Infectious Disease and Microbiology - Whipple’s Disease

Basics

Description

Whipple’s disease is a rare, chronic, multisystem infection caused by Tropheryma whipplei. The disease classically affects the small intestine but can involve many organs, including the joints, central nervous system, heart, lungs, liver, kidneys, and lymphatic system.

Typical manifestations include:

• Weight loss
• Chronic diarrhea
• Malabsorption
• Abdominal pain
• Lymphadenopathy
• Migratory arthralgia or arthritis
• Neurologic abnormalities

Untreated disease can be fatal, particularly when the central nervous system or heart is involved.

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Epidemiology

Whipple’s disease is very uncommon.

Only a relatively small number of clinically recognized cases have been reported worldwide, with most cases described in:

• Western Europe
• North America

The disease most often affects:

• Middle-aged adults
• Men much more commonly than women
• Historically, white European populations

Exposure to T. whipplei appears to be much more common than actual Whipple’s disease, suggesting that host immune factors contribute strongly to disease development.

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Risk Factors

Important associations include:

• Male sex
• Middle age
• Possible occupational or environmental exposure to sewage or wastewater
• Certain abnormalities in cell-mediated immune responses
• Immunosuppressive therapy

Symptoms may worsen dramatically after treatment with:

• Corticosteroids
• Other immunosuppressive agents

This can occur when Whipple’s disease has been mistaken for an inflammatory or rheumatologic disorder.

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Genetics

Certain host genetic factors have been investigated, including associations with specific HLA patterns.

Older literature described an association with HLA-B27, although no single genetic marker is sufficiently specific to diagnose or predict Whipple’s disease.

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Etiology

The causative organism is:

Tropheryma whipplei

It is:

• A gram-positive actinomycete-related bacterium
• Intracellular
• Non-acid-fast
• Detectable by periodic acid-Schiff staining in infected tissue

The organism can be found in several tissues, including:

• Small bowel
• Lymph nodes
• Heart valves
• Synovium
• Brain
• Liver
• Lungs
• Kidneys

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Pathophysiology

T. whipplei infects macrophages and accumulates within tissues.

In the small intestine, infected macrophages infiltrate the lamina propria and interfere with normal intestinal architecture and nutrient absorption.

This produces:

• Villous dysfunction
• Malabsorption
• Steatorrhea
• Weight loss
• Nutritional deficiencies

The organism can disseminate hematogenously or through lymphatic pathways to multiple organs.

A notable feature is that the tissue response may be relatively weak despite substantial organism burden.

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Clinical Course

Whipple’s disease often evolves through two broad phases.

Prodromal Phase

This stage may last for years.

The most characteristic early symptoms are:

• Migratory arthralgias
• Intermittent arthritis

Joint symptoms often precede gastrointestinal symptoms by several years.

The arthritis is typically:

• Migratory
• Episodic
• Nondestructive
• Seronegative

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Established Systemic Disease

Later, patients may develop:

• Weight loss
• Chronic diarrhea
• Steatorrhea
• Abdominal pain
• Fever
• Lymphadenopathy
• Neurologic disease
• Cardiac involvement

The interval between early joint symptoms and overt gastrointestinal disease may be several years.

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Gastrointestinal Manifestations

Classic gastrointestinal features include:

• Chronic diarrhea
• Steatorrhea
• Abdominal pain
• Abdominal distention
• Weight loss
• Malabsorption

Occult gastrointestinal blood loss may occur.

Frank hematochezia is uncommon.

Consequences of malabsorption may include:

• Anemia
• Vitamin deficiencies
• Hypoalbuminemia
• Coagulopathy from vitamin K deficiency
• Muscle wasting

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Musculoskeletal Manifestations

Joint disease is one of the most important early clues.

Typical features include:

• Migratory arthralgia
• Intermittent arthritis
• Large-joint involvement
• Nondestructive course

Joint symptoms may precede intestinal disease by years.

This pattern can lead to misdiagnosis as:

• Rheumatoid arthritis
• Reactive arthritis
• Other inflammatory arthritides

Immunosuppressive therapy given for an incorrect rheumatologic diagnosis may accelerate progression.

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Constitutional Features

Patients may develop:

• Fever
• Fatigue
• Malaise
• Cachexia
• Muscle wasting

Hypotension may occur in advanced disease.

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Lymphatic and Reticuloendothelial Manifestations

Possible findings include:

• Peripheral lymphadenopathy
• Abdominal lymphadenopathy
• Hepatomegaly
• Splenomegaly

Lymph nodes are often enlarged but not necessarily painful.

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Skin Manifestations

Skin hyperpigmentation may occur.

This can be related to:

• Chronic illness
• Nutritional abnormalities
• Adrenal dysfunction

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Neurologic Involvement

Central nervous system involvement is particularly important because it worsens prognosis and increases relapse risk.

Neurologic manifestations may include:

• Cognitive impairment
• Dementia
• Personality change
• Depression
• Confusion
• Cerebellar ataxia
• Seizures
• Nystagmus
• Myoclonus
• Supranuclear ophthalmoplegia

Hypothalamic involvement may produce:

• Polydipsia
• Hyperphagia
• Decreased libido
• Amenorrhea
• Sleep abnormalities

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Characteristic Neurologic Signs

A particularly characteristic but uncommon feature is:

Oculomasticatory myorhythmia

This consists of rhythmic eye movements accompanied by synchronous movements of the jaw or facial muscles.

When present, it is highly suggestive of CNS Whipple’s disease.

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Ocular Manifestations

Possible ocular findings include:

• Uveitis
• Retinitis
• Ophthalmoplegia
• Nystagmus

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Cardiac Manifestations

Cardiac involvement may include:

• Endocarditis
• Pericarditis
• Myocarditis
• Valvular disease

T. whipplei is an important cause of:

Culture-negative endocarditis

Importantly, Whipple endocarditis may occur without obvious:

• Diarrhea
• Weight loss
• Classic intestinal manifestations

Patients may present only with:

• Heart murmur
• Embolic events
• Heart failure
• Constitutional symptoms

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Pulmonary Manifestations

Possible respiratory manifestations include:

• Dyspnea
• Pleural effusion
• Pulmonary infiltrates

These findings are usually nonspecific.

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Adrenal and Endocrine Manifestations

Adrenal involvement may produce features of adrenal insufficiency.

Possible findings include:

• Hypotension
• Hyperpigmentation
• Weakness
• Electrolyte abnormalities

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Physical Examination

Possible examination findings include:

• Cachexia
• Muscle wasting
• Abdominal distention
• Ascites
• Hepatomegaly
• Splenomegaly
• Peripheral lymphadenopathy
• Hyperpigmentation
• Cardiac murmur
• Neurologic deficits

Oral nutritional abnormalities may include:

• Glossitis
• Angular cheilitis

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Diagnosis

Diagnosis requires a combination of:

• Clinical suspicion
• Histopathology
• Molecular testing

The classic diagnostic approach is:

Small-bowel biopsy showing PAS-positive macrophages

with confirmation by:

PCR for T. whipplei

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Laboratory Findings

Possible laboratory abnormalities include:

• Anemia
• Leukocytosis
• Lymphopenia
• Thrombocytosis
• Elevated inflammatory markers
• Hypoalbuminemia
• Prolonged prothrombin time
• Nutritional deficiencies

Prolonged PT may result from:

Vitamin K malabsorption

Eosinophilia may occasionally occur but is not a characteristic finding.

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Cerebrospinal Fluid

In CNS disease, CSF may demonstrate:

• Pleocytosis
• Elevated protein

However, routine CSF findings are nonspecific.

PCR of CSF for T. whipplei is much more important when neurologic disease is suspected.

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Small-Bowel Biopsy

Upper gastrointestinal endoscopy with multiple duodenal or jejunal biopsies is a classic diagnostic procedure.

Histology typically demonstrates:

Foamy macrophages within the lamina propria containing PAS-positive material

Multiple biopsies should be obtained because involvement can be patchy.

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Histopathology

The hallmark finding is:

PAS-positive macrophages in the lamina propria

The macrophages contain magenta-staining intracellular material derived from the organism.

Additional confirmation with:

• Immunohistochemistry
• PCR

helps distinguish Whipple’s disease from other conditions with PAS-positive macrophages.

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PCR

PCR is highly useful for detecting T. whipplei DNA.

Samples may include:

• Small-bowel tissue
• Lymph-node tissue
• Synovial tissue
• Cardiac valve tissue
• CSF
• Blood

Saliva and stool PCR may also detect the organism.

However:

Positive saliva or stool PCR alone does not establish Whipple’s disease

because asymptomatic carriage can occur.

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CNS Testing

When CNS involvement is suspected:

CSF PCR should be performed

even if neurologic symptoms are subtle.

CNS infection may persist despite apparent gastrointestinal improvement.

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Culture

T. whipplei can be cultured in specialized laboratories.

However:

• Growth is slow
• Culture is technically difficult
• It is not routinely required for diagnosis

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Serology

Serologic testing is generally not useful for routine diagnosis.

Antibody responses may be unreliable and can occur in asymptomatic carriers.

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Imaging

Imaging findings are usually nonspecific.

Possible studies include:

Chest radiography

May show:

• Pleural effusion
• Nonspecific pulmonary abnormalities

Abdominal CT

May demonstrate:

• Mesenteric lymphadenopathy
• Bowel-wall abnormalities
• Ascites

Brain MRI

May show nonspecific abnormalities on:

• T1
• T2
• FLAIR sequences

Imaging cannot reliably establish the diagnosis.

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Differential Diagnosis

Whipple’s disease can mimic numerous gastrointestinal, infectious, rheumatologic, and neurologic disorders.

Important differentials include:

• Celiac disease
• Inflammatory bowel disease
• Small-bowel lymphoma
• Sarcoidosis
• Mycobacterial infection
• HIV enteropathy
• Reactive arthritis
• Autoimmune disease
• Familial Mediterranean fever
• Infective endocarditis
• Hyperthyroidism
• Neurosarcoidosis
• Neurosyphilis
• Neurodegenerative disease

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Whipple’s Disease vs Mycobacterium avium Complex

Both conditions can show macrophage infiltration of the small intestine.

However:

Whipple’s disease

→ PAS-positive macrophages

→ Acid-fast stain negative

Mycobacterium avium complex

→ Acid-fast organisms present

This is a useful diagnostic distinction.

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Treatment Principles

Whipple’s disease requires prolonged antimicrobial therapy because the organism:

• Disseminates widely
• Can involve the CNS
• May persist intracellularly
• Can relapse years after treatment

Therapy should include agents with:

Good CNS penetration

even when neurologic symptoms are absent.

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Initial Treatment

A commonly used approach begins with a CNS-penetrating intravenous antibiotic for approximately 2 weeks.

Options may include:

• Ceftriaxone
• Meropenem

The purpose is to rapidly reduce systemic and CNS organism burden.

More prolonged initial IV treatment may be considered for:

• Endocarditis
• CNS disease
• Relapse
• Severe disseminated infection

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Long-Term Treatment

After induction therapy, prolonged oral treatment is required.

Historically, trimethoprim-sulfamethoxazole was widely used.

However, contemporary practice increasingly favors regimens such as:

Doxycycline plus hydroxychloroquine

for prolonged therapy because of concerns regarding intrinsic or acquired resistance patterns and relapse with trimethoprim-sulfamethoxazole.

Treatment often continues for approximately:

12 months or longer

depending on disease site and response.

Specialist infectious-disease management is strongly recommended.

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Doxycycline Plus Hydroxychloroquine

A commonly used oral combination is:

• Doxycycline
• Hydroxychloroquine

Hydroxychloroquine alkalinizes the phagolysosome and improves the activity of doxycycline against intracellular T. whipplei.

Long courses are required.

Monitoring is necessary for hydroxychloroquine toxicity, particularly:

• Retinal toxicity
• Cardiac effects in selected patients

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CNS Disease

Neurologic Whipple’s disease requires especially aggressive and prolonged treatment.

Important considerations include:

• CNS-penetrating induction therapy
• Long-term antimicrobial treatment
• Serial neurologic evaluation
• CSF PCR monitoring in selected cases

Relapse may occur years later.

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Endocarditis

Whipple endocarditis should be treated with prolonged antimicrobial therapy.

Valve replacement may be necessary if there is:

• Severe valve destruction
• Heart failure
• Persistent infection
• Major hemodynamic compromise

Not every case automatically requires valve surgery; management depends on standard endocarditis surgical indications.

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Corticosteroids

Corticosteroids are generally not routine treatment for Whipple’s disease.

They may occasionally be considered in selected severe inflammatory complications under specialist supervision.

Unrecognized Whipple’s disease can worsen substantially when immunosuppressive therapy is administered without effective antimicrobial treatment.

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Immune Reconstitution Inflammatory Syndrome

After antimicrobial therapy begins, some patients develop paradoxical inflammatory worsening.

This may present with:

• High fever
• New inflammatory lesions
• Clinical deterioration despite microbiologic treatment

This resembles an immune reconstitution inflammatory syndrome.

It appears particularly in patients with neurologic involvement or prior immunosuppression.

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Jarisch-Herxheimer-Like Reaction

A transient inflammatory reaction has occasionally been described shortly after antibiotic initiation.

Possible manifestations include:

• Fever
• Chills
• Clinical worsening

Careful observation is appropriate, particularly during initial therapy.

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Follow-Up

Long-term follow-up is essential.

Monitoring should include:

• Weight
• Gastrointestinal symptoms
• Neurologic status
• Joint symptoms
• Cardiac findings
• Nutritional status

PCR may help assess treatment response in selected cases.

Histologic abnormalities can persist after successful therapy, so persistent PAS-positive macrophages do not always indicate active infection.

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Relapse

Relapse is a major concern.

It may occur:

• Months later
• Years later
• Even after apparently successful treatment

Relapse commonly involves:

The central nervous system

Therefore new neurologic symptoms in a previously treated patient should prompt urgent investigation.

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Diet and Nutritional Support

No specific diet treats Whipple’s disease.

However, malabsorption may require replacement of:

• Fat-soluble vitamins
• Iron
• Folate
• Vitamin B12
• Electrolytes
• Protein and calories

Nutritional rehabilitation is important in severely wasted patients.

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Prognosis

With appropriate diagnosis and prolonged antimicrobial treatment, prognosis is generally favorable.

Without treatment, the disease is ultimately fatal.

Poorer outcomes are associated with:

• CNS involvement
• Delayed diagnosis
• Severe cardiac disease
• Relapse
• Inappropriate immunosuppression

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Complications

Important complications include:

• Severe malabsorption
• Cachexia
• Vitamin deficiencies
• Neurologic deterioration
• Dementia
• Seizures
• Ophthalmoplegia
• Culture-negative endocarditis
• Heart failure
• Pericarditis
• Myocarditis
• Relapse

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High-Yield Clinical Pattern

Years of migratory arthralgia followed by weight loss and chronic diarrhea

→ Think Whipple’s disease

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High-Yield Diagnostic Pattern

Small-bowel biopsy + PAS-positive foamy macrophages

→ Strongly suggestive of Whipple’s disease

Confirmation:

→ T. whipplei PCR

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High-Yield Cardiac Pattern

Culture-negative endocarditis + negative routine cultures + systemic or arthritic history

→ Consider Tropheryma whipplei

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High-Yield Neurologic Pattern

Cognitive decline + ophthalmoplegia + myoclonus in systemic Whipple’s disease

→ CNS involvement

Characteristic finding:

→ Oculomasticatory myorhythmia

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Exam Essentials

Causative organism:

→ Tropheryma whipplei

Organism type:

→ Actinomycete-related gram-positive bacterium

Classic patient:

→ Middle-aged man

Classic early manifestation:

→ Migratory arthralgia/arthritis

Classic later manifestations:

→ Weight loss + diarrhea + malabsorption

Classic biopsy:

→ PAS-positive macrophages in small-bowel lamina propria

Acid-fast stain:

→ Negative

Confirmatory test:

→ PCR for T. whipplei

Important cardiac manifestation:

→ Culture-negative endocarditis

Important neurologic complication:

→ CNS Whipple’s disease

Characteristic neurologic sign:

→ Oculomasticatory myorhythmia

Treatment principle:

→ Initial CNS-penetrating antibiotics followed by prolonged oral therapy

Important clinical warning:

→ Immunosuppressive therapy can markedly worsen undiagnosed disease

Major long-term concern:

→ Relapse, particularly in the CNS

Infectious Disease and Microbiology - Warts

Basics

Description

Warts, or verrucae, are benign proliferative lesions of the skin or mucous membranes caused by human papillomavirus (HPV) infection.

Transmission occurs through:

• Direct skin-to-skin contact
• Sexual contact
• Contact with contaminated surfaces or objects
• Autoinoculation from one body site to another

Warts may be broadly divided into:

• Cutaneous warts
• Anogenital warts
• Respiratory papillomatosis

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Epidemiology

Warts are common and affect roughly 7–10% of the population.

Cutaneous warts are seen most often in:

• Children
• Adolescents
• Young adults

They are especially common among people who regularly handle:

• Meat
• Poultry
• Fish

because repeated minor trauma facilitates viral inoculation.

Anogenital HPV infection is among the most common sexually transmitted infections worldwide.

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Risk Factors

Important risk factors include:

• Repeated skin trauma
• Meat, poultry, or fish handling
• Atopic dermatitis
• Immunosuppression
• Defects in cell-mediated immunity
• Unprotected sexual contact
• Multiple sexual partners
• Men who have sex with men
• Contact with a partner who has anogenital HPV infection

Immunocompromised patients may develop:

• Numerous lesions
• Larger lesions
• Refractory lesions
• More frequent recurrence

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Etiology

Warts are caused by human papillomaviruses, a large group of double-stranded DNA viruses with tropism for squamous epithelium.

There are more than 200 recognized HPV types.

Important associations include:

HPV 6 and 11

→ Cause most genital warts

HPV 16 and 18

→ High-risk oncogenic types strongly associated with:

• Cervical cancer
• Anal cancer
• Penile cancer
• Vulvar cancer
• Vaginal cancer
• Oropharyngeal cancer

Genital warts themselves are usually caused by low-risk HPV types, particularly 6 and 11.

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Pathophysiology

HPV gains entry through microscopic breaks in the skin or mucosa.

It infects basal keratinocytes and induces epithelial proliferation.

As infected cells migrate toward the surface, viral replication increases and produces the characteristic wart architecture.

Warts may persist for months or years, but immune recognition can eventually cause spontaneous regression.

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General Prevention

Prevention includes:

• Avoiding direct contact with visible warts
• Avoiding picking, scratching, or shaving over warts
• Wearing footwear in communal showers and pool areas
• Avoiding sharing razors or personal items
• Practicing safer sex
• Using condoms, while recognizing that condoms do not completely prevent HPV transmission because uncovered skin may remain infectious
• HPV vaccination

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HPV Vaccination

Modern HPV vaccination is one of the most important preventive measures.

The currently used vaccine in many countries is the 9-valent HPV vaccine, which protects against HPV types:

• 6
• 11
• 16
• 18
• 31
• 33
• 45
• 52
• 58

It protects against both:

• Genital warts
• HPV-associated cancers

Vaccination is most effective when given before exposure to HPV.

Routine vaccination is generally recommended beginning in early adolescence, with catch-up vaccination also recommended for older adolescents and young adults according to national guidelines.

Vaccination prevents new infection but does not treat existing warts or established HPV infection.

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Pregnancy Considerations for Vaccination

HPV vaccine is not a live vaccine.

However, routine administration during pregnancy is generally deferred.

If a dose is given inadvertently during pregnancy, this is not considered an indication for pregnancy termination.

Remaining doses can usually be completed after pregnancy.

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Clinical Types

Common Warts

Common warts, or verruca vulgaris, typically appear as:

• Firm papules
• Hyperkeratotic surface
• Rough or cauliflower-like texture

Common locations include:

• Hands
• Fingers
• Elbows
• Knees
• Periungual areas

They may occur anywhere.

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Plantar Warts

Plantar warts occur on the soles of the feet.

Typical features include:

• Pain with pressure
• Thickened keratotic surface
• Disruption of normal skin lines
• Small thrombosed capillaries appearing as black dots
• Pinpoint bleeding when pared

They may be confused with calluses.

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Flat Warts

Flat or juvenile warts are typically:

• Small
• Smooth
• Flat-topped
• Multiple

They are commonly seen on:

• Face
• Hands
• Shins

They are especially common in children and adolescents.

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Filiform Warts

Filiform warts are:

• Thin
• Finger-like
• Pedunculated

They often occur on:

• Face
• Eyelids
• Lips
• Neck

Because cosmetic outcome matters, treatment should minimize scarring.

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Anogenital Warts

Anogenital warts are also called:

Condylomata acuminata

They may appear as:

• Small papules
• Papillary lesions
• Pedunculated growths
• Large cauliflower-like masses

Possible sites include:

• Vulva
• Vagina
• Cervix
• Penis
• Scrotum
• Perineum
• Perianal region
• Anal canal
• Urethral meatus

Most are caused by HPV 6 and 11.

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Cervical HPV Infection

Cervical HPV infection may produce:

• No visible lesion
• Low-grade squamous intraepithelial lesion
• High-grade squamous intraepithelial lesion
• Cervical intraepithelial neoplasia

Persistent infection with high-risk HPV types is the major cause of cervical cancer.

The presence of external genital warts does not by itself imply cervical cancer.

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Respiratory Papillomatosis

Recurrent respiratory papillomatosis is usually associated with HPV 6 and 11.

