Chapter 48: Cases and Clinical Correlations

The management of infectious diseases requires an understanding of the presenting clinical manifestations and knowledge of microbiology. Many infections present with constellations of focal and systemic signs and symptoms that in typical cases are highly suggestive of the diagnosis, though the disease might be caused by any of several different organisms. Making a clinical diagnosis with subsequent laboratory confirmation is part of the art of medicine. This chapter presents 24 cases and brief discussions of the differential diagnosis and management of those infections.

The reader is referred to earlier chapters of this book for characterizations of the organisms; to Chapter 47 for information about diagnostic microbiology tests; and to textbooks of medicine and infectious diseases for more complete information about the clinical entities.

Clinical Features

Temperature was 39.5°C, pulse 130/min, and respirations 24/min. Blood pressure was 110/60 mm Hg.

Physical examination showed a well-developed and well-nourished child of normal height and weight who was somnolent. When her neck was passively flexed, her legs also flexed (positive Brudzinski sign, suggesting irritation of the meninges). Ophthalmoscopic examination showed no papilledema, indicating that there had been no long-term increase in intracranial pressure. The remainder of her physical examination was normal.

Laboratory Findings

Minutes later, blood was obtained for culture and other laboratory tests, and an intravenous line was placed. Lumbar puncture was performed less than 30 minutes after the patient arrived in the emergency room. The opening pressure was 350 mm of cerebrospinal fluid (CSF) (elevated). The fluid was cloudy. Several tubes of CSF were collected for culture, cell counts, and chemistry tests. One tube was taken immediately to the laboratory for Gram staining. The stain showed many polymorphonuclear (PMN) cells with cell-associated (intracellular) gram-negative diplococci suggestive of Neisseria meningitidis (Chapter 20).

Blood chemistry tests were normal. The hematocrit was normal. The white blood cell count was 25,000/μL (markedly elevated), with 88% PMN forms and an absolute PMN count of 22,000/μL (markedly elevated), 6% lymphocytes, and 6% monocytes. The CSF had 5000 PMNs/μL (normal, 0–5 lymphocytes/μL). The CSF protein was 100 mg/dL (elevated), and the glucose was 15 mg/dL (low, termed hypoglycorrhachia)—all consistent with bacterial meningitis. Cultures of blood and CSF grew serogroup B N meningitidis.

Treatment

Intravenous cefotaxime therapy was started within 35–40 minutes of the patient’s arrival; dexamethasone was also given. The patient responded quickly and was treated with the antibiotic for 7 days. She recovered without obvious sequelae. Further neurologic examinations and hearing tests were planned for the future. Rifampin prophylaxis was given to the other children who attended the day care center.

Comment

Clinical features of bacterial meningitis vary with the age of the patient. In the older child and the adult, bacterial meningitis usually presents with fever, headache, vomiting, photophobia, altered mental status ranging from sleepiness to coma, and neurologic signs ranging from abnormalities of cranial nerve function to seizures. However, subtle signs such as fever and lethargy are consistent with meningitis, particularly in infants. Meningitis is considered to be acute with signs and symptoms of less than 24 hours’ duration and subacute when signs and symptoms have been present for 1–7 days. Lumbar puncture with examination of the CSF is indicated whenever there is any suspicion of meningitis.

Acute meningitis is most often caused by bacteria of a few species (Table 48-1): Lancefield serogroup B streptococci (Streptococcus agalactiae) (Chapter 14) and Escherichia coli (Chapter 15) in neonates; Haemophilus influenzae (Chapter 18) in unvaccinated children between the ages of 6 months and 6 years; N meningitidis in children and unvaccinated adolescents and young adults; and Streptococcus pneumoniae (Chapter 14) occasionally in children and increasing in incidence in middle-aged and elderly persons. Many other species of microorganisms less commonly cause meningitis. Listeria monocytogenes (Chapter 12) causes meningitis in immunosuppressed patients and normal persons. The yeast Cryptococcus neoformans (Chapter 45) is the most common cause of meningitis in AIDS patients and can cause meningitis also in other immunosuppressed patients as well as in normal persons. Meningitis due to Listeria or Cryptococcus can be acute or insidious in onset. Gram-negative bacilli cause meningitis in acute head trauma and neurosurgical patients and neonates (encapsulated E coli). S pneumoniae is found in recurrent meningitis in patients with basilar skull fractures. Mycobacterium tuberculosis (Chapter 23) can have a slow onset (chronic; >7 days) in immunologically normal persons but progresses more rapidly (subacute) in immunosuppressed persons such as AIDS patients. Naegleria species (Chapter 46), free-living amoebas, occasionally cause meningitis in persons with a recent history of swimming in warm fresh water. Viruses (Chapters 30, 33, 36) usually cause milder meningitis than bacteria. The viruses that most commonly cause meningitis are the enteroviruses (echoviruses and coxsackieviruses) and mumps virus.

