanctuary to which host defenses have little or no
The diverse clinical manifestations of endocarditis reflect four phenomena.
(1) The continuous multiplication of microorganisms causes their constant
presence in the bloodstream in most instances. Fever and other constitutional
symptoms result, and highly virulent bacteria such as S. aureus can cause
severe sepsis progressing to septic shock. (2) Pieces of the vegetations can
break off and cause septic emboli to the lungs (in patients with right-sided
endocarditis) or to the brain, coronary arteries, kidneys, spleen, skin, and
other organs (in patients with left-sided endocarditis). (3) Antibodies made in
response to microorganisms in the bloodstream promote formation of
circulating antigen-antibody complexes (immune complexes) which can
cause disease manifestations such as arthritis, cerebritis, and
glomerulonephritis. (4) Destruction of heart valves, myocardium, and other
tissue can cause heart failure, which is now the most important cause of
death in certain types of endocarditis, or arrhythmias.
Viridans streptococci are the most common causes of endocarditis (30% to
40% of cases) and the usual cause when the disease originates from the oral
cavity, for example after dental surgery. The viridans streptococci are a
diverse group of bacteria. Streptococcus sanguis and S. mutans are the most
common in cases of endocarditis. Enterococci cause up to 18% of cases,
typically affecting young women with gynecologic or obstetrical problems
and older men with genitourinary problems. Streptococcus bovis, a group D
streptococcus that resides in the intestine, is an important cause of
endocarditis and is often associated with carcinoma or villous adenoma of the
colon. S. aureus causes up to 27% of cases of endocarditis. Coagulase-
negative staphylococci and fungi are usually found in patients with prosthetic
heart valves. Fastidious gram-negative bacteria collectively known as the
“HACEK group” occasionally cause a form of endocarditis that is not only
difficult to diagnose but also associated with large, bulky vegetations that can
cause embolic occlusion of large arteries. The acronym stands for
Haemophilus species, Actinobacillus actinomycetemcomitans,
Cardiobacterium hominis, Eikenella corrodens, and Kingella species.
Finally, numerous microorganisms occasionally cause endocarditis, such as
anaerobic bacteria, Coxiella burnetii (Q fever), and Chlamydia psittaci.
Although classification of endocarditis as “acute,” “subacute,” and “chronic”
has been largely abandoned in favor of the more general term “infective
endocarditis,” knowledge of the typical time frames associated with the
various pathogens remains useful. S. aureus typically causes “acute”
endocarditis. In younger patients, the characteristic triad consists of S. aureus
bacteremia, patchy bilateral pulmonary infiltrates, and evidence of injecting
drug use by history or by the presence of needle tracks. A murmur of
tricuspid or pulmonic regurgitation is sometimes present. In older patients,
the characteristic triad consists of S. aureus bacteremia, peripheral embolic
phenomena, and clinically-evident heart disease manifested by murmurs,
arrhythmias, or heart failure. When caused by destruction of a valve or
rupture of a papillary muscle, heart failure can progress rapidly. Viridans
streptococci are more commonly associated with a subacute course. When
first seen, patients have vague complaints that may suggest a “viral
syndrome.” If unrecognized, patients continue to have low-grade fever and
malaise punctuated by such events as transient cerebral ischemic attack
(embolism to the CNS), transient left upper quadrant pain (embolism to the
spleen), and hematuria (embolism to the kidneys). Endocarditis caused by the
HACEK organisms or by fungi can follow a more indolent course; embolic
occlusion of a large artery sometimes brings the patient to medical attention.
Overall, about 90% of patients with endocarditis have fever, 85% have a
heart murmur, more than 50% manifest embolic phenomena if carefully
sought, and about 20% to 50% have mucocutaneous manifestations of one
kind or another. The latter include splinter hemorrhages, pustular purpura,
petechiae (typically found in the conjunctivae, buccal mucosa, palate, or
extremities, Janeway lesions (hemorrhagic, painless plaques usually found on
the palms or soles), and Osler nodes (small, painful, nodular lesions usually
found on the pads of the fingers or toes). Other manifestations include
progressive anemia, delirium, intracranial hemorrhage from mycotic
aneurysms, and renal failure.
Blood cultures are the key to early diagnosis of endocarditis. It is for this
reason that, when endocarditis is suspected or when patients have a cardiac
lesion that notably predisposes to endocarditis, blood cultures should be
obtained before antibiotics are administered. The recently introduced “Duke
criteria” take into account the emerging role of echocardiography, especially
transesophageal echocardiography (TEE), in the diagnosis of the disease.
When patients present with an acute illness and endocarditis due to S. aureus
is suspected, hospitalization is usually the best course. When endocarditis is
considered a possibility in the differential diagnosis of a subacute or chronic
illness, it is often more judicious to obtain blood cultures on an outpatient
basis while arranging for close follow-up. Occasional patients who are
eventually proven to have endocarditis present thorny diagnostic problems.
Streptococci with unusual growth requirements (“nutritionally-deficient
streptococci,” now known as Abiotrophia species), HACEK organisms,
Brucella species, fungi, Coxiella burnetii, and other diverse microorganisms
are associated with so-called “culture-negative endocarditis”. Diagnosis of
these cases usually requires referral or close consultation with a good