It is most often seen in children but can also occur in adults.

Possible manifestations include:

• Hoarseness
• Chronic voice change
• Stridor
• Respiratory distress
• Upper-airway obstruction

Lesions most commonly involve the larynx and may recur repeatedly.

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Diagnosis

Most warts are diagnosed clinically from their characteristic appearance.

Routine laboratory testing is usually unnecessary.

Important questions include:

• Duration
• Number of lesions
• Prior treatment
• Immunosuppression
• Sexual history for anogenital lesions
• Rapid growth
• Bleeding
• Ulceration
• Pain
• Failure to respond to treatment

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Biopsy

Biopsy should be considered when a lesion is:

• Atypical
• Pigmented
• Ulcerated
• Indurated
• Rapidly growing
• Bleeding spontaneously
• Large
• Refractory to therapy

It is also particularly useful in:

• Immunocompromised patients
• Patients in whom malignancy cannot be excluded

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HPV Testing

HPV typing is not routinely used to diagnose ordinary cutaneous or genital warts.

Molecular tests are primarily used in cervical cancer screening and selected anogenital disease evaluation.

Methods may include:

• PCR
• Nucleic acid hybridization
• Other molecular assays

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Acetic Acid Testing

Dilute acetic acid may cause HPV-infected epithelium to become white.

This is known as:

Acetowhitening

However, the finding is nonspecific and should not be used alone to diagnose HPV infection.

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Histopathology

Typical histologic findings include:

• Papillomatosis
• Acanthosis
• Hyperkeratosis
• Parakeratosis

Koilocytes may be present, particularly in genital lesions.

A koilocyte is a squamous epithelial cell with:

• Perinuclear clearing
• Nuclear enlargement
• Nuclear irregularity

It reflects HPV-related cytopathic change.

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Differential Diagnosis

Cutaneous warts may resemble:

• Callus
• Corn
• Seborrheic keratosis
• Actinic keratosis
• Molluscum contagiosum
• Squamous cell carcinoma
• Other keratinizing skin tumors

Anogenital lesions may resemble:

• Molluscum contagiosum
• Condylomata lata of secondary syphilis
• Skin tags
• Pearly penile papules
• Vestibular papillomatosis
• Squamous neoplasia

Atypical anogenital lesions should be assessed carefully before destructive treatment.

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Natural History

Many warts resolve spontaneously.

In immunocompetent children, a substantial proportion disappear within:

• 1 year
• 2 years

Spontaneous regression reflects development of effective cell-mediated immunity.

Anogenital warts can also regress without treatment.

However, treatment may be desired because of:

• Pain
• Bleeding
• Irritation
• Cosmetic concerns
• Sexual transmission concerns
• Functional interference
• Psychological distress

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Treatment Principles

No treatment guarantees eradication of latent HPV infection.

Most therapies remove visible lesions rather than eliminate all infected cells.

Therefore:

Recurrence is common

Treatment is individualized according to:

• Wart type
• Location
• Number
• Size
• Patient age
• Pregnancy
• Immune status
• Cosmetic considerations
• Patient preference

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Cutaneous Warts

Salicylic Acid

Salicylic acid is one of the most commonly used first-line treatments for cutaneous warts.

It works by:

• Keratolysis
• Gradual removal of infected epithelium

Treatment usually requires repeated application for several weeks.

Before application:

• Soak the wart
• Pare excess keratin if appropriate
• Apply the preparation carefully to the lesion

This is particularly useful for:

• Common warts
• Plantar warts
• Palmar warts

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Cryotherapy

Cryotherapy with liquid nitrogen is another standard treatment.

It causes tissue destruction through freezing.

It is commonly used for:

• Common warts
• Plantar warts
• Genital warts

Treatment may be repeated every few weeks.

Adverse effects include:

• Pain
• Blistering
• Erosion
• Temporary pigment changes
• Hypopigmentation
• Hyperpigmentation
• Rare scarring

Pigment alteration is particularly relevant in darker skin.

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Pediatric Considerations

For younger children, salicylic acid is often favored because cryotherapy can be painful.

Treatment is generally unnecessary if:

• Lesions are asymptomatic
• They are not spreading rapidly
• Cosmetic concerns are minimal

Spontaneous resolution is common.

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Flat Warts

Possible treatments include:

• Topical retinoids
• Selected keratolytic therapy
• Cryotherapy in carefully selected lesions

Treatment on the face should be conservative because of the risk of:

• Scarring
• Pigment alteration

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Recalcitrant Cutaneous Warts

For persistent lesions, options may include:

• Intralesional immunotherapy
• Curettage
• Electrosurgery
• Laser therapy
• Selected topical immune-modifying therapies

Management is often best individualized by dermatology.

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Treatment of External Anogenital Warts

Treatment may be:

Patient-applied

or

Clinician-administered

Choice depends on the lesion and patient preference.

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Imiquimod

Imiquimod is a topical immune-response modifier.

It can be used for external anogenital warts.

It promotes local cytokine production and antiviral immune activity.

Potential adverse effects include:

• Erythema
• Burning
• Erosion
• Local irritation

Treatment may require several weeks.

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Podofilox

Podofilox, also called podophyllotoxin, is a patient-applied antimitotic treatment for external genital warts.

It causes local tissue necrosis.

It should not be used:

• Internally
• During pregnancy

Patients should receive careful instructions to avoid application to normal surrounding skin.

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Trichloroacetic Acid

Trichloroacetic acid, or TCA, is a clinician-applied chemical destructive therapy.

It may be used for:

• External genital warts
• Vaginal lesions
• Selected anal lesions

The solution is applied directly to the wart until a white frost develops.

Possible adverse effects include:

• Burning
• Pain
• Ulceration if excessive amounts are applied

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Cryotherapy for Anogenital Warts

Liquid nitrogen cryotherapy is effective for external genital warts.

Advantages include:

• Rapid lesion destruction
• No systemic drug exposure
• Use during pregnancy when needed

Repeated treatments may be required.

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Surgical Treatment

Surgical approaches are useful for:

• Large lesions
• Extensive lesions
• Refractory disease
• Lesions requiring immediate removal

Methods include:

• Scissor excision
• Curettage
• Electrosurgery
• Laser ablation

Potential disadvantages include:

• Pain
• Scarring
• Need for anesthesia
• Recurrence

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Anal Warts

External perianal warts can be managed similarly to other external genital warts.

Patients with lesions involving the anal canal should generally undergo expert evaluation because internal disease may require:

• Anoscopy
• Biopsy
• Specialist treatment

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Cervical Warts

Visible cervical lesions require specialist evaluation.

Before destructive treatment, it is important to exclude:

• High-grade squamous intraepithelial lesions
• Cervical malignancy

Management should follow cervical screening and colposcopy guidelines.

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Vaginal Warts

Potential treatments include:

• Cryotherapy
• TCA
• Surgical approaches when needed

Treatment should be performed carefully to avoid injury to surrounding mucosa.

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Urethral Meatus Warts

Small external lesions may be treated with:

• Cryotherapy
• Other specialist-directed destructive techniques

Warts extending into the urethra may require urologic evaluation.

⸻

Oral Warts

Oral HPV lesions do not always require treatment.

Treatment may be considered when lesions are:

• Painful
• Traumatized
• Growing
• Functionally problematic
• Cosmetically concerning

Options include:

• Excision
• Cryotherapy
• Electrosurgery
• Laser therapy

Persistent oral lesions should be examined carefully to exclude neoplasia.

⸻

Respiratory Papillomatosis Treatment

Recurrent respiratory papillomatosis is usually managed by otolaryngology.

Treatment may include:

• Endoscopic debulking
• Laser therapy
• Microdebrider techniques
• Selected intralesional or systemic adjunctive therapies

Repeated procedures are often necessary because recurrence is common.

Airway obstruction can be life-threatening.

⸻

Partner Management

Sex partners of patients with genital warts do not require treatment unless they have visible lesions.

However, partners may benefit from:

• STI screening
• HPV education
• Vaccination if eligible
• Counseling about transmission

Condoms reduce but do not eliminate HPV transmission.

⸻

Follow-Up

Follow-up depends on:

• Lesion type
• Treatment used
• Immune status
• Recurrence

Patients with genital warts should continue routine cervical cancer screening according to age and national recommendations.

Having external genital warts does not automatically require more frequent cervical screening than otherwise indicated.

⸻

Prognosis

The prognosis is generally excellent.

Many cutaneous warts resolve spontaneously.

Treatment often works but recurrence is common because:

• HPV may persist in surrounding clinically normal tissue
• Latent infection can reactivate

Recurrence does not necessarily represent reinfection.

⸻

Complications

Possible complications include:

• Pain
• Bleeding
• Secondary bacterial infection
• Cosmetic disfigurement
• Recurrence
• Extensive disease in immunosuppressed patients

High-risk HPV infection can lead to:

• Cervical intraepithelial neoplasia
• Cervical cancer
• Anal cancer
• Penile cancer
• Vulvar and vaginal cancer
• Oropharyngeal cancer

Genital warts caused by HPV 6 and 11 themselves are generally not considered precancerous lesions.

⸻

Pregnancy

Genital warts may enlarge during pregnancy because of:

• Hormonal changes
• Increased vascularity
• Altered immunity

They may also become:

• More friable
• More prone to bleeding

Treatment options that can be used during pregnancy include selected clinician-administered therapies such as:

• Cryotherapy
• TCA

Agents such as podofilox should be avoided.

Cesarean delivery is not routinely performed solely to prevent neonatal HPV transmission. It may be considered when massive genital lesions obstruct the birth canal or would cause excessive bleeding during vaginal delivery.

⸻

High-Yield Comparison

Common wart

→ Rough hyperkeratotic papule

→ Usually hands and fingers

Plantar wart

→ Sole of foot

→ Painful

→ Black thrombosed capillary dots

Flat wart

→ Smooth, flat-topped papules

→ Often multiple

Genital wart

→ Condyloma acuminatum

→ Usually HPV 6 or 11

High-risk oncogenic HPV

→ HPV 16 and 18 among the most important types

Respiratory papillomatosis

→ Usually HPV 6 and 11

→ Hoarseness/stridor

⸻

High-Yield Clinical Approach

Child with rough papules on fingers

→ Common warts

Painful lesion on sole + black dots

→ Plantar wart

Multiple smooth facial papules in adolescent

→ Flat warts

Cauliflower-like genital lesions

→ Condylomata acuminata

Genital wart + atypical pigmentation/ulceration

→ Biopsy before routine destructive therapy

Immunocompromised patient + extensive refractory warts

→ Consider specialist evaluation and biopsy of atypical lesions

Hoarseness + recurrent laryngeal papillomas in child

→ Recurrent respiratory papillomatosis

⸻

Exam Essentials

Cause of warts:

→ Human papillomavirus

Virus type:

→ Double-stranded DNA virus

Most common genital-wart types:

→ HPV 6 and 11

Major oncogenic types:

→ HPV 16 and 18

Classic plantar-wart clue:

→ Thrombosed capillaries/black dots

First-line treatment for many cutaneous warts:

→ Salicylic acid or cryotherapy

Common patient-applied genital-wart therapies:

→ Imiquimod or podofilox

Clinician-applied genital-wart therapies:

→ Cryotherapy or TCA

Genital warts are usually caused by:

→ Low-risk HPV

HPV vaccine treats existing warts:

→ No

HPV vaccination prevents:

→ New infection with vaccine-covered HPV types

Best prevention of HPV-associated cancer:

→ Vaccination plus appropriate screening

Recurrence after treatment:

→ Common

External genital warts mean cervical cancer is present:

→ No

Infectious Disease and Microbiology - Viral Hepatitis

Basics

Description

Viral hepatitis refers to inflammation and injury of the liver caused by hepatotropic viruses, particularly hepatitis A, B, C, D, and E viruses.

Disease may be:

• Acute and self-limited
• Chronic and progressive
• Fulminant, with massive hepatic necrosis and acute liver failure

The likelihood of chronic infection varies greatly by virus. HAV and HEV usually cause acute disease only, whereas HBV, HCV, and HDV may cause chronic infection.

Fulminant hepatitis is characterized by severe hepatic necrosis with rapid development of liver failure, coagulopathy, and encephalopathy.

⸻

Major Hepatitis Viruses

The principal hepatotropic viruses are:

• Hepatitis A virus (HAV)
• Hepatitis B virus (HBV)
• Hepatitis C virus (HCV)
• Hepatitis D virus (HDV)
• Hepatitis E virus (HEV)

Hepatitis G virus has historically been described, but it is not considered a major cause of clinically significant chronic hepatitis.

Other viruses that can cause hepatitis include:

• Epstein-Barr virus
• Cytomegalovirus
• Herpes simplex virus
• HIV
• Adenovirus
• Measles virus
• Enteroviruses

⸻

Epidemiology

Hepatitis A

HAV has a worldwide distribution.

Transmission is predominantly:

Fecal-oral

Common sources include:

• Contaminated food
• Contaminated water
• Close household contact
• Outbreaks in congregate settings

Sexual transmission, particularly with oral-anal exposure, may also occur.

Chronic infection does not occur.

⸻

Hepatitis B

HBV remains a major global infection.

Major routes of transmission include:

• Blood exposure
• Sexual transmission
• Injection drug use
• Needlestick exposure
• Perinatal transmission
• Vertical transmission
• Contaminated blood products where screening is inadequate

The probability of chronic infection is strongly related to age at acquisition.

Neonatal or perinatal infection

→ Very high risk of chronicity

Adult-acquired infection

→ Most immunocompetent adults clear the infection spontaneously

This age-dependent difference is one of the most important features of HBV infection.

⸻

Hepatitis C

HCV is predominantly a blood-borne infection.

Important routes include:

• Injection drug use
• Shared injection equipment
• Needlestick injuries
• Unscreened blood transfusion
• Organ transplantation from an infected donor
• Perinatal transmission
• Sexual transmission, although less efficient than with HBV

Without treatment, chronic infection develops in a substantial proportion of infected individuals.

⸻

Hepatitis D

HDV is a defective RNA virus that requires hepatitis B surface antigen (HBsAg) for its life cycle.

Therefore:

No HBV → no HDV infection

HDV occurs in two patterns:

Coinfection

HBV and HDV are acquired at the same time.

Superinfection

HDV infects a person who already has chronic HBV infection.

Superinfection is generally associated with more severe disease and a greater risk of chronic liver injury.

⸻

Hepatitis E

HEV resembles HAV epidemiologically.

Transmission is mainly:

Fecal-oral

Large outbreaks are especially associated with:

• Contaminated water
• Poor sanitation
• Developing regions

Most infections are acute and self-limited, although chronic HEV can occur in selected immunocompromised patients.

HEV deserves special attention during pregnancy because severe disease may occur, particularly later in gestation.

⸻

Risk Factors

Hepatitis A

Important risk factors include:

• Travel to areas with poor sanitation
• Household or close contact with an infected person
• Men who have sex with men
• Drug use
• Homelessness
• Occupational or institutional exposure in selected settings
• Contaminated food or water exposure

⸻

Hepatitis B

Important risk factors include:

• Unprotected sexual contact
• Multiple sexual partners
• Men who have sex with men
• Injection drug use
• Occupational blood exposure
• Hemodialysis
• Household exposure to chronic HBV
• Birth in or immigration from endemic regions
• Perinatal exposure
• Repeated blood-product exposure
• HIV infection

⸻

Hepatitis C

Major risk factors include:

• Injection drug use
• Sharing injection equipment
• Needlestick injury
• Blood transfusion before modern screening
• Hemodialysis
• HIV infection
• Tattoos or piercings performed with inadequately sterilized equipment
• Organ transplantation from an infected donor

Intranasal drug use may also pose risk when blood-contaminated equipment is shared.

⸻

Hepatitis D

Risk factors are essentially those of HBV because HDV depends on HBV infection.

⸻

Hepatitis E

Risk factors resemble HAV and include:

• Contaminated water
• Poor sanitation
• Travel to endemic areas

Zoonotic transmission can also occur in some regions.

⸻

Prevention

Hepatitis A Prevention

The most important strategies are:

• Handwashing
• Safe food handling
• Clean water
• Improved sanitation
• Vaccination

HAV vaccine is highly effective and is routinely used in many countries.

It is particularly important for:

• Travelers to endemic regions
• People with chronic liver disease
• Men who have sex with men
• People who use drugs
• Certain occupational or outbreak settings

Post-exposure prophylaxis may involve:

• HAV vaccination
• Immune globulin in selected high-risk individuals

The exact choice depends on age, immune status, liver disease, and timing of exposure.

⸻

Hepatitis B Prevention

HBV vaccination is one of the most effective preventive measures in infectious disease.

Vaccination is recommended broadly, including routine infant vaccination and vaccination of nonimmune adults.

Particularly important groups include:

• Healthcare workers
• Hemodialysis patients
• Injection drug users
• Sexual contacts of infected persons
• People with multiple sexual partners
• Travelers to endemic areas
• Household contacts of chronic HBV carriers

After a significant exposure in a nonimmune person, post-exposure prophylaxis may include:

• Hepatitis B immune globulin
• HBV vaccination

depending on vaccination status and the source patient.

⸻

Hepatitis C Prevention

There is currently no vaccine for HCV.

Prevention relies on:

• Avoiding shared needles
• Sterile injection practices
• Safe blood screening
• Avoiding shared razors or blood-contaminated personal items
• Appropriate occupational precautions
• Safer sex in higher-risk situations

⸻

Hepatitis D Prevention

There is no separate widely used HDV vaccine.

However:

HBV vaccination prevents HDV infection

because HDV cannot establish infection without HBV.

⸻

Hepatitis E Prevention

Prevention relies mainly on:

• Safe drinking water
• Sanitation
• Proper food handling
• Avoidance of contaminated water

An HEV vaccine exists in limited geographic availability but is not routinely available worldwide.

⸻

Etiology and Virology

HAV

HAV is:

• An RNA virus
• Non-enveloped
• A member of the Picornaviridae family

It does not cause chronic infection.

⸻

HBV

HBV is:

• A partially double-stranded DNA virus
• A member of the Hepadnaviridae family
• Enveloped

Important viral markers include:

• HBsAg
• Anti-HBs
• Anti-HBc
• HBeAg
• Anti-HBe
• HBV DNA

⸻

HCV

HCV is:

• An enveloped RNA virus
• A member of the Flaviviridae family

Multiple genotypes exist, although modern direct-acting antiviral therapy has reduced the practical importance of genotype in many treatment settings.

⸻

HDV

HDV is:

• A small RNA virus
• Dependent on HBsAg from HBV for its envelope

Therefore it can occur only in a patient infected with HBV.

⸻

HEV

HEV is:

• A non-enveloped RNA virus in blood
• Structurally quasi-enveloped during some phases of infection
• Classified within the Hepeviridae family

Most human disease is acute.

⸻

Pathophysiology

The liver injury in viral hepatitis is largely mediated by the host immune response to infected hepatocytes, rather than direct viral destruction alone.

Typical pathologic changes include:

• Lobular inflammation
• Mononuclear-cell infiltration
• Hepatocyte degeneration
• Hepatocyte necrosis
• Kupffer-cell hyperplasia
• Cholestasis

In severe disease, extensive hepatic necrosis can result in:

• Coagulopathy
• Hypoglycemia
• Encephalopathy
• Multiorgan dysfunction
• Acute liver failure

⸻

Clinical Presentation

The clinical manifestations of acute viral hepatitis are often similar regardless of the specific virus.

Many infections are asymptomatic or anicteric.

The illness may be divided into:

1. Prodromal phase
2. Icteric phase
3. Convalescent or posticteric phase

⸻

Prodromal Phase

The prodrome usually precedes jaundice by approximately several days to 1–2 weeks.

Symptoms may include:

• Fatigue
• Malaise
• Anorexia
• Nausea
• Vomiting
• Fever
• Headache
• Myalgias
• Arthralgias
• Altered taste
• Altered smell
• Cough
• Coryza

Some patients report aversion to cigarettes or certain foods.

⸻

Icteric Phase

As jaundice develops, some constitutional symptoms may improve.

Features may include:

• Jaundice
• Dark urine
• Pale stools
• Pruritus
• Right upper quadrant discomfort
• Hepatomegaly
• Tender liver

Not all patients become visibly jaundiced.

⸻

Physical Examination

Possible findings include:

• Jaundice
• Hepatomegaly
• Right upper quadrant tenderness
• Splenomegaly
• Cervical lymphadenopathy

Splenomegaly and lymphadenopathy occur in a minority of patients.

In severe disease, look for:

• Confusion
• Asterixis
• Bleeding
• Hypotension
• Signs of cerebral edema
• Evidence of acute liver failure

⸻

Incubation Periods

Approximate incubation periods are:

HAV

→ 15–50 days

HBV

→ Approximately 1–6 months

HCV

→ Approximately 2 weeks to 6 months

HDV

→ Depends on HBV coinfection or superinfection

HEV

→ Approximately 2–8 weeks

Incubation periods overlap and should not be used alone for diagnosis.

⸻

Laboratory Findings in Acute Viral Hepatitis

Common findings include:

• Markedly elevated ALT
• Markedly elevated AST
• Hyperbilirubinemia
• Mild alkaline phosphatase elevation
• Relative lymphocytosis
• Atypical lymphocytes
• Mild leukopenia early in illness

Aminotransferases may rise before jaundice appears.

In hepatocellular injury:

ALT and AST are usually disproportionately elevated compared with alkaline phosphatase.