The diagnosis of meningitis requires a high degree of suspicion when appropriate signs and symptoms are observed plus lumbar puncture without delay followed by examination of CSF. Findings in the spinal fluid typically include white blood cells in hundreds to thousands per microliter (PMNs for acute bacterial meningitis and lymphocytes for tuberculous and viral meningitis); glucose of less than 40 mg/dL, or less than 50% of the serum concentration; and protein of more than 100 mg/dL (Table 48-2). In bacterial meningitis, Gram stain of cytocentrifuged sediment of CSF shows PMNs and bacterial morphology consistent with the species subsequently cultured: N meningitidis, intracellular gram-negative diplococci; H influenzae, small gram-negative coccobacilli; and serogroup B streptococci and pneumococci, gram-positive cocci in pairs and chains. Blood cultures should be done along with the CSF cultures.

Acute bacterial meningitis is fatal if untreated. Initial therapy for bacterial meningitis in infants less than 1 month of age should consist of parenteral therapy known to be effective against the pathogens listed in Table 48-1 and including L monocytogenes. Ampicillin plus cefotaxime or ceftriaxone with or without gentamicin or ampicillin in combination with an aminoglycoside is recommended. For children between the ages of 1 month and 18 years of age and for the adult older than 50 years, the recommended therapies are vancomycin plus a third-generation cephalosporin because of the prevalence of multidrug-resistant S pneumoniae, reports of rising minimum inhibitory concentrations to penicillin among meningococci, and the prevalence of β-lactamase production among H influenzae. Since adults older than 50 years are also susceptible to L monocytogenes, the addition of ampicillin to the regimen for older children and adults as listed earlier is recommended.

Available evidence supports administration of adjunctive dexamethasone 10–20 minutes prior to or concomitant with the first antimicrobial dose to children with H influenzae meningitis and in the adult with pneumococcal meningitis with continuation of steroids for the first 2–4 days of therapy.

Several vaccines are currently available and are recommended for the prevention of the more serious causes of bacterial meningitis. The H influenzae type B conjugate vaccine and the 13-valent conjugate pneumococcal vaccine are currently part of the routine vaccination series for infants and young children. The 23-valent polysaccharide pneumococcal vaccine is recommended for prevention of invasive pneumococcal disease in certain high-risk groups older than 2 years. These include patients who are elderly and patients who have chronic underlying diseases such as cardiovascular disease, diabetes mellitus, chronic pulmonary problems, CSF leaks, and asplenia, among others. Vaccination with one of two available quadrivalent conjugated meningococcal vaccines is currently recommended for all healthy adolescents 11 or 12 years of age with a booster dose at age 16 and for 2- to 55-year-old persons at risk such as travelers to endemic areas, asplenic patients and patients with complement deficiencies. For adults older than 55, the meningococcal polysaccharide vaccine is currently recommended pending evaluation of the conjugate vaccine in this age group.

REFERENCES

Clinical Features

The temperature was 37°C, the pulse 110/min, and respirations 18/min. The blood pressure was 140/80 mm Hg.

On physical examination, the patient was sleepy and had a decreased attention span. He moved all his extremities, though the right arm moved less than the left. There was slight blurring of the left optic disk, suggesting possible increased intracranial pressure. The remainder of his physical examination was normal.