⸻

Bilirubin

When jaundice develops, bilirubin may rise substantially.

Both conjugated and unconjugated fractions may increase, although conjugated hyperbilirubinemia is common in clinically significant hepatitis.

⸻

Prothrombin Time and INR

A prolonged:

PT/INR

is an important marker of impaired hepatic synthetic function.

This is especially important in acute hepatitis because a rising INR may signal:

Acute liver failure

Aminotransferase levels alone do not reliably indicate severity.

A falling ALT in a deteriorating patient can actually be ominous if it reflects massive hepatocyte loss.

⸻

Albumin

Albumin may remain relatively preserved in acute disease because of its long half-life.

Low albumin is more suggestive of:

• Chronic liver disease
• Prolonged severe illness
• Poor synthetic function

⸻

Hypoglycemia

Hypoglycemia can occur in severe or fulminant hepatitis because of impaired hepatic glucose regulation.

It is an important marker of severe disease.

⸻

Hepatitis A Diagnosis

The key test for acute HAV is:

IgM anti-HAV

This indicates recent or acute infection.

IgG anti-HAV

Indicates:

• Previous infection
• Vaccination
• Immunity

HAV does not cause chronic hepatitis.

⸻

Hepatitis B Serology

HBV serology is particularly important and frequently tested.

HBsAg

Hepatitis B surface antigen

Indicates current HBV infection.

It appears early after infection.

Persistence for more than 6 months supports chronic infection.

⸻

Anti-HBs

Antibody to hepatitis B surface antigen

Indicates immunity.

It can result from:

• Recovery from natural infection
• Vaccination

⸻

Anti-HBc

Antibody to hepatitis B core antigen

This indicates exposure to actual HBV infection.

It is not produced by vaccination alone.

IgM anti-HBc

Suggests:

• Acute infection
• Recent infection
• Sometimes an acute flare of chronic HBV

Total or IgG anti-HBc

Usually persists for life after natural infection.

⸻

HBV Window Period

An important examination concept is the window period.

During this period:

• HBsAg has disappeared
• Anti-HBs has not yet appeared

The key marker may therefore be:

IgM anti-HBc

⸻

HBeAg

HBeAg generally indicates:

• Active viral replication
• Higher infectivity

However, some HBV variants replicate actively without detectable HBeAg, so modern assessment relies heavily on:

HBV DNA

⸻

HBV DNA

HBV DNA measured by PCR reflects:

Viral replication

It is crucial for:

• Assessing disease activity
• Deciding treatment
• Monitoring response
• Evaluating transmission risk

⸻

High-Yield HBV Serologic Patterns

Vaccinated

HBsAg: negative

Anti-HBc: negative

Anti-HBs: positive

→ Immune from vaccination

⸻

Resolved natural infection

HBsAg: negative

Anti-HBc: positive

Anti-HBs: positive

→ Past infection, now immune

⸻

Acute HBV

HBsAg: positive

IgM anti-HBc: positive

Anti-HBs: negative

→ Acute infection

⸻

Chronic HBV

HBsAg: positive for >6 months

Anti-HBc: positive

Anti-HBs: negative

→ Chronic infection

⸻

Hepatitis C Diagnosis

Initial screening is usually performed with:

Anti-HCV antibody

However, anti-HCV indicates exposure and does not distinguish:

• Active infection
• Resolved infection
• Successfully treated infection

Therefore a positive antibody test must be followed by:

HCV RNA

to determine whether active infection is present.

⸻

HCV RNA

HCV RNA can become detectable very early after infection, before antibodies develop.

Therefore:

Recent exposure + negative antibody does not exclude acute HCV

HCV RNA should be checked if acute infection is suspected.

⸻

HCV Genotype

Genotyping historically played a major role in treatment selection.

With modern pan-genotypic direct-acting antiviral regimens, genotype is less important than it once was, although it may still influence management in selected situations.

⸻

Hepatitis D Diagnosis

Diagnosis may include:

• Anti-HDV antibodies
• HDV RNA

HDV RNA confirms active replication.

Because HDV requires HBV, patients should also undergo a complete HBV evaluation.

⸻

Hepatitis E Diagnosis

Testing may include:

• IgM anti-HEV
• HEV RNA

IgM anti-HEV supports recent infection.

HEV RNA is especially useful in:

• Immunocompromised patients
• Suspected chronic infection

⸻

Imaging

Ultrasound is not usually needed to diagnose uncomplicated viral hepatitis.

However, it may be useful to:

• Exclude biliary obstruction
• Evaluate liver morphology
• Assess portal or hepatic vessels
• Look for ascites
• Assess chronic liver disease

Doppler ultrasound may be added when vascular disease is a consideration.

⸻

Liver Biopsy

Liver biopsy is rarely required in straightforward acute viral hepatitis.

It may be considered when:

• Diagnosis is uncertain
• Autoimmune hepatitis is suspected
• Chronic hepatitis requires staging
• Another liver disease needs exclusion

Noninvasive fibrosis assessment has replaced biopsy for many chronic hepatitis patients.

⸻

Differential Diagnosis

The differential diagnosis of acute hepatitis includes:

• Drug-induced liver injury
• Acetaminophen toxicity
• Alcohol-associated hepatitis
• Autoimmune hepatitis
• Ischemic hepatitis
• Sepsis-associated liver injury
• Biliary obstruction
• Wilson disease
• EBV
• CMV
• HSV hepatitis
• Leptospirosis

Clinical context and targeted testing are essential.

⸻

Treatment of Hepatitis A

There is no specific antiviral therapy for uncomplicated HAV.

Treatment is supportive and includes:

• Hydration
• Adequate nutrition
• Antiemetics if needed
• Avoidance of hepatotoxic substances
• Monitoring for acute liver failure

Most patients recover completely.

⸻

Treatment of Acute Hepatitis B

Most immunocompetent adults with uncomplicated acute HBV recover spontaneously and do not require antiviral therapy.

Antiviral treatment is considered for:

• Severe acute hepatitis
• Protracted severe disease
• Acute liver failure

Potent nucleos(t)ide analogues such as:

• Tenofovir
• Entecavir

are generally preferred when antiviral treatment is indicated.

⸻

Treatment of Chronic Hepatitis B

Modern first-line oral agents generally include potent drugs with a high barrier to resistance, particularly:

• Tenofovir disoproxil fumarate
• Tenofovir alafenamide
• Entecavir

Pegylated interferon may be used in selected patients.

Older drugs such as lamivudine are used much less frequently because resistance develops readily.

The major goals are:

• Suppression of HBV DNA
• Prevention of cirrhosis
• Prevention of liver failure
• Reduction of hepatocellular carcinoma risk
• HBeAg seroconversion when applicable
• Ideally, loss of HBsAg

⸻

Treatment of Hepatitis C

The historical interferon-ribavirin regimens are now largely obsolete.

Modern HCV treatment uses:

Direct-acting antiviral agents (DAAs)

These regimens are:

• Oral
• Shorter
• Better tolerated
• Highly effective

Common modern pan-genotypic regimens include combinations such as:

• Sofosbuvir/velpatasvir
• Glecaprevir/pibrentasvir

Most appropriately treated patients can achieve cure rates exceeding 95%.

⸻

Sustained Virologic Response

The goal of HCV therapy is:

Sustained virologic response (SVR)

This means HCV RNA remains undetectable after completion of therapy, typically assessed at least 12 weeks afterward.

SVR is considered a virologic cure.

⸻

Treatment of Hepatitis D

Treatment of HDV has historically relied on pegylated interferon alfa in suitable patients.

Newer targeted therapies are becoming available in some regions, and specialist management is recommended.

The older statement that interferon gamma is standard therapy is not current practice.

⸻

Treatment of Hepatitis E

Most immunocompetent patients require only:

• Supportive care

Chronic HEV may occur in immunocompromised patients, particularly transplant recipients.

Management may include:

• Reduction of immunosuppression when possible
• Ribavirin in selected chronic cases under specialist guidance

⸻

Fulminant Hepatitis

Fulminant hepatitis refers to acute severe hepatic injury with:

• Coagulopathy
• Encephalopathy
• No established preexisting cirrhosis

Patients may develop:

• Cerebral edema
• Hypoglycemia
• Renal failure
• Metabolic disturbances
• Bleeding
• Multiorgan failure

These patients require urgent admission to a liver-transplant-capable center.

⸻

Liver Transplantation

Liver transplantation may be life-saving in:

• Acute liver failure
• Decompensated cirrhosis
• Selected hepatocellular carcinoma
• End-stage chronic viral hepatitis

Early transplant referral is essential in fulminant disease.

⸻

Hepatitis A Complications

Most HAV infections resolve completely.

Possible complications include:

• Prolonged cholestatic hepatitis
• Relapsing hepatitis
• Rare acute liver failure

HAV does not become chronic.

⸻

Hepatitis B Complications

Chronic HBV may lead to:

• Chronic hepatitis
• Fibrosis
• Cirrhosis
• Portal hypertension
• Liver failure
• Hepatocellular carcinoma

HBV can cause hepatocellular carcinoma even in the absence of cirrhosis.

Extrahepatic manifestations include:

• Polyarteritis nodosa
• Glomerulonephritis
• Serum-sickness-like syndrome
• Arthralgias
• Cryoglobulinemia

⸻

Hepatitis C Complications

Chronic HCV may lead to:

• Progressive fibrosis
• Cirrhosis
• Portal hypertension
• Liver failure
• Hepatocellular carcinoma

Important extrahepatic associations include:

• Mixed cryoglobulinemia
• Membranoproliferative glomerulonephritis
• Porphyria cutanea tarda
• Lichen planus
• B-cell lymphoma
• Insulin resistance and diabetes

⸻

Hepatitis D Complications

HDV infection may accelerate HBV-associated liver disease.

Superinfection can produce:

• Severe acute hepatitis
• Rapid progression of fibrosis
• Cirrhosis
• Liver failure

HDV is generally more severe than HBV infection alone.

⸻

Hepatitis E and Pregnancy

One of the classic high-yield features of HEV is severe disease during pregnancy.

In certain endemic settings, particularly with some HEV genotypes, pregnant women—especially in the second and third trimesters—have an increased risk of:

• Fulminant hepatitis
• Acute liver failure
• Maternal death
• Fetal complications

This association is particularly important in examinations.

⸻

High-Yield Comparison

HAV

→ RNA

→ Fecal-oral

→ Acute only

→ No chronic infection

→ Vaccine available

HBV

→ DNA

→ Blood, sexual, perinatal

→ Acute or chronic

→ Vaccine available

→ Can cause cirrhosis and hepatocellular carcinoma

HCV

→ RNA

→ Mainly blood-borne

→ High rate of chronic infection

→ No vaccine

→ Curable with direct-acting antivirals

HDV

→ RNA

→ Requires HBV

→ Coinfection or superinfection

→ Prevented by HBV vaccination

HEV

→ RNA

→ Fecal-oral

→ Usually acute

→ Particularly severe in pregnancy

⸻

High-Yield Clinical Approach

Acute hepatitis + recent contaminated food/water exposure

→ Think HAV or HEV

Acute hepatitis + sexual/blood exposure

→ Think HBV

Injection drug use + chronic hepatitis

→ Think HCV

HBsAg-positive patient with unexpectedly severe hepatitis

→ Consider HDV

Pregnant patient + acute hepatitis after travel to endemic region

→ Consider HEV

Positive anti-HCV

→ Confirm active disease with HCV RNA

HBsAg negative + anti-HBs positive + anti-HBc negative

→ Vaccinated

HBsAg negative + anti-HBs positive + anti-HBc positive

→ Resolved natural HBV infection

HBsAg positive + IgM anti-HBc positive

→ Acute HBV

HBsAg positive for >6 months

→ Chronic HBV

HBV window period

→ IgM anti-HBc may be the key positive marker

⸻

Exam Essentials

HAV transmission:

→ Fecal-oral

HAV chronic infection:

→ Does not occur

HAV acute diagnostic marker:

→ IgM anti-HAV

HBV type:

→ DNA virus

HBV vaccination marker:

→ Anti-HBs only

Marker of natural HBV exposure:

→ Anti-HBc

HBV window-period marker:

→ IgM anti-HBc

HBV replication marker:

→ HBV DNA

HBeAg:

→ Usually indicates increased replication/infectivity

HCV screening test:

→ Anti-HCV antibody

HCV active infection test:

→ HCV RNA

HCV chronicity:

→ Common if untreated

Modern HCV treatment:

→ Direct-acting antivirals

HCV cure endpoint:

→ Sustained virologic response

HDV requirement:

→ HBV/HBsAg

Best prevention of HDV:

→ HBV vaccination

HEV transmission:

→ Fecal-oral

HEV major high-risk group for severe disease:

→ Pregnant women

Severe acute hepatitis marker:

→ Rising PT/INR

Fulminant hepatitis + encephalopathy:

→ Urgent liver-transplant-center referral

Infectious Disease and Microbiology - Viral Hepatitis

Basics

Description

Viral hepatitis refers to inflammation and injury of the liver caused by hepatotropic viruses, particularly hepatitis A, B, C, D, and E viruses.

Disease may be:

• Acute and self-limited
• Chronic and progressive
• Fulminant, with massive hepatic necrosis and acute liver failure

The likelihood of chronic infection varies greatly by virus. HAV and HEV usually cause acute disease only, whereas HBV, HCV, and HDV may cause chronic infection.

Fulminant hepatitis is characterized by severe hepatic necrosis with rapid development of liver failure, coagulopathy, and encephalopathy.

⸻

Major Hepatitis Viruses

The principal hepatotropic viruses are:

• Hepatitis A virus (HAV)
• Hepatitis B virus (HBV)
• Hepatitis C virus (HCV)
• Hepatitis D virus (HDV)
• Hepatitis E virus (HEV)

Hepatitis G virus has historically been described, but it is not considered a major cause of clinically significant chronic hepatitis.

Other viruses that can cause hepatitis include:

• Epstein-Barr virus
• Cytomegalovirus
• Herpes simplex virus
• HIV
• Adenovirus
• Measles virus
• Enteroviruses

⸻

Epidemiology

Hepatitis A

HAV has a worldwide distribution.

Transmission is predominantly:

Fecal-oral

Common sources include:

• Contaminated food
• Contaminated water
• Close household contact
• Outbreaks in congregate settings

Sexual transmission, particularly with oral-anal exposure, may also occur.

Chronic infection does not occur.

⸻

Hepatitis B

HBV remains a major global infection.

Major routes of transmission include:

• Blood exposure
• Sexual transmission
• Injection drug use
• Needlestick exposure
• Perinatal transmission
• Vertical transmission
• Contaminated blood products where screening is inadequate

The probability of chronic infection is strongly related to age at acquisition.

Neonatal or perinatal infection

→ Very high risk of chronicity

Adult-acquired infection

→ Most immunocompetent adults clear the infection spontaneously

This age-dependent difference is one of the most important features of HBV infection.

⸻

Hepatitis C

HCV is predominantly a blood-borne infection.

Important routes include:

• Injection drug use
• Shared injection equipment
• Needlestick injuries
• Unscreened blood transfusion
• Organ transplantation from an infected donor
• Perinatal transmission
• Sexual transmission, although less efficient than with HBV

Without treatment, chronic infection develops in a substantial proportion of infected individuals.

⸻

Hepatitis D

HDV is a defective RNA virus that requires hepatitis B surface antigen (HBsAg) for its life cycle.

Therefore:

No HBV → no HDV infection

HDV occurs in two patterns:

Coinfection

HBV and HDV are acquired at the same time.

Superinfection

HDV infects a person who already has chronic HBV infection.

Superinfection is generally associated with more severe disease and a greater risk of chronic liver injury.

⸻

Hepatitis E

HEV resembles HAV epidemiologically.

Transmission is mainly:

Fecal-oral

Large outbreaks are especially associated with:

• Contaminated water
• Poor sanitation
• Developing regions

Most infections are acute and self-limited, although chronic HEV can occur in selected immunocompromised patients.

HEV deserves special attention during pregnancy because severe disease may occur, particularly later in gestation.

⸻

Risk Factors

Hepatitis A

Important risk factors include:

• Travel to areas with poor sanitation
• Household or close contact with an infected person
• Men who have sex with men
• Drug use
• Homelessness
• Occupational or institutional exposure in selected settings
• Contaminated food or water exposure

⸻

Hepatitis B

Important risk factors include:

• Unprotected sexual contact
• Multiple sexual partners
• Men who have sex with men
• Injection drug use
• Occupational blood exposure
• Hemodialysis
• Household exposure to chronic HBV
• Birth in or immigration from endemic regions
• Perinatal exposure
• Repeated blood-product exposure
• HIV infection

⸻

Hepatitis C

Major risk factors include:

• Injection drug use
• Sharing injection equipment
• Needlestick injury
• Blood transfusion before modern screening
• Hemodialysis
• HIV infection
• Tattoos or piercings performed with inadequately sterilized equipment
• Organ transplantation from an infected donor

Intranasal drug use may also pose risk when blood-contaminated equipment is shared.

⸻

Hepatitis D

Risk factors are essentially those of HBV because HDV depends on HBV infection.

⸻

Hepatitis E

Risk factors resemble HAV and include:

• Contaminated water
• Poor sanitation
• Travel to endemic areas

Zoonotic transmission can also occur in some regions.

⸻

Prevention

Hepatitis A Prevention

The most important strategies are:

• Handwashing
• Safe food handling
• Clean water
• Improved sanitation
• Vaccination

HAV vaccine is highly effective and is routinely used in many countries.

It is particularly important for:

• Travelers to endemic regions
• People with chronic liver disease
• Men who have sex with men
• People who use drugs
• Certain occupational or outbreak settings

Post-exposure prophylaxis may involve:

• HAV vaccination
• Immune globulin in selected high-risk individuals

The exact choice depends on age, immune status, liver disease, and timing of exposure.

⸻

Hepatitis B Prevention

HBV vaccination is one of the most effective preventive measures in infectious disease.

Vaccination is recommended broadly, including routine infant vaccination and vaccination of nonimmune adults.

Particularly important groups include:

• Healthcare workers
• Hemodialysis patients
• Injection drug users
• Sexual contacts of infected persons
• People with multiple sexual partners
• Travelers to endemic areas
• Household contacts of chronic HBV carriers

After a significant exposure in a nonimmune person, post-exposure prophylaxis may include:

• Hepatitis B immune globulin
• HBV vaccination

depending on vaccination status and the source patient.

⸻

Hepatitis C Prevention

There is currently no vaccine for HCV.

Prevention relies on:

• Avoiding shared needles
• Sterile injection practices
• Safe blood screening
• Avoiding shared razors or blood-contaminated personal items
• Appropriate occupational precautions
• Safer sex in higher-risk situations

⸻

Hepatitis D Prevention

There is no separate widely used HDV vaccine.

However:

HBV vaccination prevents HDV infection

because HDV cannot establish infection without HBV.

⸻

Hepatitis E Prevention

Prevention relies mainly on:

• Safe drinking water
• Sanitation
• Proper food handling
• Avoidance of contaminated water

An HEV vaccine exists in limited geographic availability but is not routinely available worldwide.

⸻

Etiology and Virology

HAV

HAV is:

• An RNA virus
• Non-enveloped
• A member of the Picornaviridae family

It does not cause chronic infection.

⸻

HBV

HBV is:

• A partially double-stranded DNA virus
• A member of the Hepadnaviridae family
• Enveloped

Important viral markers include:

• HBsAg
• Anti-HBs
• Anti-HBc
• HBeAg
• Anti-HBe
• HBV DNA

⸻

HCV

HCV is:

• An enveloped RNA virus
• A member of the Flaviviridae family

Multiple genotypes exist, although modern direct-acting antiviral therapy has reduced the practical importance of genotype in many treatment settings.

⸻

HDV

HDV is:

• A small RNA virus
• Dependent on HBsAg from HBV for its envelope

Therefore it can occur only in a patient infected with HBV.

⸻

HEV

HEV is:

• A non-enveloped RNA virus in blood
• Structurally quasi-enveloped during some phases of infection
• Classified within the Hepeviridae family

Most human disease is acute.

⸻

Pathophysiology

The liver injury in viral hepatitis is largely mediated by the host immune response to infected hepatocytes, rather than direct viral destruction alone.

Typical pathologic changes include:

• Lobular inflammation
• Mononuclear-cell infiltration
• Hepatocyte degeneration
• Hepatocyte necrosis
• Kupffer-cell hyperplasia
• Cholestasis

In severe disease, extensive hepatic necrosis can result in:

• Coagulopathy
• Hypoglycemia
• Encephalopathy
• Multiorgan dysfunction
• Acute liver failure

⸻

Clinical Presentation

The clinical manifestations of acute viral hepatitis are often similar regardless of the specific virus.

Many infections are asymptomatic or anicteric.

The illness may be divided into:

1. Prodromal phase
2. Icteric phase
3. Convalescent or posticteric phase

⸻

Prodromal Phase

The prodrome usually precedes jaundice by approximately several days to 1–2 weeks.

Symptoms may include:

• Fatigue
• Malaise
• Anorexia
• Nausea
• Vomiting
• Fever
• Headache
• Myalgias
• Arthralgias
• Altered taste
• Altered smell
• Cough
• Coryza

Some patients report aversion to cigarettes or certain foods.

⸻

Icteric Phase

As jaundice develops, some constitutional symptoms may improve.

Features may include:

• Jaundice
• Dark urine
• Pale stools
• Pruritus
• Right upper quadrant discomfort
• Hepatomegaly
• Tender liver

Not all patients become visibly jaundiced.