Laboratory Findings and Imaging

Laboratory tests were all normal, including hemoglobin and hematocrit, white blood cell count and differential, serum electrolytes, blood urea nitrogen, serum creatinine, urinalysis, chest x-ray, and electrocardiogram (ECG). Lumbar puncture was not done and cerebrospinal fluid was not examined because of possible increased intracranial pressure due to a mass lesion. Blood cultures were negative. Computed tomography (CT) scan with contrast enhancement of the patient’s head showed a 1.5-cm localized ring-enhancing lesion in the left parietal hemisphere suggestive of a brain abscess.

Treatment

The patient had a neurosurgical procedure with complete drainage of the lesion. Culture of necrotic material from the lesion yielded Prevotella melaninogenica (Chapter 21) and Streptococcus anginosus (Chapter 14). Pathologic examination of the tissue suggested that the lesion was several weeks old. The patient received antibiotic therapy for 6 weeks. He had no more seizures and no subsequent neurologic deficits. One year later, anticonvulsant medications were discontinued and a follow-up CT scan was negative.

Comment

A brain abscess is a localized pyogenic bacterial infection within the brain parenchyma. The major clinical manifestations are related to the presence of a space-occupying mass in the brain rather than the classic signs and symptoms of infection. Thus, patients commonly present with headache and a change in mental status from normal to lethargy or coma. Focal neurologic findings related to location of the abscess occur in less than half of patients; one-third have seizures, and less than half have fever. Occasionally, patients present with signs and symptoms suggesting acute meningitis. Initially, the clinician must differentiate brain abscess from other central nervous system processes, including primary or metastatic cancers, subdural or epidural abscesses, meningitis, stroke, and a variety of other diseases.

Significant predisposing factors for brain abscess include distant site infections with bacteremia, such as endocarditis, lung infections, or other occult infections. Brain abscess can also occur via spread from contiguous sites of infection such as in the middle ear, mastoid, sinuses, from dental infections or recent dental work. Disruption of protective barriers as in the case of neurosurgery or following penetrating trauma is another factor. Finally, immunosuppressive agents or immunocompromising conditions such as HIV are also important. However, 20% of patients with brain abscesses have no discernible predisposing factors.

Brain abscess can be caused by a single species of bacteria, but more often infections are polymicrobial. Of the facultative and aerobic bacteria, the viridans streptococci (including nonhemolytic and α- and β-hemolytic strains, the S anginosus group, Streptococcus mitis, etc; see Chapter 14) are most common, occurring in one-third to one-half of patients. Staphylococcus aureus (Chapter 13) is isolated in 10–15% and, when present, is often the only isolate found. Enteric gram-negative rods occur in about 25%, often in mixed cultures. Many other facultative or aerobic bacteria (eg, S pneumoniae, Nocardia sp., M tuberculosis and nontuberculous Mycobacteria) also occur in brain abscesses. Anaerobic bacteria are found in 50% or more of cases (Chapter 21). Peptostreptococcus is most common, followed by Bacteroides and Prevotella species. Fusobacterium, Actinomyces, and Eubacterium are less common, followed by other anaerobes. Fungi (Chapter 45) are seen almost exclusively in immunocompromised patients. Candida species are the most prevalent fungi, but opportunistic molds such as Aspergillus sp. and Scedosporium apiospermum are increasing in frequency. Dimorphic fungi such as Coccidioides immitis may also cause brain abscesses. C neoformans is an important pathogen in AIDS patients. Parasites (Chapter 46) responsible for brain abscesses include Toxoplasma gondii, the most common protozoan cause, particularly among AIDS patients, neurocysticercosis (larval form of Taenia solium), Entamoeba histolytica, Schistosoma sp., and Paragonimus.

Lumbar puncture to obtain CSF is generally not indicated in patients with brain abscess (or other mass lesions in the brain). The increased intracranial pressure makes the procedure life threatening, because herniation of the brain through the tentorium cerebelli can result in midbrain compression. The findings in CSF are not specific for brain abscess: White blood cells, predominantly mononuclear cells, are often present; the glucose level may be moderately low and the protein concentration elevated. Thus, when fever and signs suggesting acute meningitis are absent and brain abscess is suspected, the clinician should obtain a CT scan with contrast enhancement. Brain abscesses typically show ring-enhanced uptake of contrast material on CT scan, though similar findings can be found in patients with brain tumors and other diseases. Magnetic resonance imaging (MRI) may be helpful in differentiating brain abscesses from tumors. Definitive differentiation between brain abscess and tumor is done by pathologic examination and culture of tissue from the lesion obtained by a neurosurgical procedure.