⸻

Physical Examination

Possible findings include:

• Jaundice
• Hepatomegaly
• Right upper quadrant tenderness
• Splenomegaly
• Cervical lymphadenopathy

Splenomegaly and lymphadenopathy occur in a minority of patients.

In severe disease, look for:

• Confusion
• Asterixis
• Bleeding
• Hypotension
• Signs of cerebral edema
• Evidence of acute liver failure

⸻

Incubation Periods

Approximate incubation periods are:

HAV

→ 15–50 days

HBV

→ Approximately 1–6 months

HCV

→ Approximately 2 weeks to 6 months

HDV

→ Depends on HBV coinfection or superinfection

HEV

→ Approximately 2–8 weeks

Incubation periods overlap and should not be used alone for diagnosis.

⸻

Laboratory Findings in Acute Viral Hepatitis

Common findings include:

• Markedly elevated ALT
• Markedly elevated AST
• Hyperbilirubinemia
• Mild alkaline phosphatase elevation
• Relative lymphocytosis
• Atypical lymphocytes
• Mild leukopenia early in illness

Aminotransferases may rise before jaundice appears.

In hepatocellular injury:

ALT and AST are usually disproportionately elevated compared with alkaline phosphatase.

⸻

Bilirubin

When jaundice develops, bilirubin may rise substantially.

Both conjugated and unconjugated fractions may increase, although conjugated hyperbilirubinemia is common in clinically significant hepatitis.

⸻

Prothrombin Time and INR

A prolonged:

PT/INR

is an important marker of impaired hepatic synthetic function.

This is especially important in acute hepatitis because a rising INR may signal:

Acute liver failure

Aminotransferase levels alone do not reliably indicate severity.

A falling ALT in a deteriorating patient can actually be ominous if it reflects massive hepatocyte loss.

⸻

Albumin

Albumin may remain relatively preserved in acute disease because of its long half-life.

Low albumin is more suggestive of:

• Chronic liver disease
• Prolonged severe illness
• Poor synthetic function

⸻

Hypoglycemia

Hypoglycemia can occur in severe or fulminant hepatitis because of impaired hepatic glucose regulation.

It is an important marker of severe disease.

⸻

Hepatitis A Diagnosis

The key test for acute HAV is:

IgM anti-HAV

This indicates recent or acute infection.

IgG anti-HAV

Indicates:

• Previous infection
• Vaccination
• Immunity

HAV does not cause chronic hepatitis.

⸻

Hepatitis B Serology

HBV serology is particularly important and frequently tested.

HBsAg

Hepatitis B surface antigen

Indicates current HBV infection.

It appears early after infection.

Persistence for more than 6 months supports chronic infection.

⸻

Anti-HBs

Antibody to hepatitis B surface antigen

Indicates immunity.

It can result from:

• Recovery from natural infection
• Vaccination

⸻

Anti-HBc

Antibody to hepatitis B core antigen

This indicates exposure to actual HBV infection.

It is not produced by vaccination alone.

IgM anti-HBc

Suggests:

• Acute infection
• Recent infection
• Sometimes an acute flare of chronic HBV

Total or IgG anti-HBc

Usually persists for life after natural infection.

⸻

HBV Window Period

An important examination concept is the window period.

During this period:

• HBsAg has disappeared
• Anti-HBs has not yet appeared

The key marker may therefore be:

IgM anti-HBc

⸻

HBeAg

HBeAg generally indicates:

• Active viral replication
• Higher infectivity

However, some HBV variants replicate actively without detectable HBeAg, so modern assessment relies heavily on:

HBV DNA

⸻

HBV DNA

HBV DNA measured by PCR reflects:

Viral replication

It is crucial for:

• Assessing disease activity
• Deciding treatment
• Monitoring response
• Evaluating transmission risk

⸻

High-Yield HBV Serologic Patterns

Vaccinated

HBsAg: negative

Anti-HBc: negative

Anti-HBs: positive

→ Immune from vaccination

⸻

Resolved natural infection

HBsAg: negative

Anti-HBc: positive

Anti-HBs: positive

→ Past infection, now immune

⸻

Acute HBV

HBsAg: positive

IgM anti-HBc: positive

Anti-HBs: negative

→ Acute infection

⸻

Chronic HBV

HBsAg: positive for >6 months

Anti-HBc: positive

Anti-HBs: negative

→ Chronic infection

⸻

Hepatitis C Diagnosis

Initial screening is usually performed with:

Anti-HCV antibody

However, anti-HCV indicates exposure and does not distinguish:

• Active infection
• Resolved infection
• Successfully treated infection

Therefore a positive antibody test must be followed by:

HCV RNA

to determine whether active infection is present.

⸻

HCV RNA

HCV RNA can become detectable very early after infection, before antibodies develop.

Therefore:

Recent exposure + negative antibody does not exclude acute HCV

HCV RNA should be checked if acute infection is suspected.

⸻

HCV Genotype

Genotyping historically played a major role in treatment selection.

With modern pan-genotypic direct-acting antiviral regimens, genotype is less important than it once was, although it may still influence management in selected situations.

⸻

Hepatitis D Diagnosis

Diagnosis may include:

• Anti-HDV antibodies
• HDV RNA

HDV RNA confirms active replication.

Because HDV requires HBV, patients should also undergo a complete HBV evaluation.

⸻

Hepatitis E Diagnosis

Testing may include:

• IgM anti-HEV
• HEV RNA

IgM anti-HEV supports recent infection.

HEV RNA is especially useful in:

• Immunocompromised patients
• Suspected chronic infection

⸻

Imaging

Ultrasound is not usually needed to diagnose uncomplicated viral hepatitis.

However, it may be useful to:

• Exclude biliary obstruction
• Evaluate liver morphology
• Assess portal or hepatic vessels
• Look for ascites
• Assess chronic liver disease

Doppler ultrasound may be added when vascular disease is a consideration.

⸻

Liver Biopsy

Liver biopsy is rarely required in straightforward acute viral hepatitis.

It may be considered when:

• Diagnosis is uncertain
• Autoimmune hepatitis is suspected
• Chronic hepatitis requires staging
• Another liver disease needs exclusion

Noninvasive fibrosis assessment has replaced biopsy for many chronic hepatitis patients.

⸻

Differential Diagnosis

The differential diagnosis of acute hepatitis includes:

• Drug-induced liver injury
• Acetaminophen toxicity
• Alcohol-associated hepatitis
• Autoimmune hepatitis
• Ischemic hepatitis
• Sepsis-associated liver injury
• Biliary obstruction
• Wilson disease
• EBV
• CMV
• HSV hepatitis
• Leptospirosis

Clinical context and targeted testing are essential.

⸻

Treatment of Hepatitis A

There is no specific antiviral therapy for uncomplicated HAV.

Treatment is supportive and includes:

• Hydration
• Adequate nutrition
• Antiemetics if needed
• Avoidance of hepatotoxic substances
• Monitoring for acute liver failure

Most patients recover completely.

⸻

Treatment of Acute Hepatitis B

Most immunocompetent adults with uncomplicated acute HBV recover spontaneously and do not require antiviral therapy.

Antiviral treatment is considered for:

• Severe acute hepatitis
• Protracted severe disease
• Acute liver failure

Potent nucleos(t)ide analogues such as:

• Tenofovir
• Entecavir

are generally preferred when antiviral treatment is indicated.

⸻

Treatment of Chronic Hepatitis B

Modern first-line oral agents generally include potent drugs with a high barrier to resistance, particularly:

• Tenofovir disoproxil fumarate
• Tenofovir alafenamide
• Entecavir

Pegylated interferon may be used in selected patients.

Older drugs such as lamivudine are used much less frequently because resistance develops readily.

The major goals are:

• Suppression of HBV DNA
• Prevention of cirrhosis
• Prevention of liver failure
• Reduction of hepatocellular carcinoma risk
• HBeAg seroconversion when applicable
• Ideally, loss of HBsAg

⸻

Treatment of Hepatitis C

The historical interferon-ribavirin regimens are now largely obsolete.

Modern HCV treatment uses:

Direct-acting antiviral agents (DAAs)

These regimens are:

• Oral
• Shorter
• Better tolerated
• Highly effective

Common modern pan-genotypic regimens include combinations such as:

• Sofosbuvir/velpatasvir
• Glecaprevir/pibrentasvir

Most appropriately treated patients can achieve cure rates exceeding 95%.

⸻

Sustained Virologic Response

The goal of HCV therapy is:

Sustained virologic response (SVR)

This means HCV RNA remains undetectable after completion of therapy, typically assessed at least 12 weeks afterward.

SVR is considered a virologic cure.

⸻

Treatment of Hepatitis D

Treatment of HDV has historically relied on pegylated interferon alfa in suitable patients.

Newer targeted therapies are becoming available in some regions, and specialist management is recommended.

The older statement that interferon gamma is standard therapy is not current practice.

⸻

Treatment of Hepatitis E

Most immunocompetent patients require only:

• Supportive care

Chronic HEV may occur in immunocompromised patients, particularly transplant recipients.

Management may include:

• Reduction of immunosuppression when possible
• Ribavirin in selected chronic cases under specialist guidance

⸻

Fulminant Hepatitis

Fulminant hepatitis refers to acute severe hepatic injury with:

• Coagulopathy
• Encephalopathy
• No established preexisting cirrhosis

Patients may develop:

• Cerebral edema
• Hypoglycemia
• Renal failure
• Metabolic disturbances
• Bleeding
• Multiorgan failure

These patients require urgent admission to a liver-transplant-capable center.

⸻

Liver Transplantation

Liver transplantation may be life-saving in:

• Acute liver failure
• Decompensated cirrhosis
• Selected hepatocellular carcinoma
• End-stage chronic viral hepatitis

Early transplant referral is essential in fulminant disease.

⸻

Hepatitis A Complications

Most HAV infections resolve completely.

Possible complications include:

• Prolonged cholestatic hepatitis
• Relapsing hepatitis
• Rare acute liver failure

HAV does not become chronic.

⸻

Hepatitis B Complications

Chronic HBV may lead to:

• Chronic hepatitis
• Fibrosis
• Cirrhosis
• Portal hypertension
• Liver failure
• Hepatocellular carcinoma

HBV can cause hepatocellular carcinoma even in the absence of cirrhosis.

Extrahepatic manifestations include:

• Polyarteritis nodosa
• Glomerulonephritis
• Serum-sickness-like syndrome
• Arthralgias
• Cryoglobulinemia

⸻

Hepatitis C Complications

Chronic HCV may lead to:

• Progressive fibrosis
• Cirrhosis
• Portal hypertension
• Liver failure
• Hepatocellular carcinoma

Important extrahepatic associations include:

• Mixed cryoglobulinemia
• Membranoproliferative glomerulonephritis
• Porphyria cutanea tarda
• Lichen planus
• B-cell lymphoma
• Insulin resistance and diabetes

⸻

Hepatitis D Complications

HDV infection may accelerate HBV-associated liver disease.

Superinfection can produce:

• Severe acute hepatitis
• Rapid progression of fibrosis
• Cirrhosis
• Liver failure

HDV is generally more severe than HBV infection alone.

⸻

Hepatitis E and Pregnancy

One of the classic high-yield features of HEV is severe disease during pregnancy.

In certain endemic settings, particularly with some HEV genotypes, pregnant women—especially in the second and third trimesters—have an increased risk of:

• Fulminant hepatitis
• Acute liver failure
• Maternal death
• Fetal complications

This association is particularly important in examinations.

⸻

High-Yield Comparison

HAV

→ RNA

→ Fecal-oral

→ Acute only

→ No chronic infection

→ Vaccine available

HBV

→ DNA

→ Blood, sexual, perinatal

→ Acute or chronic

→ Vaccine available

→ Can cause cirrhosis and hepatocellular carcinoma

HCV

→ RNA

→ Mainly blood-borne

→ High rate of chronic infection

→ No vaccine

→ Curable with direct-acting antivirals

HDV

→ RNA

→ Requires HBV

→ Coinfection or superinfection

→ Prevented by HBV vaccination

HEV

→ RNA

→ Fecal-oral

→ Usually acute

→ Particularly severe in pregnancy

⸻

High-Yield Clinical Approach

Acute hepatitis + recent contaminated food/water exposure

→ Think HAV or HEV

Acute hepatitis + sexual/blood exposure

→ Think HBV

Injection drug use + chronic hepatitis

→ Think HCV

HBsAg-positive patient with unexpectedly severe hepatitis

→ Consider HDV

Pregnant patient + acute hepatitis after travel to endemic region

→ Consider HEV

Positive anti-HCV

→ Confirm active disease with HCV RNA

HBsAg negative + anti-HBs positive + anti-HBc negative

→ Vaccinated

HBsAg negative + anti-HBs positive + anti-HBc positive

→ Resolved natural HBV infection

HBsAg positive + IgM anti-HBc positive

→ Acute HBV

HBsAg positive for >6 months

→ Chronic HBV

HBV window period

→ IgM anti-HBc may be the key positive marker

⸻

Exam Essentials

HAV transmission:

→ Fecal-oral

HAV chronic infection:

→ Does not occur

HAV acute diagnostic marker:

→ IgM anti-HAV

HBV type:

→ DNA virus

HBV vaccination marker:

→ Anti-HBs only

Marker of natural HBV exposure:

→ Anti-HBc

HBV window-period marker:

→ IgM anti-HBc

HBV replication marker:

→ HBV DNA

HBeAg:

→ Usually indicates increased replication/infectivity

HCV screening test:

→ Anti-HCV antibody

HCV active infection test:

→ HCV RNA

HCV chronicity:

→ Common if untreated

Modern HCV treatment:

→ Direct-acting antivirals

HCV cure endpoint:

→ Sustained virologic response

HDV requirement:

→ HBV/HBsAg

Best prevention of HDV:

→ HBV vaccination

HEV transmission:

→ Fecal-oral

HEV major high-risk group for severe disease:

→ Pregnant women

Severe acute hepatitis marker:

→ Rising PT/INR

Fulminant hepatitis + encephalopathy:

→ Urgent liver-transplant-center referral

Infectious Disease and Microbiology - Typhoid Fever

Basics

Description

Typhoid fever is a systemic bacterial infection caused by Salmonella enterica serovar Typhi, commonly called Salmonella Typhi.

Unlike most nontyphoidal Salmonella infections, which usually remain confined to the gastrointestinal tract, typhoid fever is characterized by invasion of the intestinal mucosa, bacteremia, and dissemination to the reticuloendothelial system and other organs.

The illness may range from an uncomplicated febrile disease to severe infection with:

• Encephalopathy
• Gastrointestinal hemorrhage
• Intestinal perforation
• Septic complications
• Multiorgan involvement

⸻

Epidemiology

Typhoid fever remains an important global infection, particularly in regions with inadequate sanitation and limited access to safe drinking water.

The greatest burden occurs in:

• South Asia
• Southeast Asia
• Parts of Africa
• Areas of Latin America
• Other regions with poor sanitation infrastructure

In countries with low endemicity, most cases are associated with:

• International travel
• Recent residence in endemic areas
• Household exposure to infected individuals or chronic carriers

Humans are the only important reservoir of S. Typhi.

⸻

Risk Factors

Important risk factors include:

• Travel to an endemic region
• Household contact with a recent case
• Consumption of contaminated food or water
• Eating food from street vendors in high-risk areas
• Inadequate hand hygiene
• Lack of proper toilet facilities
• Use of contaminated ice
• Reduced gastric acidity

Conditions that reduce gastric acidity may lower the infectious dose required for disease.

These include:

• Achlorhydria
• Previous gastrectomy
• Proton-pump inhibitor use
• Histamine-2 receptor blocker use

⸻

General Prevention

Prevention depends on interrupting fecal-oral transmission.

Important measures include:

• Frequent handwashing with soap and safe water
• Safe drinking water
• Proper sewage disposal
• Adequate sanitation
• Safe preparation and storage of food
• Identification and management of chronic carriers
• Appropriate vaccination before travel to endemic areas

Travelers should avoid:

• Untreated water
• Ice made from unsafe water
• Raw or undercooked foods
• Unpeeled fruits and vegetables
• Food from vendors with questionable hygiene

⸻

Vaccination

Vaccination is recommended for selected travelers to areas where typhoid fever is endemic.

Available vaccine strategies include oral live-attenuated and injectable Vi-based vaccines.

Vaccination reduces risk but does not provide complete protection, so food and water precautions remain essential.

⸻

Transmission and Pathophysiology

Transmission occurs predominantly through the:

Fecal-oral route

The organism is acquired by ingesting food or water contaminated by feces from:

• An acutely infected patient
• A recovering patient
• A chronic carrier

After ingestion, the bacteria must survive gastric acidity and reach the small intestine.

They then:

1. Attach to and invade the intestinal mucosa.
2. Penetrate particularly through lymphoid tissue in the Peyer patches.
3. Enter lymphatic tissue.
4. Spread to macrophages in the reticuloendothelial system.
5. Disseminate through the bloodstream.

Important sites of dissemination include:

• Liver
• Spleen
• Bone marrow
• Gallbladder
• Terminal ileum

Biliary excretion can reintroduce organisms into the intestine, contributing to intestinal inflammation and shedding in stool.

⸻

Incubation Period

The incubation period is usually approximately:

7–14 days

but may vary depending on:

• Infectious dose
• Host immunity
• Gastric acidity

⸻

Etiology

Salmonella enterica serovar Typhi is a:

• Gram-negative rod
• Facultative anaerobe
• Member of the Enterobacterales
• Intracellular pathogen capable of surviving within macrophages

Typhoid fever should be distinguished from infection caused by:

• Salmonella Paratyphi
• Nontyphoidal Salmonella

⸻

Clinical Course

Traditionally, untreated typhoid fever has been described as progressing through several clinical stages.

First Week

Bacteremia becomes established.

Common features include:

• Progressive fever
• Headache
• Malaise
• Cough
• Myalgias
• Abdominal discomfort

⸻

Second Week

Systemic illness becomes more obvious.

Patients may develop:

• Persistent high fever
• Abdominal pain
• Hepatomegaly
• Splenomegaly
• Diarrhea or constipation
• Rose spots

⸻

Third Week

Without effective treatment, the patient may become markedly toxic.

Serious complications are more likely to develop, particularly:

• Intestinal hemorrhage
• Intestinal perforation
• Encephalopathy
• Severe systemic illness

Modern antibiotic treatment often alters this classic progression.

⸻

Clinical Presentation

Fever is the most consistent feature and occurs in nearly all patients.

Other manifestations include:

• Headache
• Malaise
• Fatigue
• Abdominal pain
• Nausea
• Diarrhea
• Constipation
• Cough
• Myalgias
• Arthralgias

Children may be more likely to develop diarrhea.

Adults may more commonly report constipation.

Neurologic symptoms can include:

• Confusion
• Delirium
• Encephalopathy
• Seizures, particularly in young children with severe disease

⸻

Physical Examination

Fever

The fever may initially be low grade and progressively rise.

By the second week, temperatures may approach:

39–40°C

⸻

Relative Bradycardia

Some patients demonstrate relative bradycardia, meaning the heart rate is lower than expected for the degree of fever.

This is sometimes called Faget sign, although it is neither sensitive nor specific.

⸻

Abdominal Findings

Possible findings include:

• Diffuse abdominal tenderness
• Abdominal distention
• Hepatomegaly
• Splenomegaly

Marked abdominal tenderness, rigidity, or sudden deterioration should raise concern for intestinal perforation.

⸻

Rose Spots

Rose spots are a classic but uncommon physical finding.

They are:

• Faint
• Blanching
• Pink or erythematous
• Maculopapular
• Usually approximately a few millimeters in diameter

They most often appear on:

• Abdomen
• Chest

and less commonly on:

• Back
• Arms
• Legs

They may be transient and therefore easily missed.

⸻

Other Physical Findings

Depending on severity, patients may demonstrate:

• Cervical lymphadenopathy
• Pulmonary crackles or rhonchi
• Meningismus
• New cardiac murmur
• Altered mental status
• Joint swelling
• Bone tenderness

Severe disease may give the patient an apathetic or toxic appearance.

⸻

Diagnosis

The diagnosis should be suspected in a patient with:

Prolonged fever + compatible systemic symptoms + epidemiologic exposure

Important exposure clues include:

• Recent travel to an endemic region
• Consumption of unsafe food or water
• Household contact with a case
• Exposure to a chronic carrier

Microbiologic confirmation should be pursued whenever possible.

⸻

Laboratory Findings

Routine laboratory abnormalities are variable.

Possible findings include:

• Leukopenia
• Leukocytosis, particularly in infants
• Anemia
• Thrombocytopenia
• Elevated transaminases
• Elevated bilirubin

None of these findings is sufficiently specific to establish the diagnosis.

⸻

Blood Culture

Blood culture is one of the most important diagnostic tests.

It is most likely to be positive early in disease.

Sensitivity is imperfect and can be reduced by:

• Previous antibiotic therapy
• Low bacterial burden
• Delayed specimen collection

Multiple cultures may improve yield.

⸻

Bone Marrow Culture

Bone marrow culture has historically been the most sensitive conventional culture technique for typhoid fever.

It may remain positive even after antibiotic exposure.

However, because it is invasive, it is generally reserved for selected difficult diagnostic situations.

⸻

Stool Culture

Stool cultures may become positive later in the course.

They can be useful for:

• Diagnosis
• Assessing fecal shedding
• Evaluating possible carrier states

A negative stool culture does not exclude acute disease.