Untreated brain abscesses are fatal. Surgical excision provides the initial therapy as well as the diagnosis of brain abscess. Needle aspiration using stereotactic technique is an alternative to surgical excision. Antibiotic therapy should be parenteral and should include high-dose penicillin G for streptococci and many anaerobes, metronidazole for anaerobes resistant to penicillin G, plus a third-generation cephalosporin for enteric gram-negative rods. Vancomycin or another drug specific for S aureus should be included in the initial therapy if the patient has endocarditis or is known to have staphylococcal bacteremia, or the abscess yields staphylococci. Initial therapy with antibiotics rather than surgery can be instituted in some patients whose brain abscesses are small (<2 cm), multiple, or difficult to reach surgically, but deteriorating neurologic functions indicate the need for surgery. Once culture results from the abscess material are known, initial antibiotic therapy should be modified to be specific for the bacteria, fungus, or parasite isolated from the lesion. Antibiotic therapy should be continued for at least 3–4 weeks when surgical excision has been done or for 8 weeks or longer when there has been no surgery. Nonbacterial causes of brain abscesses generally require definitive diagnoses and specific therapy of possibly longer duration. Steroids to decrease swelling should be used only when there is mass effect.

REFERENCES

Clinical Features

Temperature was 39°C, pulse 130/min, and respirations 28/min. Blood pressure was 120/80 mm Hg.

Physical examination showed a slightly overweight man who was coughing frequently and holding his left chest when he coughed. He produced very little thick rust-colored sputum. His chest examination showed normal movement of the diaphragm. There was dullness to percussion of the left lateral posterior chest, suggesting consolidation of the lung. Tubular (bronchial) breath sounds were heard in the same area along with dry crepitant sounds (rales), consistent with lung consolidation and viscous mucus in the airway. The remainder of his physical examination was normal.

Laboratory Findings and Imaging

Chest films showed a dense left lower lobe consolidation consistent with bacterial pneumonia. The hematocrit was 45% (normal). The white blood cell count was 16,000/μL (markedly elevated) with 80% PMN forms with an absolute PMN count of 12,800/μL (markedly elevated), 12% lymphocytes, and 8% monocytes. Blood chemistry tests, including electrolytes, were normal. Sputum was thick, yellow to rust colored, and purulent in appearance. Gram stain of the sputum showed many PMN cells and lancet-shaped gram-positive diplococci. Twenty-four hours later, the blood cultures were positive for S pneumoniae (Chapter 14). Cultures of sputum grew numerous S pneumoniae and a few colonies of H influenzae (Chapter 18).

Treatment

The initial diagnosis was bacterial pneumonia, probably pneumococcal. Parenteral aqueous penicillin G therapy was begun on the basis of local data which showed little penicillin resistance among pneumococci, and the patient was given parenteral fluids. Within 48 hours, his temperature was normal and he was coughing up large amounts of purulent sputum. Penicillin G was continued for 7 days. At follow-up 4 weeks after admission to the hospital, the lung consolidation had cleared.

Clinical Features

The temperature was 39°C, pulse 110/min, and respirations 30/min. Blood pressure was 115/70 mm Hg. The patient appeared to be acutely uncomfortable. He had a skin rash consisting of multiple crops or stages of lesions ranging from red maculopapules to vesicles that were broken and crusted over. His fingers and lips appeared to be slightly blue. Rales were heard bilaterally throughout both lung fields. The remainder of the physical examination was normal.

Laboratory Findings and Imaging

Chest films showed diffuse bilateral interstitial pulmonary infiltrates. Arterial blood gases showed a PO₂ of 60 mm Hg with 91% hemoglobin saturation. The hematocrit, white blood cell count, and serum electrolytes and liver tests were normal.