⸻

Other Culture Sites

S. Typhi may occasionally be recovered from:

• Urine
• Bile
• Rose-spot biopsy specimens
• Duodenal samples

These are not usually required for routine diagnosis.

⸻

Widal Test

The Widal test detects antibodies against Salmonella O and H antigens.

Its usefulness is limited because it can produce:

• False-positive results
• False-negative results
• Cross-reactions with other organisms
• Difficulty distinguishing previous exposure from acute infection

Therefore, it should not be relied upon as the sole diagnostic test when better microbiologic methods are available.

⸻

Molecular Testing

PCR-based and other molecular assays can detect S. Typhi DNA.

Advantages include rapid results.

However, availability and standardized performance vary considerably, and culture remains important because it permits:

• Confirmation
• Antimicrobial susceptibility testing

⸻

Imaging

Imaging is not routinely required in uncomplicated typhoid fever.

It becomes important when complications are suspected.

Possible studies include:

Chest imaging

May show pulmonary infiltrates if pneumonia develops.

Abdominal CT or ultrasound

May demonstrate:

• Bowel-wall inflammation
• Colitis
• Hepatosplenomegaly
• Abscesses
• Free air or other evidence of perforation

⸻

Pathology

Histologic examination may demonstrate infiltration by macrophages sometimes called typhoid cells.

These macrophages may contain:

• Bacteria
• Cellular debris
• Erythrocytes

The terminal ileum and Peyer patches are particularly important sites of intestinal pathology.

Necrosis and ulceration in this region contribute to the risk of:

• Hemorrhage
• Perforation

⸻

Differential Diagnosis

Important differential diagnoses include:

• Paratyphoid fever
• Nontyphoidal salmonellosis
• Malaria
• Dengue
• Leptospirosis
• Brucellosis
• Tuberculosis
• Viral hepatitis
• Rickettsial infections
• Bacterial endocarditis
• Intra-abdominal abscess
• Yersiniosis
• Campylobacter infection

The differential is particularly broad in returning travelers with prolonged fever.

⸻

Treatment

Antimicrobial treatment should be guided by:

• Disease severity
• Region of acquisition
• Local resistance patterns
• Culture and susceptibility results
• Patient age
• Pregnancy
• Ability to tolerate oral medications

The historical reliance on fluoroquinolones has declined because of widespread resistance.

⸻

Contemporary Resistance Considerations

Antimicrobial resistance is one of the most important issues in typhoid fever.

Resistance patterns include:

• Fluoroquinolone nonsusceptibility
• Multidrug-resistant strains
• Extensively drug-resistant strains in some regions

This is particularly important in infections acquired in:

• Pakistan
• India
• Bangladesh
• Other parts of South Asia

Therefore, older recommendations that automatically use ciprofloxacin as universal first-line therapy should not be applied without considering susceptibility patterns.

⸻

Ceftriaxone

Ceftriaxone is widely used for:

• Severe disease
• Hospitalized patients
• Suspected fluoroquinolone-resistant infection
• Patients unable to tolerate oral therapy

It is administered intravenously.

The exact dose and duration depend on severity, susceptibility, and current guidelines.

⸻

Azithromycin

Azithromycin is an important oral option for uncomplicated typhoid fever when the isolate is susceptible.

It is particularly useful where fluoroquinolone resistance is common.

⸻

Fluoroquinolones

Fluoroquinolones such as ciprofloxacin were historically highly effective.

However, resistance and reduced susceptibility are now common in many endemic regions.

They should therefore be used only when susceptibility is known or strongly expected.

⸻

Extensively Drug-Resistant Typhoid

Some S. Typhi strains have acquired resistance to multiple traditional agents, including:

• Ampicillin
• Chloramphenicol
• Trimethoprim-sulfamethoxazole
• Fluoroquinolones
• Certain third-generation cephalosporins

Severe suspected extensively drug-resistant disease may require agents such as a carbapenem, guided by susceptibility testing and infectious-disease expertise.

⸻

Older Antibiotics

Historically effective agents include:

• Ampicillin
• Amoxicillin
• Trimethoprim-sulfamethoxazole
• Chloramphenicol

Their use is now dependent on demonstrated susceptibility because resistance is common.

⸻

Pregnancy

Typhoid fever during pregnancy requires prompt treatment because maternal infection can be associated with:

• Severe maternal illness
• Miscarriage
• Fetal complications

Agents with more established use during pregnancy, such as selected:

• β-lactams
• Cephalosporins
• Macrolides

are generally preferred when active against the organism.

Treatment should be individualized according to susceptibility results and maternal disease severity.

⸻

Supportive Treatment

Supportive care is extremely important.

Measures include:

• Oral or intravenous fluid replacement
• Electrolyte correction
• Antipyretics
• Nutritional support
• Monitoring for complications

Severely ill patients may require intensive care.

⸻

Severe Typhoid Fever

Severe disease may be characterized by:

• Shock
• Severe encephalopathy
• Delirium
• Major gastrointestinal bleeding
• Intestinal perforation
• Multiorgan dysfunction

These patients require:

• Hospitalization
• Intravenous antibiotics
• Careful hemodynamic monitoring
• Rapid evaluation for complications

⸻

Surgical Management

Surgery may be necessary for:

• Intestinal perforation
• Uncontrolled gastrointestinal hemorrhage
• Peritonitis
• Other serious intra-abdominal complications

Intestinal perforation is a surgical emergency.

⸻

Admission Criteria

Hospital admission should be strongly considered for:

• Severe systemic illness
• Hemodynamic instability
• Significant dehydration
• Persistent vomiting
• Encephalopathy
• Suspected intestinal bleeding
• Suspected perforation
• Very young or frail patients
• Patients unable to reliably take oral therapy

⸻

Follow-up

Patients should be followed for:

• Clinical improvement
• Relapse
• Persistent fecal shedding
• Chronic carriage

Fever may take several days to resolve even after appropriate antibiotic therapy.

Failure to improve should prompt reassessment for:

• Drug resistance
• Incorrect diagnosis
• Abscess
• Intestinal complication
• Inadequate antimicrobial exposure

⸻

Relapse

Relapse may occur after apparently successful treatment.

It usually develops within several weeks after clinical recovery.

Symptoms generally resemble the initial illness but may be milder.

Relapse should prompt:

• Repeat cultures
• Repeat susceptibility testing where possible
• Appropriate retreatment

⸻

Chronic Carrier State

A small proportion of patients continue to excrete S. Typhi for prolonged periods after recovery.

Chronic carriage is especially associated with:

• Older age
• Female sex
• Gallbladder disease
• Cholelithiasis

The gallbladder is an important reservoir in chronic carriers.

Carriers may be completely asymptomatic yet remain capable of transmitting infection.

⸻

Public Health Importance of Carriers

Chronic carriers are particularly important if they work as:

• Food handlers
• Healthcare workers
• Childcare workers

Public-health authorities may require microbiologic clearance before certain individuals return to high-risk occupations.

⸻

Prognosis

With timely diagnosis and appropriate antibiotics, the prognosis is generally good.

Mortality is now usually low with modern treatment.

Risk of poor outcome increases with:

• Delayed therapy
• Very young age
• Older age
• Encephalopathy
• Shock
• Intestinal perforation
• Severe bleeding
• Antimicrobial resistance

⸻

Complications

Gastrointestinal Hemorrhage

Bleeding may result from ulceration of intestinal lymphoid tissue.

It may range from occult blood loss to severe hemorrhage.

⸻

Intestinal Perforation

One of the most dangerous complications.

It most often involves the:

Terminal ileum

It classically occurs later in untreated disease.

Clinical clues include:

• Sudden worsening abdominal pain
• Rigidity
• Peritoneal signs
• Shock
• Free intraperitoneal air

⸻

Hepatobiliary Complications

Possible complications include:

• Hepatitis
• Cholecystitis
• Hepatic abscess

The gallbladder plays an important role in chronic carriage.

⸻

Neurologic Complications

These may include:

• Encephalopathy
• Delirium
• Psychosis
• Meningoencephalitis
• Cerebral abscess
• Seizures

⸻

Cardiovascular Complications

Rare complications include:

• Myocarditis
• Pericarditis
• Endocarditis
• Arteritis

⸻

Pulmonary Complications

Possible complications include:

• Pneumonia
• Empyema

⸻

Musculoskeletal Complications

Possible manifestations include:

• Osteomyelitis
• Septic arthritis
• Psoas abscess

Patients with hemoglobinopathies may have particular susceptibility to Salmonella bone infections, although this association is especially recognized with nontyphoidal Salmonella.

⸻

High-Yield Clinical Approach

Traveler from South Asia + prolonged fever + abdominal symptoms

→ Think typhoid fever

Progressively increasing fever + headache + abdominal pain

→ Consider Salmonella Typhi

Fever + relative bradycardia + splenomegaly

→ Classic clue for typhoid fever

Faint blanching pink lesions on trunk

→ Rose spots

Early disease

→ Blood cultures have the highest routine diagnostic value

Most sensitive traditional culture

→ Bone marrow culture

Widal test

→ Limited reliability; do not depend on it alone

Third week + sudden severe abdominal pain

→ Suspect terminal ileal perforation

Persistent shedding after recovery

→ Think chronic carrier state

Chronic carrier reservoir

→ Gallbladder

Travel to South Asia

→ Always consider antimicrobial resistance

Fluoroquinolone use

→ Only when susceptibility is appropriate

Uncomplicated susceptible disease

→ Azithromycin or other susceptibility-directed therapy

Severe disease

→ IV therapy such as ceftriaxone, adjusted for resistance patterns

⸻

Exam Essentials

Causative organism:

→ Salmonella enterica serovar Typhi

Type of organism:

→ Gram-negative rod

Reservoir:

→ Humans

Transmission:

→ Fecal-oral

Incubation period:

→ Usually 7–14 days

Major intestinal site:

→ Peyer patches of the terminal ileum

Most common symptom:

→ Fever

Classic skin finding:

→ Rose spots

Classic pulse finding:

→ Relative bradycardia

Important organ enlargement:

→ Hepatosplenomegaly

Routine diagnostic cornerstone:

→ Blood culture

Most sensitive traditional culture:

→ Bone marrow culture

Widal test:

→ Poor specificity and variable sensitivity

Major late gastrointestinal complication:

→ Intestinal perforation

Typical site of perforation:

→ Terminal ileum

Major resistance concern:

→ Fluoroquinolone-resistant and multidrug/extensively drug-resistant S. Typhi

Important oral treatment option in susceptible uncomplicated disease:

→ Azithromycin

Common IV option for severe susceptible disease:

→ Ceftriaxone

Important site in chronic carriage:

→ Gallbladder

Relapse:

→ Can occur several weeks after apparent recovery

Most important prevention:

→ Safe food, safe water, sanitation, hand hygiene, and vaccination before high-risk travel

Infectious Disease and Microbiology - Tularemia

Basics

Description

Tularemia is a zoonotic bacterial infection caused by Francisella tularensis. It can produce several distinct clinical syndromes depending on how the organism enters the body.

The most common presentation is ulceroglandular tularemia, characterized by a skin ulcer at the inoculation site with painful regional lymphadenopathy. Other forms include:

• Glandular
• Oculoglandular
• Oropharyngeal
• Pneumonic
• Typhoidal/systemic disease

The organism is highly infectious and is also considered a potential bioterrorism agent.

⸻

Epidemiology

Tularemia is uncommon.

In the United States, only a few hundred cases are reported annually.

The disease occurs primarily in the Northern Hemisphere, especially in:

• North America
• Europe
• Parts of Asia

In the US, cases are concentrated particularly in the south-central states, including:

• Arkansas
• Oklahoma
• Missouri

Tick-associated cases are more common during the warmer months, while hunting-associated cases may occur during colder months when people handle infected animals.

A wide range of animals can harbor F. tularensis, including:

• Rabbits
• Rodents
• Other small mammals
• Birds

In the US, rabbits are an important reservoir.

Vectors include:

• Ticks
• Deer flies
• Mosquitoes in some geographic regions

Important tick vectors in the US include:

• American dog tick
• Wood tick
• Lone star tick

⸻

Risk Factors

People at increased risk include:

• Hunters
• Trappers
• Farmers
• Veterinarians
• Wildlife workers
• Laboratory personnel
• People with frequent tick exposure

Risk is increased by:

• Handling infected animal carcasses
• Skinning rabbits or other wild animals
• Arthropod bites
• Drinking contaminated water
• Inhaling contaminated aerosols

⸻

General Prevention

Prevention focuses on minimizing exposure to infected animals, arthropods, and contaminated material.

Important precautions include:

• Use insect repellent in tick-endemic areas.
• Wear long sleeves and trousers when outdoors.
• Check the body carefully for attached ticks.
• Wear gloves while skinning or handling wild animals.
• Cook game meat thoroughly.
• Avoid untreated surface water in endemic regions.
• Follow strict biosafety procedures when handling suspected laboratory specimens.

There is no routinely available vaccine for the general public.

⸻

Pathophysiology

Humans may acquire tularemia through several routes:

• Tick or other arthropod bite
• Direct skin contact with infected animals
• Inhalation
• Ingestion
• Animal bites or scratches
• Laboratory exposure

After entering the body, F. tularensis spreads to regional lymph nodes.

The organism survives and replicates within macrophages and can subsequently disseminate through lymphatic and bloodstream routes.

Transient bacteremia may occur early in the disease.

⸻

Etiology

Francisella tularensis is a:

• Small
• Gram-negative
• Aerobic
• Facultative intracellular coccobacillus

It is highly virulent, and only a very small inoculum is required to produce infection.

The organism:

• Requires enriched media for growth
• Grows slowly
• Can survive for prolonged periods in the environment
• May remain viable in animal tissues and water
• Poses an important laboratory-acquired infection risk

⸻

Incubation Period

The incubation period is usually:

3–5 days

but can range from approximately:

1–14 days

Symptoms usually begin abruptly.

⸻

Clinical Presentation

Common systemic manifestations include:

• Fever
• Chills
• Severe fatigue
• Headache
• Myalgias
• Sore throat
• Dry cough
• Malaise

Some patients experience relapsing or prolonged fever.

The clinical syndrome depends strongly on the route of infection.

⸻

Ulceroglandular Tularemia

This is the most common form, accounting for the majority of cases.

It typically follows:

• Tick bite
• Deer fly bite
• Direct contact with an infected animal

A papule develops at the inoculation site and progresses to an ulcer.

The lesion may become:

• Painful
• Necrotic
• Crusted

A scar may remain after healing.

The characteristic accompanying finding is:

Markedly enlarged and tender regional lymph nodes

The lymphadenopathy may persist for weeks or even months.

⸻

Glandular Tularemia

Glandular tularemia resembles the ulceroglandular form but no obvious skin ulcer is identified.

The major findings are:

• Fever
• Painful regional lymphadenopathy
• Constitutional symptoms

⸻

Pneumonic Tularemia

Pulmonary involvement may occur by:

1. Direct inhalation of contaminated aerosols
2. Hematogenous spread from another site

Symptoms include:

• Fever
• Dry cough
• Dyspnea
• Pleuritic chest pain
• Myalgias
• Fatigue

Pneumonic tularemia can be severe and may progress to:

• Respiratory failure
• Lung abscess
• Acute respiratory distress syndrome

⸻

Typhoidal Tularemia

Typhoidal tularemia refers to a systemic febrile illness without an obvious inoculation lesion or prominent lymphadenopathy.

Patients may develop:

• High fever
• Severe constitutional symptoms
• Headache
• Abdominal symptoms
• Diarrhea
• Cough

Pneumonic findings are common.

This form can resemble:

• Sepsis
• Enteric fever
• Other severe systemic infections

⸻

Oculoglandular Tularemia

This occurs when the organism is inoculated into the eye.

Features include:

• Painful conjunctivitis
• Conjunctival injection
• Yellowish conjunctival ulcers
• Preauricular lymphadenopathy
• Cervical lymphadenopathy

The combination of conjunctivitis plus regional lymphadenopathy is an important clue.

⸻

Oropharyngeal Tularemia

This form usually results from ingestion of contaminated food or water.

Manifestations may include:

• Severe sore throat
• Tonsillitis
• Pharyngitis
• Oral or pharyngeal ulcers
• Cervical lymphadenopathy

A pharyngeal membrane may occasionally resemble diphtheria.

⸻

Physical Examination

Possible findings include:

• Fever
• Relative bradycardia in some patients
• Skin ulcer
• Regional lymphadenopathy
• Rash
• Conjunctivitis
• Pharyngeal inflammation
• Pulmonary findings

A rash may begin as:

• Macular
• Maculopapular

and occasionally evolve into pustular lesions.

⸻

Diagnosis

Diagnosis requires a strong epidemiologic and clinical suspicion.

Important clues include:

• Tick exposure
• Rabbit or wildlife exposure
• Hunting
• Occupational exposure
• Unexplained ulcer with lymphadenopathy
• Severe atypical pneumonia
• Exposure to contaminated aerosols or water

⸻

Laboratory Findings

Routine laboratory abnormalities are nonspecific.

Possible findings include:

• Mild leukocytosis
• Mild elevation of liver enzymes
• Sterile pyuria

More severe disease may produce:

• Elevated inflammatory markers
• Renal dysfunction
• Hepatic dysfunction
• Rhabdomyolysis

Rhabdomyolysis may indicate more severe disease.

⸻

Serology

Serology is commonly used to confirm tularemia.

Antibodies usually do not become reliably detectable during the first several days of illness.

Diagnostic evidence may include:

• A significant rise in antibody titer between acute and convalescent samples
• A high single titer in an appropriate clinical setting

Because early serology may be negative, repeat testing is often necessary.

Cross-reactivity may occur with other organisms, so results should be interpreted in conjunction with the clinical picture.

⸻

Culture

Culture of F. tularensis is possible but requires specialized laboratory handling.

The organism grows slowly and requires enriched media.

Because tularemia poses a substantial laboratory-acquired infection risk, clinicians must notify microbiology personnel before specimens are processed whenever the diagnosis is suspected.

This is a critical practical point.

⸻

Molecular Testing

PCR and other molecular methods may be available through specialized or public-health laboratories.

These tests can be particularly helpful when:

• Early diagnosis is needed
• Culture is hazardous
• Serology is still negative

⸻

Imaging

Chest radiographs in pneumonic tularemia may show:

• Patchy pulmonary infiltrates
• Nodular infiltrates
• Hilar lymphadenopathy
• Pleural effusions

Findings are nonspecific and may resemble other bacterial or atypical pneumonias.

⸻

Pathology

Early lesions may show:

• Focal tissue necrosis
• Neutrophilic inflammation
• Macrophages

Later disease may produce:

• Granulomatous inflammation
• Necrotizing granulomas

These histologic findings can resemble tuberculosis and some fungal infections.

⸻

Differential Diagnosis

Important differential diagnoses include:

• Plague
• Cat-scratch disease
• Staphylococcal or streptococcal lymphadenitis
• Typhoid fever
• Atypical pneumonia
• Q fever
• Psittacosis
• Rickettsial infections
• Tuberculosis
• Brucellosis

The ulceroglandular form may particularly resemble:

• Plague
• Anthrax
• Cat-scratch disease

⸻

Treatment

Prompt antimicrobial therapy is important because untreated tularemia can become severe or disseminated.

Modern treatment depends on:

• Disease severity
• Clinical syndrome
• Age
• Pregnancy
• Drug availability
• Ability to tolerate oral treatment

⸻

First-Line Therapy

Gentamicin

Gentamicin is a traditional first-line agent for severe tularemia.

It is given intravenously or intramuscularly.

Typical treatment duration is approximately:

7–10 days, sometimes longer depending on severity and clinical response.

⸻

Streptomycin

Streptomycin has historically been considered a highly effective treatment.

It is usually administered intramuscularly.

Its use may be limited by:

• Availability
• Ototoxicity
• Nephrotoxicity
• Need for parenteral therapy

⸻

Oral Alternatives

For mild or moderate disease, depending on the patient and current recommendations, oral therapy may include:

• Doxycycline
• Ciprofloxacin

These agents can be effective, although shorter tetracycline courses have historically been associated with relapse.

Adequate duration is therefore important.

⸻

Doxycycline

Doxycycline may be used in uncomplicated disease.

Typical therapy is usually continued for:

14–21 days

to reduce the risk of relapse.

⸻

Fluoroquinolones

Fluoroquinolones, particularly ciprofloxacin, have substantial activity against F. tularensis and are increasingly used in appropriate cases.

They can be useful for:

• Mild-to-moderate disease
• Oral step-down therapy
• Selected severe cases after initial stabilization

⸻

Antibiotics That Should Not Be Relied Upon

F. tularensis is intrinsically resistant to many commonly used β-lactam antibiotics.

Therefore, agents such as:

• Penicillin
• Amoxicillin
• Many cephalosporins

should not be relied upon for treatment.

This is an important examination point.

⸻

CNS Tularemia

Meningitis is uncommon but serious.

Management requires antimicrobial agents selected for activity against F. tularensis and adequate CNS treatment, usually under infectious-disease specialist guidance.

⸻

Additional Treatment

Supportive care may include:

• Intravenous fluids
• Antipyretics
• Analgesia
• Oxygen
• Respiratory support when necessary

Severe disease may require ICU care.

⸻

Surgical Management

Most enlarged lymph nodes do not require immediate surgery.

However, lymph nodes that become:

• Fluctuant
• Suppurative
• Persistently painful

may require aspiration or drainage.