Treatment and Hospital Course

The patient was hospitalized and placed on oxygen therapy, which improved his hypoxia. He was given high-dose intravenous acyclovir. Over the next several days, his respiratory status improved, and on day 6, oxygen therapy was discontinued. The acyclovir was changed to oral therapy on day 3 and continued for a total of 10 days. The patient was discharged to home care on day 7.

Comment

Acute bacterial pneumonia commonly presents with an abrupt onset of chills and fever, cough, and often pleuritic chest pain. The cough frequently is productive of purulent sputum, but many patients with pneumonia are not adequately hydrated and do not produce sputum until they receive fluids, as in this case. Pleuritic chest pain occurs when the inflammatory process of the pneumonia involves the pleural lining of the lung and chest cavity; movement of the pleura, as occurs with coughing or deep breathing, yields localized pain. Patients with acute pneumonia appear ill and usually have tachypnea (rapid breathing) and tachycardia (rapid heart rate). Many patients with pneumonia have predisposing factors (congestive heart failure, chronic obstructive pulmonary disease, etc), which become exacerbated before or in association with the pneumonia.

The findings on physical examination are those associated with consolidation of the lung tissue, purulent mucus (sputum) in the airway, and, in some patients, fluid in the chest cavity. On percussion, there is dullness over the area of consolidation (or fluid). When consolidation occurs, the small airways are closed, leaving only the large airways open; on auscultation, there are tubular breath sounds over the area. If all the airways are blocked, no breath sounds are audible. Dry crepitant sounds (rales) or crackling sounds on auscultation indicate fluid or mucus in the airways; these sounds may change when the patient coughs.

Viral pneumonia is characterized by interstitial inflammation of the lung tissue and hyaline membrane formation in the alveolar spaces, often accompanied by bronchiolitis and sloughing of the ciliated cells of the small airways with peribronchial inflammation. The viruses that most commonly cause pneumonia are respiratory syncytial virus, parainfluenza viruses (typically type 3), influenza viruses, adenoviruses, measles virus, and varicella-zoster virus (Chapters 32, 39, 40). Cytomegalovirus (Chapter 33) causes pneumonia in allogeneic bone marrow and solid organ transplant patients; varicella-zoster virus may cause pneumonia in these patients as well. Emerging viral pathogens such as Metapneumovirus and newly discovered Coronaviruses such as MERS-Coronavirus (case 23) may cause disease that mimics that of the more common viral respiratory pathogens (Chapters 40, 41). SARS Coronavirus was responsible for epidemic fatal respiratory disease in several countries (case 20). Many other infectious agents (and noninfectious agents also) can cause interstitial pneumonitis with or without focal consolidation in the lung. Examples include Legionella pneumophila (Chapter 22), Mycoplasma pneumoniae (Chapter 25), and Pneumocystis jirovecii (Chapter 45). The physical findings on chest examination in viral pneumonia frequently are limited; often only rales are heard on auscultation. Some of the viruses cause characteristic rashes that may serve as clues to diagnosis. Chest films show diffuse bilateral interstitial infiltrates. Focal areas of consolidation may be present. Supportive care such as oxygen therapy and specific antiviral chemotherapy, when possible, are important.

Community acquired pneumonia (CAP) is defined as an acute infection of the lungs in persons not recently hospitalized or otherwise exposed to a heath care facility. The most common causes of CAP are S pneumoniae (Chapter 14), H influenzae (Chapter 18), Moraxella catarrhalis (Chapter 16), S aureus (Chapter 13), and less commonly, certain gram-negative bacilli, the latter occurring more frequently in patients with chronic lung disease. Data on the frequency of “atypical” pathogens, namely M pneumoniae (Chapter 25), L pneumophila (Chapter 22), and Chlamydia pneumoniae (Chapter 27) varies (Table 48-3) but these should be considered when choosing empiric therapy regimens; Pleural pulmonary infections with mixed anaerobic bacteria are associated with predisposing factors such as periodontal disease, seizure disorders, stupor or coma, and aspiration of oropharyngeal bacteria into the lung. Pneumonia, lung abscesses, and infection of the pleural space (empyema, or pus in the chest cavity) occur with mixed anaerobic infections.