Necrotic or secondarily infected lesions may occasionally require debridement.

⸻

Inpatient Considerations

Hospitalization is appropriate for patients with:

• Septic shock
• Severe pneumonia
• Respiratory failure
• ARDS
• Meningitis
• Severe disseminated disease
• Inability to tolerate oral medications

⸻

Infection Control

Routine person-to-person transmission of tularemia is essentially not recognized.

Therefore, standard precautions are generally sufficient for hospitalized patients.

The major occupational risk is to laboratory personnel, particularly during manipulation of cultures or aerosol-generating procedures.

⸻

Bioterrorism Consideration

Francisella tularensis is considered a potential bioterrorism agent because:

• It is highly infectious.
• Only a small inoculum is required.
• It can potentially be aerosolized.
• Inhalational disease can be severe.

An unusual cluster of severe febrile pneumonia without an obvious natural exposure should prompt consideration of deliberate aerosol exposure and notification of public-health authorities.

⸻

Prognosis

With appropriate antimicrobial therapy, prognosis is generally excellent.

Mortality is low in treated disease.

Untreated severe tularemia can cause:

• Sepsis
• Respiratory failure
• Multiorgan dysfunction
• Death

Pneumonic and typhoidal forms tend to be more severe than uncomplicated ulceroglandular disease.

⸻

Complications

Possible complications include:

• Persistent suppurative lymphadenitis
• Pneumonia
• Lung abscess
• Acute respiratory distress syndrome
• Meningitis
• Pericarditis
• Endocarditis
• Osteomyelitis
• Peritonitis
• Hepatic dysfunction
• Renal failure
• Disseminated intravascular coagulation
• Septic shock

⸻

High-Yield Clinical Approach

Tick bite + painful ulcer + tender regional lymph nodes

→ Think ulceroglandular tularemia

Tender regional lymphadenopathy without a skin lesion

→ Think glandular tularemia

Rabbit exposure + ulcer + lymphadenopathy

→ Strongly consider Francisella tularensis

Conjunctivitis + preauricular lymphadenopathy after animal exposure

→ Think oculoglandular tularemia

Contaminated water + severe pharyngitis + cervical lymphadenopathy

→ Think oropharyngeal tularemia

Aerosol exposure + fever + atypical pneumonia

→ Think pneumonic tularemia

Systemic fever without ulcer or prominent lymphadenopathy

→ Consider typhoidal tularemia

Suspected tularemia specimen

→ Notify the microbiology laboratory before processing

Severe tularemia

→ Aminoglycoside therapy such as gentamicin or streptomycin

Mild/moderate disease

→ Doxycycline or ciprofloxacin may be appropriate

β-lactam antibiotics

→ Generally unreliable against F. tularensis

⸻

Exam Essentials

Causative organism:

→ Francisella tularensis

Type of organism:

→ Small gram-negative intracellular coccobacillus

Main reservoirs in the US:

→ Rabbits and other small mammals

Important vectors:

→ Ticks and deer flies

Most common form:

→ Ulceroglandular tularemia

Classic presentation:

→ Skin ulcer + painful regional lymphadenopathy

Glandular form:

→ Lymphadenopathy without a visible ulcer

Eye involvement:

→ Oculoglandular tularemia

Ingestion-associated form:

→ Oropharyngeal tularemia

Inhalation-associated form:

→ Pneumonic tularemia

Average incubation:

→ Approximately 3–5 days

Common diagnostic confirmation:

→ Serology, often with paired acute and convalescent titers

Important laboratory safety rule:

→ Warn the laboratory when tularemia is suspected

Traditional drugs of choice for severe disease:

→ Gentamicin or streptomycin

Useful oral drugs:

→ Doxycycline or ciprofloxacin

Important resistance clue:

→ β-lactams are generally ineffective

Person-to-person spread:

→ Essentially absent

Bioterrorism significance:

→ Highly infectious organism capable of causing severe aerosol-associated pneumonia

Infectious Disease and Microbiology - Tuberculosis

Basics

Description

Tuberculosis (TB) is an infectious disease caused primarily by Mycobacterium tuberculosis. The organism most commonly affects the lungs, but virtually any organ can be involved. Infection may remain clinically silent as latent tuberculosis infection (LTBI) or progress to active tuberculosis disease.

After inhalation, the organism may be eliminated by the immune system, contained within granulomas as latent infection, or progress directly to active disease. Latent organisms can reactivate years later when host immunity declines.

⸻

Special Populations

Older Adults

Older adults have an increased risk of reactivation TB and may present atypically. Classic symptoms such as fever, productive cough, or marked constitutional symptoms may be absent, so a high index of suspicion is important.

⸻

Children

Tuberculosis remains an important cause of morbidity and mortality among children worldwide.

Children, particularly very young children, are more likely than adults to progress rapidly from initial infection to active disease. They also have a higher risk of severe forms such as:

• Miliary tuberculosis
• Tuberculous meningitis

Microbiologic confirmation is often difficult because children frequently have paucibacillary disease and may not produce sputum.

Specimens may therefore be obtained by:

• Induced sputum
• Early-morning gastric aspirate or lavage
• Nasopharyngeal aspirate in selected settings

Clinical findings, exposure history, imaging, and immunologic testing therefore play an important role.

Treatment principles are similar to those used in adults, although drug doses must be calculated carefully according to body weight.

⸻

Pregnancy

Pregnancy itself does not necessarily increase progression of tuberculosis, but active TB poses significant risks to both mother and fetus.

When treatment of latent infection is necessary during pregnancy, careful consideration of hepatotoxicity is important.

For active drug-susceptible TB, commonly used agents during pregnancy include:

• Isoniazid
• Rifampin
• Ethambutol

Management should follow current specialist and public-health recommendations.

Congenital tuberculosis is rare and results from transplacental or perinatal transmission. Neonatal infection may also occur after birth through close exposure to an infectious mother.

⸻

Epidemiology

Tuberculosis remains one of the most important infectious diseases worldwide.

The global disease burden is substantially greater in:

• South and Southeast Asia
• Sub-Saharan Africa
• Parts of the Western Pacific
• Regions with high HIV prevalence
• Areas with limited access to healthcare

In countries with lower incidence, cases occur disproportionately among:

• Persons born in high-prevalence countries
• Immunocompromised patients
• Individuals living in congregate settings
• Patients with socioeconomic barriers to healthcare

⸻

Risk Factors

Factors that increase the likelihood of acquiring infection or progressing from latent infection to active TB include:

• Close exposure to an infectious patient
• Overcrowded living conditions
• Homelessness
• Poverty
• Incarceration
• Residence in shelters or institutional settings
• HIV infection
• Diabetes mellitus
• Chronic kidney disease
• Silicosis
• Malnutrition
• Use of tumor necrosis factor inhibitors
• Organ transplantation
• Other immunosuppressive therapy
• Alcohol misuse
• Injection drug use
• Recent immigration from a high-prevalence region

The strongest risk factor for progression from latent infection to active disease is impaired cell-mediated immunity, especially advanced HIV infection.

⸻

General Prevention

Prevention depends on rapid recognition of infectious cases, appropriate isolation, effective therapy, and identification of exposed contacts.

Patients with suspected infectious pulmonary TB should be placed in airborne isolation, ideally in a negative-pressure room.

Healthcare workers entering the room should use appropriate respiratory protection such as an N95 respirator or equivalent.

Other important preventive measures include:

• Prompt treatment of active TB
• Contact investigation
• Screening of high-risk populations
• Treatment of latent tuberculosis infection
• Reporting cases to public-health authorities
• Appropriate infection-control procedures in healthcare facilities

Patients with contagious pulmonary TB should avoid close contact with vulnerable individuals, particularly:

• Young children
• Immunocompromised persons

⸻

Transmission and Pathophysiology

Tuberculosis is transmitted mainly by airborne droplet nuclei generated when a person with infectious pulmonary or laryngeal TB:

• Coughs
• Sneezes
• Speaks
• Sings

The small particles remain suspended in the air and may be inhaled into the alveoli.

Once inhaled, M. tuberculosis is engulfed by alveolar macrophages.

Several outcomes are possible:

1. The organism is eliminated.
2. Primary disease develops.
3. The immune system contains the organism, producing latent infection.
4. Latent infection later reactivates.

The host response involves formation of granulomas, which limit bacterial spread but may contain viable organisms for many years.

⸻

Etiology

Mycobacterium tuberculosis is a:

• Slender bacillus
• Obligate aerobe
• Slow-growing organism
• Acid-fast bacterium

Its acid-fast property results from the lipid-rich mycolic acid content of the bacterial cell wall.

On Ziehl-Neelsen staining, acid-fast bacilli appear as red rods against a contrasting background.

Humans are the major reservoir for M. tuberculosis.

⸻

Clinical Presentation

The clinical presentation depends on:

• Whether disease is primary or reactivated
• Organ involvement
• Host immune status
• Age
• Bacterial burden

⸻

Primary Pulmonary Tuberculosis

Primary infection may be asymptomatic.

When symptoms occur, they can include:

• Cough
• Fever
• Malaise
• Fatigue
• Pleuritic discomfort

Primary disease more commonly involves the lower or middle lung zones and may be associated with hilar or mediastinal lymphadenopathy.

⸻

Reactivation Pulmonary Tuberculosis

Reactivation or postprimary TB typically presents more gradually.

Classic manifestations include:

• Persistent cough
• Fever
• Night sweats
• Weight loss
• Fatigue
• Loss of appetite
• Hemoptysis
• Pleuritic chest pain

Upper-lobe or apical involvement is characteristic.

Cavitation may develop because of tissue necrosis.

⸻

Extrapulmonary Tuberculosis

TB can involve almost any organ.

Common extrapulmonary forms include:

• Lymph-node TB
• Pleural TB
• Tuberculous meningitis
• Bone and joint TB
• Genitourinary TB
• Abdominal TB
• Pericardial TB

Extrapulmonary disease is more common among immunocompromised patients.

⸻

Tuberculous Lymphadenitis

Tuberculous lymphadenitis commonly affects cervical lymph nodes and is sometimes termed scrofula.

Nodes may be:

• Enlarged
• Firm
• Relatively painless
• Matted together

Advanced disease may produce fluctuation, sinus formation, or drainage.

⸻

Tuberculous Meningitis

Tuberculous meningitis generally develops gradually.

Symptoms may include:

• Persistent headache
• Fever
• Malaise
• Vomiting
• Altered mental status

Neurologic findings can include:

• Meningismus
• Cranial nerve palsies
• Focal neurologic deficits
• Seizures

This is a medical emergency because delayed therapy can result in severe neurologic disability or death.

⸻

Skeletal Tuberculosis

Spinal tuberculosis is classically referred to as Pott disease.

It may cause:

• Back pain
• Vertebral destruction
• Kyphotic deformity
• Paravertebral abscess
• Spinal cord compression

Other bones and joints may also be affected.

⸻

Gastrointestinal Tuberculosis

Gastrointestinal TB may cause:

• Abdominal pain
• Diarrhea
• Weight loss
• Intestinal obstruction
• Ascites

The terminal ileum and ileocecal region are commonly involved.

⸻

Genitourinary Tuberculosis

Genitourinary TB may remain asymptomatic for prolonged periods.

Possible manifestations include:

• Dysuria
• Hematuria
• Flank discomfort
• Infertility

Persistent sterile pyuria should raise suspicion for genitourinary TB in an appropriate epidemiologic setting.

⸻

Miliary and Disseminated Tuberculosis

Miliary TB results from hematogenous dissemination of M. tuberculosis.

It can involve multiple organs, including:

• Lungs
• Liver
• Spleen
• Bone marrow
• Brain
• Kidneys

Patients may present with:

• Prolonged fever
• Night sweats
• Weight loss
• Weakness
• Hepatosplenomegaly

Severe disease may resemble sepsis or multiorgan failure.

⸻

Physical Examination

Physical findings may be minimal, even in significant disease.

Possible findings include:

Pulmonary disease

• Crackles
• Dullness to percussion
• Increased tactile fremitus
• Reduced breath sounds over an effusion

Lymph-node disease

• Enlarged cervical nodes
• Firm or matted lymphadenopathy

CNS disease

• Meningismus
• Cranial nerve deficits
• Altered mental status

Abdominal disease

• Tenderness
• Ascites
• Signs of obstruction

⸻

Diagnosis

Diagnosis requires distinction between:

• Latent tuberculosis infection
• Active tuberculosis disease

Neither the tuberculin skin test nor an interferon-gamma release assay can by itself prove active disease.

Active disease requires microbiologic, molecular, radiographic, and clinical evaluation.

⸻

Tuberculin Skin Test

The tuberculin skin test, or TST, measures delayed-type hypersensitivity to purified protein derivative.

The result is interpreted according to the diameter of induration, not erythema.

Traditionally:

≥5 mm is considered positive in high-risk patients such as:

• HIV-positive individuals
• Recent close contacts of infectious TB cases
• Certain severely immunocompromised patients

≥10 mm may be considered positive in patients with significant epidemiologic or medical risk factors.

≥15 mm is considered positive in persons without known risk factors.

Interpretation should follow current public-health guidance.

⸻

Interferon-Gamma Release Assays

Interferon-gamma release assays, or IGRAs, detect a T-cell response to M. tuberculosis-specific antigens.

Advantages include:

• Single patient visit
• No booster phenomenon
• Less interference from prior BCG vaccination

IGRAs are particularly useful in:

• BCG-vaccinated patients
• Patients unlikely to return for TST reading

Neither TST nor IGRA reliably differentiates latent infection from active disease.

⸻

BCG Vaccination

The Bacille Calmette-Guérin (BCG) vaccine is used routinely in many countries with high TB prevalence.

It provides its greatest benefit in children by reducing the risk of severe forms such as:

• Miliary TB
• Tuberculous meningitis

Prior BCG vaccination can cause false-positive TST results, although the effect decreases with time.

IGRAs are generally not affected by BCG vaccination.

⸻

Laboratory Diagnosis of Active Tuberculosis

Acid-Fast Bacillus Smear

Respiratory specimens are examined for acid-fast bacilli.

A positive smear supports mycobacterial infection but is not fully specific for M. tuberculosis because nontuberculous mycobacteria may also stain acid-fast.

Smear positivity generally indicates a higher bacterial burden and greater infectiousness.

⸻

Mycobacterial Culture

Culture remains an important reference method because it:

• Confirms viable organisms
• Allows species identification
• Permits drug-susceptibility testing

The major disadvantage is that M. tuberculosis grows slowly, so conventional culture can require several weeks.

⸻

Molecular Testing

Nucleic-acid amplification tests can rapidly identify M. tuberculosis directly from clinical samples and may simultaneously detect important drug-resistance mutations.

They are particularly valuable because results are available much faster than conventional culture.

Culture should still be obtained for complete susceptibility testing.

⸻

Sputum Collection

For suspected pulmonary TB, respiratory specimens should be obtained for:

• AFB smear
• Molecular testing
• Mycobacterial culture

Multiple specimens improve diagnostic sensitivity.

Induced sputum may be used when a patient cannot produce an adequate spontaneous sample.

If sputum studies remain nondiagnostic despite strong suspicion, bronchoscopy with bronchoalveolar lavage may be considered.

⸻

Extrapulmonary Diagnosis

Smears and cultures from extrapulmonary specimens are often less sensitive because disease may be paucibacillary.

Diagnosis may therefore rely heavily on:

• Tissue biopsy
• Histopathology
• Molecular testing
• Culture

⸻

Pathology

The classic histopathologic finding is a caseating granuloma.

Granulomas contain:

• Activated macrophages
• Epithelioid histiocytes
• Multinucleated giant cells
• Lymphocytes

Central caseous necrosis may develop.

However, granulomas are not specific for tuberculosis and may be seen in fungal infections and other diseases.

⸻

Imaging

Chest X-ray

Primary TB

Typical findings can include:

• Lower- or middle-lobe infiltrates
• Hilar or mediastinal lymphadenopathy
• Pleural effusion

Reactivation TB

More commonly demonstrates:

• Upper-lobe infiltrates
• Apical disease
• Cavitation
• Fibrotic changes
• Nodules

⸻

Chest CT

CT may reveal abnormalities not easily visible on plain radiographs.

Important findings include:

• Cavities
• Nodules
• Bronchial wall abnormalities
• Tree-in-bud opacities

The tree-in-bud pattern suggests endobronchial spread of infection but is not specific for tuberculosis.

⸻

Differential Diagnosis

Pulmonary tuberculosis can resemble many other diseases.

Important alternatives include:

• Nontuberculous mycobacterial infection
• Histoplasmosis
• Other endemic fungal infections
• Lung abscess
• Necrotizing bacterial pneumonia
• Sarcoidosis
• Lung cancer
• Lymphoma

The differential diagnosis depends on the patient’s epidemiology, immune status, radiographic pattern, and microbiologic findings.

⸻

Treatment of Latent Tuberculosis Infection

Treatment of LTBI significantly reduces the risk of future active disease.

Modern practice favors shorter rifamycin-based regimens in many patients because adherence is generally better than with prolonged isoniazid monotherapy.

Common contemporary approaches may include:

• Isoniazid plus rifapentine
• Rifampin alone
• Isoniazid plus rifampin
• Isoniazid monotherapy when other regimens are unsuitable

The regimen should be chosen based on:

• Age
• Pregnancy
• HIV status
• Drug interactions
• Potential source-case resistance
• Liver disease
• Adherence considerations

⸻

Pyridoxine

Pyridoxine, or vitamin B6, is often administered with isoniazid to reduce the risk of peripheral neuropathy.

It is particularly important in patients at higher risk, including:

• Pregnancy
• Diabetes
• HIV infection
• Malnutrition
• Alcohol use disorder
• Chronic kidney disease
• Pre-existing neuropathy

⸻

Treatment of Active Drug-Susceptible Pulmonary TB

The classic initial regimen consists of four drugs:

• Isoniazid
• Rifampin
• Pyrazinamide
• Ethambutol

This combination is often abbreviated as:

RIPE

⸻

Intensive Phase

During the first 2 months, treatment generally consists of:

Rifampin + isoniazid + pyrazinamide + ethambutol

⸻

Continuation Phase

For drug-susceptible pulmonary disease that responds appropriately, treatment then usually continues with:

Isoniazid + rifampin

for an additional 4 months, giving a typical total treatment duration of 6 months.

Longer treatment may be necessary in selected circumstances.

⸻

Extrapulmonary Tuberculosis Treatment

Many forms of extrapulmonary TB are treated using the same basic regimen as pulmonary TB.

Some forms may require prolonged therapy or additional interventions, particularly:

• CNS tuberculosis
• Bone and joint disease
• Complicated disease

Treatment duration should be individualized according to the site and response.

⸻

Tuberculous Meningitis

Tuberculous meningitis requires prompt multidrug therapy.

Adjunctive corticosteroids reduce mortality and are commonly recommended.

Treatment courses are generally longer than those used for uncomplicated pulmonary disease.

⸻

HIV and Tuberculosis

TB is a major opportunistic infection in patients with HIV.

HIV alters the clinical picture.

Patients with advanced immunosuppression may have:

• Less cavitation
• Lower-lobe disease
• Diffuse infiltrates
• Normal chest radiographs
• More extrapulmonary or disseminated disease

Treatment of drug-susceptible TB generally uses the same major drugs, but management must consider:

• Timing of antiretroviral therapy
• Drug-drug interactions
• Immune reconstitution inflammatory syndrome
• Rifamycin interactions

⸻

Drug-Resistant Tuberculosis

Drug-Resistant TB

This refers to infection resistant to one or more antituberculous drugs.

⸻

Multidrug-Resistant TB

MDR-TB traditionally means resistance to at least:

• Isoniazid
• Rifampin

Treatment requires specialist management and susceptibility-directed multidrug therapy.

⸻

Rifampin-Resistant TB

Resistance to rifampin is particularly important because it often predicts broader resistance and requires an MDR-type treatment approach.

⸻

Extensively Drug-Resistant TB

Definitions of XDR-TB have evolved over time.

Current classifications emphasize resistance beyond rifampin and isoniazid to important second-line agents, particularly fluoroquinolones and key newer drugs.

Older definitions based primarily on injectable agents should not be used automatically for contemporary classification.

⸻

Second-Line and Drug-Resistant TB Agents

Depending on susceptibility and current guidelines, treatment may include agents such as:

• Levofloxacin
• Moxifloxacin
• Linezolid
• Bedaquiline
• Pretomanid
• Clofazimine
• Cycloserine
• Other specialist-selected agents

Modern treatment of resistant TB increasingly uses all-oral regimens, reducing reliance on older toxic injectable drugs.

⸻

Drug Toxicities

Antituberculous drugs require careful monitoring because adverse effects may be significant.

⸻

Isoniazid

Important adverse effects include:

• Hepatitis
• Peripheral neuropathy

The risk of neuropathy is reduced with pyridoxine.

⸻

Rifampin

Important effects include:

• Hepatotoxicity
• Orange-red discoloration of urine, sweat, tears, and other body fluids
• Numerous drug-drug interactions

Rifampin strongly induces hepatic drug-metabolizing enzymes.

⸻

Pyrazinamide

Important adverse effects include:

• Hepatotoxicity
• Hyperuricemia
• Arthralgia

⸻

Ethambutol

The major toxicity is optic neuritis.

Patients should be monitored for:

• Reduced visual acuity
• Impaired red-green color discrimination

Visual symptoms require prompt evaluation.

⸻

Inpatient Considerations

Hospitalization may be required for:

• Respiratory isolation
• Severe pulmonary disease
• Disseminated TB
• CNS involvement
• Major complications
• Diagnostic uncertainty
• Inability to safely isolate at home

Discharge decisions should be coordinated with infection-control and public-health authorities rather than relying on a single fixed rule.

⸻

Follow-up

Close follow-up during therapy is essential to assess:

• Symptom improvement
• Medication adherence
• Drug toxicity
• Microbiologic response
• Development of resistance

Patients with pulmonary TB typically undergo repeat sputum testing during therapy until culture conversion is documented.

Long-term follow-up may be appropriate in patients at increased risk of relapse.

⸻

Patient Education

Patients should understand that successful treatment requires strict adherence to the full multidrug regimen.

Stopping therapy early or taking drugs inconsistently can result in:

• Relapse
• Persistent infectiousness
• Treatment failure
• Drug resistance

Patients should also be taught the warning signs of medication toxicity, including:

• Jaundice
• Persistent nausea or vomiting
• Severe abdominal pain
• Vision changes
• Numbness or tingling
• Severe rash

⸻

Prognosis

Drug-susceptible tuberculosis is usually curable when:

• Diagnosis is timely
• The correct multidrug regimen is used
• The patient adheres to treatment
• Drug resistance is absent

Prognosis is less favorable with:

• Delayed diagnosis
• Advanced HIV
• CNS disease
• Disseminated TB
• Severe malnutrition
• Drug-resistant disease

⸻

Complications

Pulmonary TB may lead to:

• Massive or recurrent hemoptysis
• Bronchiectasis
• Fibrotic lung disease
• Pulmonary cavitation
• Pneumothorax
• Pleural disease
• Secondary infection of residual cavities

Old cavities may occasionally become colonized by fungi, particularly Aspergillus, producing an aspergilloma.

Extrapulmonary complications depend on the affected organ and may include:

• Neurologic disability
• Spinal deformity
• Renal dysfunction
• Infertility
• Pericardial constriction

⸻

High-Yield Clinical Approach

Persistent cough + fever + night sweats + weight loss

→ Think pulmonary tuberculosis

Upper-lobe cavitary lesion

→ Strongly consider reactivation TB

Primary infection + hilar lymphadenopathy

→ Think primary pulmonary TB

TB + cervical painless lymphadenopathy

→ Think tuberculous lymphadenitis / scrofula

TB + back pain + vertebral destruction

→ Think Pott disease

TB + subacute headache + cranial nerve palsy

→ Think tuberculous meningitis

Sterile pyuria + epidemiologic risk

→ Think genitourinary TB

Diffuse tiny pulmonary nodules + systemic illness

→ Think miliary TB

Acid-fast bacilli on sputum smear

→ Supports mycobacterial disease; confirm M. tuberculosis with molecular testing/culture

BCG vaccination + need for TB infection testing

→ IGRA is particularly useful

Active drug-susceptible TB

→ Think RIPE therapy

Isoniazid toxicity

→ Hepatitis + peripheral neuropathy

Ethambutol toxicity

→ Optic neuritis and red-green color impairment

Rifampin

→ Orange body fluids + numerous drug interactions

⸻

Exam Essentials

Causative organism:

→ Mycobacterium tuberculosis

Transmission:

→ Airborne

Major reservoir:

→ Humans

Characteristic stain:

→ Acid-fast stain

Classic pathology:

→ Caseating granulomas

Latent infection:

→ Immune containment without active clinical disease

Tests for latent infection:

→ TST or IGRA

Does TST/IGRA prove active TB?

→ No

Best tests for active pulmonary TB:

→ Molecular testing + AFB smear + mycobacterial culture

Classic primary TB imaging:

→ Hilar lymphadenopathy with lower/middle lung involvement

Classic reactivation TB imaging:

→ Apical or upper-lobe disease with possible cavitation

Cervical TB lymphadenitis:

→ Scrofula

Spinal TB:

→ Pott disease

Disseminated hematogenous TB:

→ Miliary TB

Standard four-drug initial therapy:

→ Rifampin + isoniazid + pyrazinamide + ethambutol

Mnemonic:

→ RIPE

Isoniazid supplementation:

→ Pyridoxine

Major isoniazid toxicity:

→ Hepatitis and peripheral neuropathy

Major ethambutol toxicity:

→ Optic neuritis

Major rifampin clue:

→ Orange-red discoloration of body fluids

MDR-TB:

→ Resistance to at least isoniazid and rifampin

Major prevention strategy:

→ Early identification, airborne isolation, contact tracing, and treatment of latent infection

Infectious Disease and Microbiology - Trypanosomiasis: American (Chagas Disease) and African (Sleeping Sickness)

Basics

Description

Trypanosomiasis refers to a group of zoonotic protozoal infections caused by Trypanosoma species and transmitted primarily by blood-feeding insect vectors.

Two major human diseases are recognized:

• American trypanosomiasis (Chagas disease) — caused by Trypanosoma cruzi
• Human African trypanosomiasis (sleeping sickness) — caused by Trypanosoma brucei gambiense or T. brucei rhodesiense

Although both are caused by trypanosomes, their vectors, geographic distributions, clinical manifestations, diagnostic approaches, and treatments are substantially different.

Chagas disease is particularly important because chronic infection can eventually cause severe cardiomyopathy, arrhythmias, megaesophagus, and megacolon.

African trypanosomiasis initially produces a systemic hemolymphatic illness and later invades the central nervous system, producing the characteristic sleep and neurologic disturbances responsible for the term sleeping sickness.

⸻

Etiology

American trypanosomiasis

Chagas disease is caused by:

Trypanosoma cruzi

The principal vector is the triatomine bug, also called the:

• Kissing bug
• Reduviid bug

Unlike many vector-borne infections, the parasite is not primarily transmitted through the insect’s saliva during the bite.

Instead, the infected bug defecates near the bite site, and parasites in the feces enter through damaged skin or mucous membranes.

⸻

African trypanosomiasis

Human African trypanosomiasis is transmitted by the tsetse fly (Glossina species).

Two major organisms cause disease.

Trypanosoma brucei gambiense

Causes West and Central African trypanosomiasis.

It typically produces a relatively slowly progressive, chronic illness, developing over months to years.

Trypanosoma brucei rhodesiense

Causes East and Southern African trypanosomiasis.

It generally produces a more acute and rapidly progressive disease, often developing over weeks to months.

⸻

Epidemiology

Chagas disease

T. cruzi infection is primarily associated with:

• Mexico
• Central America
• South America

Historically, the greatest burden has occurred in rural areas of Latin America where triatomine insects can colonize poorly constructed housing.

Migration has resulted in infected individuals living throughout North America, Europe, and other regions outside traditional endemic areas.

Locally acquired vector-borne infection in the United States is possible but uncommon.

⸻

African trypanosomiasis

Human African trypanosomiasis occurs in sub-Saharan Africa, corresponding to the geographic distribution of the tsetse fly.

T. b. gambiense historically accounts for most cases and occurs primarily in West and Central Africa.

T. b. rhodesiense occurs mainly in East and Southern Africa.

The geographic distribution is therefore an important clue when distinguishing the two forms.

⸻

Risk factors

Chagas disease

Important risk factors include:

• Residence in endemic areas
• Poor-quality rural housing
• Mud or adobe houses that permit triatomine infestation
• Exposure to infected triatomine bugs
• Consumption of food or beverages contaminated with T. cruzi
• Receiving infected blood products
• Receiving an infected organ transplant
• Maternal infection during pregnancy

Immunosuppression can cause reactivation of latent Chagas disease, particularly in patients with:

• HIV infection
• Organ transplantation
• Other major forms of immunosuppression

⸻

African trypanosomiasis

Risk is associated primarily with exposure to tsetse flies in endemic regions of sub-Saharan Africa.

Exposure may occur through:

• Residence in endemic rural regions
• Agricultural activities
• Hunting
• Fishing
• Travel to affected game parks or rural areas

⸻

Transmission of Chagas disease

T. cruzi can be transmitted by several mechanisms.

Vector-borne transmission

This is the classic route.

The triatomine bug feeds on human blood and subsequently deposits infected feces near the bite.

Scratching or rubbing allows parasites to enter through:

• Broken skin
• The bite wound
• Conjunctiva
• Other mucosal surfaces

Congenital transmission

An infected pregnant woman can transmit T. cruzi across the placenta to the fetus.

Blood transfusion

Transmission through infected blood products can occur, although screening programs have substantially reduced this risk in countries where blood donations are routinely tested.

Organ transplantation

An infected donor organ can transmit the parasite to a seronegative recipient.

Oral transmission

Outbreaks have occurred after consumption of food or beverages contaminated with infected triatomine material.

⸻

Pathophysiology of Chagas disease

After entering the human body, T. cruzi trypomastigotes invade host cells and transform into intracellular amastigotes.

The organisms multiply intracellularly and subsequently differentiate back into trypomastigotes, which enter the bloodstream and infect additional tissues.

Over time, chronic inflammation, tissue destruction, fibrosis, and autonomic neuronal injury can produce characteristic chronic complications.

The organs most importantly affected are:

• Heart
• Esophagus
• Colon
• Nervous system

⸻

Clinical presentation of Chagas disease

Chagas disease can be divided into:

1. Acute infection
2. Chronic indeterminate infection
3. Chronic determinate disease

⸻

Acute Chagas disease

Acute disease generally develops after initial infection and is often mild, particularly in children.

Many patients have few or no symptoms.

Possible manifestations include:

• Fever
• Malaise
• Fatigue
• Lymphadenopathy
• Hepatomegaly
• Splenomegaly
• Local inflammatory lesions

Most acute manifestations resolve spontaneously over several weeks.

⸻

Chagoma

A chagoma is an inflammatory lesion that develops at the site where T. cruzi enters through the skin.

It typically appears as:

• Indurated papule
• Local erythema
• Swelling
• Regional lymphadenopathy

⸻

Romaña sign

Romaña sign is a classic manifestation of acute Chagas disease.

It occurs when the parasite enters through the conjunctiva.

The patient develops:

• Unilateral painless periorbital or eyelid edema
• Conjunctival inflammation
• Regional lymphadenopathy

This finding in a patient from an endemic region strongly suggests acute Chagas disease.

⸻

Severe acute Chagas disease

Although uncommon, acute infection can occasionally produce:

• Myocarditis
• Pericardial involvement
• Meningoencephalitis

Severe disease occurs more frequently in young children and immunocompromised patients.

⸻

Chronic Chagas disease

After the acute phase, patients enter a chronic infection.

Many remain in an indeterminate phase, characterized by positive serology without obvious clinical disease.

However, a proportion of infected individuals eventually develop clinically significant organ involvement, sometimes decades after the initial infection.

The major manifestations involve the:

• Heart
• Esophagus
• Colon

⸻

Chagas cardiomyopathy

Cardiac involvement is the most important chronic manifestation of Chagas disease.

Chronic myocardial inflammation and fibrosis can produce progressive cardiomyopathy.

Patients may develop:

• Palpitations
• Presyncope
• Syncope
• Exercise intolerance
• Dyspnea
• Heart failure
• Atypical chest discomfort
• Thromboembolic events

⸻

Arrhythmias and conduction disease

Damage to the cardiac conduction system can produce:

• Bundle branch block
• Atrioventricular block
• Ventricular premature beats
• Ventricular tachycardia
• Other ventricular arrhythmias

Sudden cardiac death may occur from malignant ventricular arrhythmias or complete heart block.

⸻

Apical aneurysm

A characteristic cardiac complication is formation of a left ventricular apical aneurysm.

This can promote:

• Mural thrombus formation
• Systemic embolization
• Ischemic stroke

The presence of an apical aneurysm therefore indicates important thromboembolic risk.

⸻

Gastrointestinal Chagas disease

Destruction of neurons within the enteric nervous system can impair gastrointestinal motility.

The major manifestations are:

• Megaesophagus
• Megacolon

⸻

Megaesophagus

Esophageal dysfunction resembles achalasia.

Patients may develop:

• Dysphagia
• Regurgitation
• Weight loss
• Chest discomfort
• Aspiration

Repeated aspiration can produce respiratory complications.

⸻

Megacolon

Colonic involvement produces progressive dilation and impaired motility.

Manifestations include:

• Severe constipation
• Abdominal distention
• Abdominal discomfort
• Fecal impaction

Advanced disease can occasionally lead to volvulus or bowel obstruction.

⸻

Diagnosis of acute Chagas disease

During acute infection, parasitemia is relatively high, making direct demonstration of circulating parasites possible.

Blood can be examined using:

• Wet preparation
• Thick blood smear
• Thin blood smear
• Giemsa staining
• Buffy-coat examination

Motile trypomastigotes may be visualized in peripheral blood.

Molecular methods such as PCR can also be useful, particularly for acute infection, congenital infection, and suspected reactivation.

⸻

Diagnosis of chronic Chagas disease

Parasitemia becomes very low during chronic infection, so direct microscopy is usually insensitive.

Diagnosis therefore relies primarily on serologic detection of IgG antibodies against T. cruzi.

Available techniques include:

• ELISA
• Indirect immunofluorescence
• Other validated serologic assays

Because no single serologic test has perfect sensitivity and specificity, chronic infection is generally confirmed using two different serologic assays based on different antigens or techniques.

⸻

Evaluation for chronic Chagas complications

Once chronic Chagas disease is identified, patients should be evaluated for organ involvement.

Cardiac assessment

Important investigations include:

• Resting ECG
• Echocardiography

Depending on symptoms and initial findings, additional testing may include:

• Ambulatory ECG monitoring
• Exercise testing
• Additional cardiac imaging

Gastrointestinal assessment

Patients with dysphagia or constipation may require:

• Barium swallow
• Contrast studies of the colon
• Esophageal manometry
• Other gastrointestinal investigations according to symptoms

⸻

Pathology of chronic Chagas disease

Chronic Chagas cardiomyopathy may demonstrate:

• Ventricular enlargement
• Ventricular wall thinning
• Apical aneurysm
• Mural thrombi

Microscopically, the myocardium can show:

• Chronic lymphocytic inflammation
• Interstitial fibrosis
• Myocyte degeneration and atrophy

In megaesophagus and megacolon, there is progressive loss of neurons within the myenteric plexus, leading to dilation and muscular abnormalities.

⸻

Treatment of Chagas disease

The two principal antitrypanosomal drugs are:

Benznidazole

and

Nifurtimox

Treatment is most effective when administered early in the course of infection.

⸻

Benznidazole

Benznidazole is generally preferred because it is usually better tolerated than nifurtimox.

The traditional adult regimen is approximately:

5–7 mg/kg/day orally in divided doses for about 60 days.

Exact dosing depends on age, weight, and contemporary treatment recommendations.

⸻

Nifurtimox

Nifurtimox is an alternative antitrypanosomal drug.

Traditional treatment requires multiple daily doses for a prolonged period.

Adverse effects can limit tolerability.

⸻

Who should receive treatment?

Antiparasitic treatment is particularly important for:

• Acute Chagas disease
• Congenital infection
• Reactivation during immunosuppression
• Children with chronic infection
• Many adolescents and younger adults with chronic infection
• Selected patients who are expected to undergo substantial immunosuppression

Treatment decisions in older adults and patients with established cardiomyopathy should be individualized according to disease severity, age, comorbidities, and expected benefit.

Antiparasitic therapy is considerably more effective at achieving parasitologic cure in younger patients and earlier infection.

Established cardiac and gastrointestinal complications require appropriate organ-specific management in addition to consideration of antiparasitic therapy.

⸻

African trypanosomiasis

Human African trypanosomiasis, or sleeping sickness, is fundamentally different from Chagas disease.

The infection is transmitted through the bite of an infected tsetse fly.

Disease progression is divided into two major stages:

Stage I — Hemolymphatic stage

Parasites are present predominantly in:

• Blood
• Lymphatic system

Stage II — Meningoencephalitic stage

Parasites cross the blood-brain barrier and invade the:

• Brain
• Cerebrospinal fluid
• Central nervous system

Determining the stage is essential because treatment depends on whether CNS invasion has occurred.

⸻

West African trypanosomiasis

Trypanosoma brucei gambiense

This form generally follows a slow, chronic course.

Symptoms may develop over months, and neurologic disease may not appear until months or years after infection.

⸻

Stage I — Hemolymphatic disease

A trypanosomal chancre may develop at the site of the tsetse fly bite.

The lesion may be:

• Painful
• Indurated
• Erythematous
• Occasionally ulcerated

Systemic manifestations subsequently develop.

These may include:

• Intermittent fever
• Headache
• Malaise
• Pruritus
• Arthralgia
• Facial edema
• Peripheral edema
• Rash
• Lymphadenopathy

Lymph nodes are typically enlarged but relatively painless.

⸻

Lymphadenopathy

Posterior cervical lymphadenopathy is a classic feature of gambiense sleeping sickness.

Prominent enlargement of the posterior cervical nodes is traditionally called Winterbottom sign.

⸻

Stage II — Meningoencephalitic disease

Once parasites invade the CNS, neurologic and psychiatric abnormalities develop.

Possible manifestations include:

• Severe headache
• Personality changes
• Behavioral abnormalities
• Irritability
• Confusion
• Tremor
• Fasciculations
• Ataxia
• Abnormal movements
• Progressive somnolence

The normal sleep-wake cycle becomes disturbed, producing the characteristic sleeping sickness syndrome.

As disease progresses, patients may develop:

• Profound neurologic impairment
• Stupor
• Coma
• Death

Without appropriate treatment, advanced disease can be fatal.

⸻

East African trypanosomiasis

Trypanosoma brucei rhodesiense

East African disease is generally much more acute and aggressive than gambiense disease.

Symptoms may begin within days to weeks after infection.

Patients may develop:

• Fever
• Severe headache
• Malaise
• Rash
• Lymphadenopathy
• Trypanosomal chancre

CNS invasion tends to occur earlier.

Cardiac involvement may also be prominent.

Untreated disease can progress rapidly and become fatal within months.

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Diagnosis of African trypanosomiasis

Definitive diagnosis requires demonstration of the parasite.

Organisms may be sought in:

• Blood
• Chancre fluid
• Lymph-node aspirate
• Cerebrospinal fluid

Microscopy can include:

• Wet preparations
• Giemsa-stained preparations

Concentration techniques may increase diagnostic sensitivity when parasitemia is low.

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Serologic screening

Serologic methods have been particularly useful for population screening for T. b. gambiense in endemic settings.

Historically, the card agglutination test for trypanosomiasis (CATT) has been widely used for this purpose.

A positive screening test requires appropriate parasitologic confirmation and staging.

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Lumbar puncture and staging

After African trypanosomiasis is confirmed, assessment for CNS involvement is critical because therapy differs between early and late disease.

Cerebrospinal fluid may demonstrate:

• Increased white blood cells
• Elevated protein
• Trypanosomes

Evidence of CNS involvement indicates stage II disease.

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Treatment of African trypanosomiasis

Treatment depends on:

• Trypanosoma subspecies
• Geographic region
• Stage of disease
• CNS involvement
• Availability of medications

Modern treatment recommendations have evolved considerably, so older textbook regimens should not automatically be applied without checking current guidance.

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West African disease —

T. b. gambiense

Historically, early-stage disease was treated with pentamidine.

Pentamidine does not adequately penetrate the CNS and therefore is not suitable as sole therapy for established late-stage neurologic disease.

For CNS disease, older regimens included eflornithine, while combination approaches and newer oral therapy have substantially changed contemporary management.

Fexinidazole is now an important oral treatment option for eligible patients with gambiense human African trypanosomiasis.

The exact regimen depends on disease severity and current recommendations.

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East African disease —

T. b. rhodesiense

Historically, suramin has been used for first-stage disease.

Because suramin can cause significant adverse reactions, treatment requires careful medical supervision.

Historically, CNS disease was treated with melarsoprol.

Melarsoprol is an arsenical drug associated with substantial toxicity, including potentially fatal encephalopathic reactions.

Treatment of African trypanosomiasis should therefore be coordinated with clinicians and public-health authorities experienced in tropical medicine.

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Prevention

Chagas disease

Prevention focuses on reducing contact with triatomine vectors and preventing nonvector transmission.

Important strategies include:

• Improving housing quality
• Eliminating triatomine infestation
• Using insecticides where appropriate
• Avoiding sleeping in heavily infested structures
• Screening donated blood
• Screening appropriate organ donors and recipients
• Preventing contamination of food and beverages
• Screening individuals at risk for congenital transmission

There is currently no routinely available vaccine.

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African trypanosomiasis

Prevention primarily involves avoiding tsetse fly exposure.

Travelers to endemic areas should:

• Wear long-sleeved clothing
• Wear long trousers
• Avoid known areas of heavy tsetse infestation when possible
• Follow local vector-control advice

No routinely available vaccine prevents African trypanosomiasis.

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Follow-up

Chagas disease

Patients with chronic infection require ongoing assessment for:

• Cardiac conduction abnormalities
• Arrhythmias
• Cardiomyopathy
• Heart failure
• Thromboembolic complications
• Dysphagia
• Megaesophagus
• Constipation
• Megacolon

Periodic clinical assessment and ECG monitoring are particularly important.

Individuals with T. cruzi infection should not donate blood.

Screening may also be appropriate for:

• Children born to infected mothers
• Other family members with similar epidemiologic exposure
• Individuals who lived in endemic regions with substantial vector exposure

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Prognosis

Chagas disease

Many infected individuals remain asymptomatic for life.