Health care–associated pneumonia (HCAP) is a category of infection created in 2005 to distinguish persons in the community with recent hospitalization, who reside in long-term care facilities, or who frequently have exposure to health care environments (such as hemodialysis clinics and who are at risk for acquisition of the same types of multidrug resistant pathogens that are seen among hospitalized patients [HAP] and patients who are on ventilator support [VAP]). The organisms responsible for these infections are quite different from the etiologies of CAP. HCAP, HAP, and VAP are frequently caused by multidrug-resistant enteric gram-negative bacilli such as E coli, Klebsiella pneumoniae, Enterobacter sp. (Chapter 15), and Pseudomonas aeruginosa (Chapter 16); S aureus (Chapter 13), and Legionella may also cause hospital-acquired pneumonia. Fungi, including Histoplasma capsulatum, C immitis, and C neoformans (Chapter 45), cause CAP; Candida and Aspergillus species (Chapter 45) are more likely to cause nosocomial infections.

Blood counts in patients with pneumonia usually show leukocytosis with increased PMN cells. Chest radiography shows segmental or lobar infiltrates. Cavities may be seen especially with mixed anaerobic infections or pneumonia due to S aureus or group A streptococci. Pleural effusions may also be found and, if present, may call for thoracentesis to obtain fluid for cell counts and culture and for therapeutic purposes in the case of empyema. Blood cultures should be done in all patients admitted to the hospital with acute pneumonia even though the yield is variable (eg, 20–25% with S pneumoniae, much less in disease caused by H influenzae). Sputum, when available, may be useful for Gram stain and culture as well.

Many patients with bacterial pneumonia and pneumonia due to other causes have mucopurulent sputum. Rust-colored sputum suggests alveolar involvement and is associated with pneumococcal pneumonia but occurs with other organisms also. Foul-smelling sputum suggests mixed anaerobic infection. A purulent portion of the sputum should be chosen for Gram stain and microscopic examination; an adequate sputum specimen will have over 25 PMN cells and fewer than 10 epithelial cells per low-power field (100× magnification). Traditionally, microscopic examination of the sputum has been used to help determine the cause of pneumonia; however, it may be difficult to differentiate organisms that are part of the normal oropharyngeal microbiota from those that are causing the pneumonia. The finding of numerous lancet-shaped gram-positive diplococci strongly suggests S pneumoniae, but streptococci that are part of the oropharyngeal microbiota can have the same appearance. The major value of stained sputum smears is when organisms that would not be expected are found (eg, numerous PMN cells along with numerous gram-negative bacilli suggesting enteric bacilli or Pseudomonas, or numerous gram-positive cocci in clusters suggesting staphylococci). Sputum cultures have many of the same drawbacks as smears; it may be difficult to differentiate normal microbiota or colonizing bacteria from the cause of the pneumonia.

True demonstration of the cause of pneumonia comes from a limited set of specimens: a positive blood culture in a pneumonia patient with no confounding infections; a positive pleural fluid or direct lung aspirate culture; and detection of circulating antigen of a specific organism with no confounding infection (eg, S pneumoniae or L pneumophila urinary antigen). Bronchoscopy is often used to obtain material for diagnostic studies in severely ill patients with pneumonia and is recommended for health care–associated pneumonia and pneumonia in the immunocompromised host. Quantitative bacterial culture performed on a carefully collected bronchoalveolar lavage (BAL) sample using 10⁴ colony-forming units (CFU)/mL of a specific pathogen per sample as the cutoff for clinical significance is useful for establishing an etiology of bacterial pneumonia in patients not previously treated with antibiotics. Bronchoscopy with BAL may also yield a nonbacterial pathogen such as a filamentous mold or viral pathogen in the at-risk patient.

Several commercially available multiplex nucleic acid amplification methods are now available to assist in the diagnosis of viral pneumonia and pneumonia caused by the atypical pathogens such as M pneumoniae and C pneumoniae. Other platforms specifically for the detection of CAP and HCAP are in development.