However, a substantial minority eventually develop chronic cardiac or gastrointestinal disease.

Chronic Chagas cardiomyopathy can cause:

• Progressive heart failure
• Ventricular arrhythmias
• Complete heart block
• Systemic embolization
• Stroke
• Sudden cardiac death

Cardiac involvement is the major determinant of long-term mortality.

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African trypanosomiasis

Prognosis is excellent when infection is recognized and appropriately treated before advanced neurologic damage occurs.

Untreated disease can progress to severe CNS dysfunction, coma, and death.

The rhodesiense form generally progresses more rapidly than the gambiense form.

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Complications

Chagas disease

Major complications include:

• Dilated cardiomyopathy
• Chronic heart failure
• Ventricular arrhythmias
• Conduction abnormalities
• Sudden cardiac death
• Apical ventricular aneurysm
• Mural thrombus
• Systemic embolization
• Stroke
• Megaesophagus
• Aspiration
• Megacolon
• Severe constipation
• Intestinal obstruction or volvulus

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African trypanosomiasis

Major complications include:

• Meningoencephalitis
• Sleep-wake disturbances
• Neuropsychiatric abnormalities
• Seizures
• Progressive neurologic deterioration
• Coma
• Cardiac involvement
• Death

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High-yield clinical approach

Latin America + kissing bug exposure + unilateral periorbital swelling

→ Think acute Chagas disease with Romaña sign

Chronic T. cruzi infection + palpitations/syncope

→ Think Chagas cardiomyopathy and conduction disease

Chagas disease + ventricular apical aneurysm

→ Increased risk of mural thrombus and embolic stroke

Chagas disease + progressive dysphagia

→ Think megaesophagus

Chagas disease + severe chronic constipation and abdominal distention

→ Think megacolon

Sub-Saharan Africa + tsetse fly exposure + fever and lymphadenopathy

→ Think African trypanosomiasis

Posterior cervical lymphadenopathy

→ Winterbottom sign

African trypanosomiasis + behavioral changes + abnormal sleep pattern

→ Think CNS invasion / stage II sleeping sickness

Slow disease over months to years

→ T. b. gambiense

Rapid, aggressive illness over weeks to months

→ T. b. rhodesiense

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Exam essentials

American trypanosomiasis:

→ Chagas disease

Cause of Chagas disease:

→ Trypanosoma cruzi

Vector:

→ Triatomine/reduviid “kissing” bug

Important transmission mechanism:

→ Parasites in bug feces enter damaged skin or mucosa

Classic acute Chagas finding:

→ Romaña sign

Romaña sign:

→ Unilateral periorbital edema after conjunctival inoculation

Local inoculation lesion:

→ Chagoma

Diagnosis of acute Chagas disease:

→ Demonstration of circulating parasites or molecular detection

Diagnosis of chronic Chagas disease:

→ Serology, generally confirmed with two different assays

Major chronic Chagas complication:

→ Cardiomyopathy

Classic gastrointestinal complications:

→ Megaesophagus and megacolon

Important cardiac structural abnormality:

→ Apical aneurysm

Major causes of death in chronic cardiac Chagas disease:

→ Ventricular arrhythmia, conduction block, heart failure, or thromboembolism

Main Chagas drugs:

→ Benznidazole and nifurtimox

African trypanosomiasis vector:

→ Tsetse fly

West/Central African sleeping sickness:

→ T. brucei gambiense

East/Southern African sleeping sickness:

→ T. brucei rhodesiense

Gambiense disease:

→ Chronic, slowly progressive

Rhodesiense disease:

→ Acute, rapidly progressive

Classic lymph-node finding in African disease:

→ Posterior cervical lymphadenopathy — Winterbottom sign

Stage I African trypanosomiasis:

→ Hemolymphatic disease

Stage II African trypanosomiasis:

→ CNS/meningoencephalitic disease

Characteristic late manifestation:

→ Disruption of the sleep-wake cycle

Critical investigation for staging African trypanosomiasis:

→ Cerebrospinal fluid assessment

Most important treatment principle:

→ Identify the organism and determine whether CNS involvement is present before selecting therapy

Infectious Disease and Microbiology - Traveler’s diarrhea

Basics

Description

Traveler’s diarrhea is the most frequent illness encountered by people traveling internationally. It usually represents an acute gastrointestinal infection acquired after ingestion of food or water contaminated by fecal organisms. The likelihood of developing illness depends heavily on the travel destination, local sanitation, food preparation and storage practices, and the traveler’s own dietary and hygiene habits.

Most episodes are mild and resolve spontaneously. However, symptoms may significantly interfere with travel plans, and substantial fluid loss can occasionally produce clinically important dehydration.

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Epidemiology

Incidence

Approximately 20–50% of international travelers may develop diarrhea during travel. Men and women appear to have similar attack rates, but the overall risk varies considerably according to destination.

Historically, the highest-risk regions have included Latin America, Africa, much of Asia, and the Middle East, where attack rates may exceed 20% and sometimes 50%. Intermediate-risk areas have included parts of Southern Europe, Israel, and selected Caribbean islands. Lower-risk destinations generally include the United States, Canada, Northern Europe, Australia, New Zealand, Japan, and much of the Caribbean.

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Risk factors

Factors that increase the likelihood of traveler’s diarrhea include travel to regions with poor sanitation, failure to follow food and water precautions, immunocompromised status, inflammatory bowel disease, and reduced gastric acidity, particularly in people taking proton-pump inhibitors.

Students, backpackers, adventure travelers, and individuals with repeated previous episodes may also be at increased risk. Pregnancy may increase susceptibility because physiologic changes can alter gastric acidity and gastrointestinal function.

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Etiology

Most cases of traveler’s diarrhea are infectious, with bacteria responsible for the majority of episodes.

Bacterial causes

Bacteria account for roughly 80–90% of identified cases. The classic and important pathogen is enterotoxigenic Escherichia coli (ETEC). Enteroaggregative E. coli is also increasingly recognized.

Other bacterial causes include Campylobacter, nontyphoidal Salmonella, Shigella, Aeromonas, Plesiomonas shigelloides, and non-cholera Vibrio species.

Viral causes

Viruses account for a smaller proportion of disease. Important agents include norovirus and rotavirus.

Norovirus is particularly associated with outbreaks in cruise ships, camps, and other closed or semi-closed environments. Prominent vomiting is a useful clinical clue.

Parasitic causes

Protozoal infections become increasingly important in travelers with prolonged symptoms or long-duration travel. Important organisms include Giardia duodenalis, Entamoeba histolytica, Cryptosporidium, Cyclospora cayetanensis, Cystoisospora belli, and Balantidium coli.

Giardia is especially associated with contaminated food or water and wilderness exposure. E. histolytica may be acquired from contaminated food, water, or vegetables. Cryptosporidium can be transmitted through contaminated water or animal exposure, while Cyclospora is commonly linked to contaminated food or water.

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Incubation period

The incubation period can help suggest the likely category of pathogen.

Cause

Typical incubation

Bacterial infection

6–48 hours

Viral infection

6–48 hours

Protozoal infection

Usually 1–2 weeks

A rapid onset shortly after exposure favors a bacterial or viral cause, whereas delayed onset with persistent diarrhea should raise suspicion for protozoal infection.

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Clinical presentation

Classic traveler’s diarrhea

Traditionally, classic disease has been defined as three or more unformed stools within 24 hours together with at least one additional symptom such as nausea, vomiting, abdominal pain, cramps, fever, or blood in the stool.

Moderate disease

Moderate illness has traditionally included one or two loose stools accompanied by additional enteric symptoms, or multiple unformed stools with enough discomfort to interfere with usual activities.

Mild disease

Mild illness typically consists of only one or two loose stools with little or no associated systemic disturbance.

In contemporary practice, severity is increasingly judged by how much the illness interferes with planned activities, rather than by stool number alone.

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Clinical patterns according to cause

Bacterial diarrhea

Bacterial illness usually begins abruptly. Manifestations range from mild urgency, cramping, and watery stools to severe abdominal pain, fever, vomiting, and bloody diarrhea.

Without treatment, bacterial traveler’s diarrhea commonly lasts around 3–5 days.

Viral diarrhea

Viral gastroenteritis may closely resemble bacterial disease. Norovirus often produces prominent vomiting and usually resolves within approximately 2–3 days.

Protozoal diarrhea

Protozoal disease tends to develop more gradually and often produces fewer but persistent loose stools. Patients may have approximately two to five loose stools daily, with symptoms continuing for weeks or even months if untreated.

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Physical examination

Examination may reveal loose or watery stools, abdominal tenderness, and evidence of dehydration. Bloody stool occurs in a minority of cases and should increase concern for an invasive enteric pathogen.

Important signs of dehydration include tachycardia, orthostatic hypotension, dry mucous membranes, reduced urine output, poor skin turgor, and altered mental status in severe cases.

Young children, older adults, pregnant patients, and medically vulnerable individuals are particularly susceptible to complications from fluid loss.

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Diagnosis

Traveler’s diarrhea is usually diagnosed clinically from the combination of recent travel and compatible gastrointestinal symptoms. Routine laboratory testing is unnecessary in most uncomplicated, short-lived episodes.

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Diagnostic testing

Stool studies

Microbiologic stool testing should be considered when there is high fever, bloody diarrhea, severe illness, features of colitis, immunocompromise, failure of empiric treatment, or prolonged symptoms.

Stool culture is particularly appropriate in patients with fever and inflammatory or bloody diarrhea.

Persistent diarrhea

Diarrhea lasting longer than approximately 10–14 days should prompt evaluation for protozoal infection.

Important organisms include:

• Giardia duodenalis
• Entamoeba histolytica
• Cryptosporidium
• Cyclospora cayetanensis

A useful clinical rule is:

Traveler with diarrhea lasting more than 2 weeks → think protozoa.

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Differential diagnosis

Not every gastrointestinal illness that develops during travel is infectious traveler’s diarrhea. Other possibilities include food poisoning caused by preformed toxins, shellfish poisoning, scombroid poisoning, and ciguatera poisoning.

Depending on the clinical presentation, other infectious diarrheal illnesses, inflammatory bowel disease, and noninfectious gastrointestinal disorders may also need to be considered.

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General prevention

The major preventive goal is to avoid ingestion of fecally contaminated food and water.

Travelers should avoid unsafe tap water, including its use for brushing teeth when water quality is uncertain. Ice should be avoided unless made from purified water. Unpasteurized dairy products, raw or undercooked meat or seafood, unpeeled raw fruits, inadequately washed vegetables, raw leafy vegetables, and food from vendors with questionable hygiene should also be avoided.

A practical rule is:

Boil it, cook it, peel it—or leave it.

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Water safety

Boiling

Boiling remains one of the most dependable simple methods of making water microbiologically safer.

Chlorination and iodination

Chemical disinfection can reduce many infectious risks, but it is less reliable against organisms such as Cryptosporidium.

Bottled water

Commercial bottled water is generally considered safer when the original cap and seal remain intact.

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Hand hygiene

Travelers should wash their hands with soap and safe water whenever possible, especially before eating or handling food. When soap and water are unavailable, an alcohol-based hand sanitizer containing at least 60% alcohol can be used.

Good hand hygiene reduces both foodborne transmission and direct person-to-person spread.

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Chemoprophylaxis

Antibiotic prophylaxis

Although prophylactic antibiotics can decrease the frequency of traveler’s diarrhea, routine use is not recommended for most travelers because of adverse effects, alteration of normal intestinal flora, and increasing antimicrobial resistance.

Preventive antibiotics may occasionally be considered for selected high-risk individuals when even a brief diarrheal illness could have serious medical, occupational, or logistical consequences.

Historically used agents have included rifaximin and fluoroquinolones, but contemporary decisions should take current resistance patterns into account.

Bismuth subsalicylate

Bismuth subsalicylate can reduce the incidence of traveler’s diarrhea and is one of the better studied non-antibiotic preventive strategies.

A historically used regimen is two 262-mg tablets or 60 mL four times daily for up to about 3 weeks.

It should be avoided or used cautiously in patients taking anticoagulants or other salicylates and in those with contraindications to salicylate therapy. It may also interfere with doxycycline absorption.

Probiotics

Evidence supporting probiotics for prevention remains inconsistent. Preparations studied include Lactobacillus species and Saccharomyces boulardii.

They should not replace food, water, and hygiene precautions.

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Treatment

Rehydration is the priority

The most important treatment for traveler’s diarrhea is replacement of fluids and electrolytes.

Most infections are self-limited, and the greatest immediate danger—especially in vulnerable patients—is dehydration.

Oral rehydration solution (ORS) is particularly useful for infants, children, older adults, and patients with substantial fluid loss. Severe dehydration or inability to tolerate oral fluids may require intravenous therapy.

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Antibiotic treatment

Antibiotics can shorten the duration of moderate-to-severe bacterial disease but are unnecessary for every mild episode.

Choice of therapy depends on the travel destination, illness severity, presence of fever or dysentery, local resistance patterns, pregnancy status, age, and underlying medical conditions.

Azithromycin

Azithromycin is especially useful when there is febrile diarrhea, dysentery, or travel to regions with high rates of fluoroquinolone-resistant Campylobacter, particularly parts of South and Southeast Asia.

A commonly cited regimen is azithromycin 1 g orally as a single dose.

It is also an important option for children and pregnant patients when antimicrobial treatment is indicated.

Fluoroquinolones

Ciprofloxacin was historically a major treatment option. A classic regimen is ciprofloxacin 500 mg orally twice daily for 3 days.

However, fluoroquinolones are less universally useful today because resistance has increased, particularly among Campylobacter and some other enteric organisms. Safety concerns related to the drug class must also be considered.

Rifaximin

Rifaximin is a poorly absorbed antibiotic that may be used for afebrile, noninvasive, nondysenteric traveler’s diarrhea.

A commonly cited regimen is 200 mg orally twice daily for 3 days.

It should not be relied on when there is fever, bloody diarrhea, or concern for an invasive bacterial infection.

A useful distinction is:

Watery + afebrile → rifaximin may be appropriate.

Fever or blood → think invasive disease and choose another approach.

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Symptomatic therapy

Loperamide

Loperamide decreases intestinal motility and can provide rapid symptomatic relief, particularly when the traveler needs short-term control of diarrhea.

It may also be combined with an appropriate antibiotic in selected moderate-to-severe cases.

Loperamide should generally not be used alone when there is bloody diarrhea, high fever, or suspected invasive bacterial colitis. Extra caution is required in young children.

Bismuth subsalicylate

Bismuth subsalicylate may also reduce diarrhea and gastrointestinal discomfort. A traditional regimen is two 262-mg tablets or 60 mL up to four times daily.

It should be avoided when salicylates are contraindicated.

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Protozoal infections

Persistent post-travel diarrhea requires a different diagnostic and therapeutic approach from ordinary acute bacterial traveler’s diarrhea.

Giardiasis

Giardia should be suspected when persistent diarrhea is accompanied by bloating, flatulence, malabsorption, greasy or foul-smelling stools, or a history of contaminated water exposure.

A traditional treatment regimen is metronidazole 250 mg orally three times daily for 5 days.

Amebiasis

Invasive Entamoeba histolytica infection requires therapy against both invasive trophozoites and organisms remaining within the intestinal lumen.

A classic regimen is metronidazole 500–750 mg orally three times daily for 10 days, followed by a luminal agent such as paromomycin or iodoquinol.

A key principle is:

Metronidazole alone is not adequate treatment for invasive amebiasis. A luminal amebicide must follow.

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Pregnancy considerations

Pregnant travelers require careful attention to dehydration and medication safety.

Azithromycin may be used when antibiotic treatment is required. Fluoroquinolones are generally avoided when suitable alternatives are available. Bismuth subsalicylate is usually avoided, and the safety of rifaximin in pregnancy has not been sufficiently established for routine use.

Loperamide may sometimes be considered depending on the clinical circumstances. Medication choices should be individualized.

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Pediatric considerations

Infants and young children can become dehydrated quickly. The priority is oral rehydration and close monitoring.

Medical evaluation is especially important when a child has persistent vomiting, inability to drink, markedly reduced urine output, lethargy, high fever, bloody diarrhea, or other signs of significant dehydration.

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Diet during recovery

Normal feeding can usually be resumed early as tolerated. Prolonged fasting is unnecessary.

Temporary reduction of alcohol, coffee or caffeine, carbonated drinks, and dairy products may be helpful if these worsen symptoms.

The main priority remains adequate fluid, electrolyte, and nutritional intake.

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Prognosis

Most cases of traveler’s diarrhea resolve without lasting consequences.

Typical untreated durations are approximately:

• Viral illness: 2–3 days
• Bacterial illness: 3–5 days
• Protozoal illness: potentially weeks to months

The most important immediate threat is dehydration, especially in young children, older adults, pregnant patients, and people with significant underlying disease.

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Complications

Dehydration

This is the most important acute complication. Severe volume loss can cause electrolyte abnormalities, hypotension, acute kidney injury, and shock.

Reactive arthritis

Reactive arthritis can develop after infections caused by organisms such as Campylobacter, Salmonella, and Shigella.

Guillain–Barré syndrome

Campylobacter jejuni infection is a well-known infectious trigger for Guillain–Barré syndrome.

Postinfectious irritable bowel syndrome

Some patients develop persistent gastrointestinal symptoms even after the original infection has cleared. Manifestations may include abdominal discomfort, altered bowel frequency, diarrhea, constipation, and bloating.

This condition is known as postinfectious irritable bowel syndrome.

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High-yield approach to traveler’s diarrhea

Clinical pattern

Likely consideration

Acute watery diarrhea after travel

ETEC or another bacterial cause

Prominent vomiting during a cruise-ship or camp outbreak

Norovirus

Fever with bloody diarrhea

Invasive bacterial infection

South/Southeast Asia with inflammatory diarrhea

Resistant Campylobacter; azithromycin often useful

Diarrhea persisting >2 weeks

Protozoal infection

Persistent diarrhea with bloating or greasy stools

Giardia

Dysentery with appropriate exposure

E. histolytica

Weakness after Campylobacter infection

Guillain–Barré syndrome

Arthritis after bacterial diarrhea

Reactive arthritis

Chronic bowel symptoms after infection

Postinfectious IBS

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Exam essentials

Most common illness affecting international travelers:

→ Traveler’s diarrhea

Major route of acquisition:

→ Fecally contaminated food or water

Most cases are caused by:

→ Bacteria

Classic major pathogen:

→ Enterotoxigenic Escherichia coli (ETEC)

Prominent vomiting suggests:

→ Norovirus

Persistent or delayed diarrhea suggests:

→ Protozoal infection

Most important treatment:

→ Fluid and electrolyte replacement

Common antimotility drug:

→ Loperamide

Avoid loperamide alone when there is:

→ Bloody diarrhea or high fever

Rifaximin is best suited for:

→ Afebrile, noninvasive, nondysenteric diarrhea

Important fluoroquinolone resistance problem:

→ Campylobacter, especially in South and Southeast Asia

Useful antibiotic for dysentery or resistant Campylobacter:

→ Azithromycin

Treatment principle for invasive amebiasis:

→ Tissue-active therapy followed by a luminal amebicide

Diarrhea lasting >10–14 days:

→ Investigate for protozoa

Important Campylobacter complication:

→ Guillain–Barré syndrome

Important long-term complication after traveler’s diarrhea:

→ Postinfectious irritable bowel syndrome

Ophthalmology – Hyphema

Basics

Description

Hyphema is the presence of blood within the anterior chamber of the eye. The blood may appear as suspended red blood cells, a layered collection, or a clot.

Most cases follow ocular trauma, but hyphema may also occur after intraocular surgery, laser procedures, neovascularization, tumors, inflammation, or bleeding disorders.

Because a hyphema can be associated with other serious ocular injuries, the first priority is always to exclude open-globe injury and intraocular foreign body.

General Prevention

Prevention centers on the use of appropriate protective eyewear, especially during sports, occupational activities, and situations involving high-velocity objects.

Polycarbonate protective lenses are particularly useful for patients at increased risk of recurrent ocular trauma.

Pathophysiology

Hyphema results from bleeding from anterior-segment structures.

In traumatic cases, the mechanism commonly involves tearing of vessels in the:

• Iris
• Ciliary body
• Anterior chamber angle

Associated injuries may include:

• Iris sphincter tears
• Iridodialysis
• Cyclodialysis
• Angle recession

Blood then accumulates within the aqueous-filled anterior chamber.

Red blood cells can obstruct the trabecular meshwork and produce elevated intraocular pressure.

Etiology

The most common cause is blunt ocular trauma.

Other causes include:

• Penetrating trauma
• Intraocular surgery
• Laser procedures
• Iris or angle neovascularization
• Intraocular tumors
• Uveitis
• Coagulopathy
• Anticoagulant or antiplatelet therapy
• Hemoglobinopathies such as sickle cell disease

Commonly Associated Conditions

Hyphema may be associated with:

• Open-globe injury
• Lens dislocation
• Traumatic cataract
• Angle recession
• Iridodialysis
• Cyclodialysis
• Vitreous hemorrhage
• Retinal tears or detachment
• Choroidal rupture
• Traumatic optic neuropathy
• Coagulopathies
• Intraocular neoplasms
• Neovascular glaucoma

Diagnosis

History

When trauma is suspected, obtain a careful description of the mechanism.

Important details include:

• Type of object
• Size and shape
• Velocity
• Direction of impact
• Exact site of impact
• Use of protective eyewear
• Time since injury