In the United States, several professional societies (see ATS and IDSA guidelines below) have established practice guidelines for the diagnosis and empirical and definitive treatment of community-acquired pneumonia and health care–associated and ventilator-associated pneumonia. For patients with community-acquired pneumonia, a macrolide, fluoroquinolone, or doxycycline is recommended as monotherapy for previously healthy outpatients. A macrolide plus a β-lactam or a fluoroquinolone alone is recommended for initial empiric treatment of outpatients in whom resistance is an issue and for patients who require hospitalization. A recent update by Musher et al (see References) suggests modifications to the guidelines for outpatient treatment because of the increases in macrolide and tetracycline resistance among common CAP organisms. In brief, amoxicillin-clavulanate with the addition of azithromycin, if Legionella is a concern, is suggested for outpatients. It is also recommended that fluoroquinolones such as levofloxacin or moxifloxacin be reserved for patients with predisposing lung disease or other comorbidities. These regimens should be modified in the event that an etiology is established and once the susceptibility of the causative agent is determined. In the case of HCAP, multidrug resistance is often a major problem, and targeted antipseudomonal therapy with third-generation cephalosporins, carbapenems, or β-lactam/β-lactamase inhibitor combinations with or without an aminoglycoside may be required. More recently, the increase in prevalence of multidrug-resistant organisms, such as carbapenem resistant K pneumoniae and Acinetobacter baumannii resistant to all antimicrobials except colistin, has challenged these recommendations and has contributed to increased mortality.

REFERENCES

Clinical Features

Temperature was 38°C, pulse 90/min, and respirations 18/min. Blood pressure was 130/80 mm Hg.

Physical examination showed a moderately overweight woman who was alert and oriented. She became short of breath while walking up two flights of stairs. Examination of her eyes showed a Roth spot (a round white spot surrounded by hemorrhage) in the retina of her right eye. Petechiae were seen in the conjunctiva of both eyes. Her head and neck were otherwise normal. Splinter hemorrhages were seen under two fingernails of her right hand and one finger of the left hand. Osler’s nodes (tender, small, raised, red or purple lesions of the skin) were seen in the pads of one finger and one toe. Her heart size was normal to percussion. On auscultation, a low-pitched diastolic murmur consistent with mitral valve stenosis was heard at the apex; a loud mitral valve opening snap was heard over the left chest. Examination of her abdomen was difficult because of obesity; one observer felt an enlarged spleen. The remainder of her physical examination was normal.

Laboratory Findings and Imaging

The films from a chest x-ray showed a normal heart size and normal lungs. The ECG showed a normal sinus rhythm with broad P waves (atrial conduction). Echocardiography showed an enlarged left atrium, thickened mitral valve leaflets, and a vegetation on the posterior leaflet. The hematocrit was 29% (low). The white blood cell count was 9800/μL (high normal), with 68% PMNs (high), 24% lymphocytes, and 8% monocytes. The erythrocyte sedimentation rate was 68 mm/h (high). Blood chemistry tests, including electrolytes and tests of renal function, were normal. Three blood cultures were obtained on the day of admission; 1 day later, all three were positive for gram-positive cocci in chains that were viridans streptococci and subsequently identified as Streptococcus sanguinis (Chapter 14).

Treatment

Endocarditis of the mitral valve was diagnosed. Intravenous penicillin G and gentamicin were begun and continued for 2 weeks. The patient was afebrile within 3 days after starting therapy. Following the successful treatment of her endocarditis, she was referred for long-term management of her heart disease.

Comment

The symptoms and signs of endocarditis are quite varied because any organ system can be secondarily (or primarily) involved. Fever occurs in 80–90% of patients, chills in 50%, anorexia and weight loss in about 25%, and skin lesions in about 25%. Nonspecific symptoms such as headache, backache, cough, and arthralgia are very common. Up to 25% of endocarditis patients present with neurologic signs or strokes secondary to emboli from heart valve vegetations. Backache, chest pain, and abdominal pain occur in 10–20% of the patients. Physical findings typically include fever in 90–95%, a heart murmur in 80–90% with a new or changing heart murmur in about 15%, and splenomegaly and skin lesions in about 50% of patients. Many other symptoms and physical findings are directly related to the complications of metastatic infection and embolization from vegetations.

Streptococci and staphylococci cause about 80% of endocarditis cases. Viridans streptococci of several species (eg, S sanguinis, Streptococcus salivarius, Streptococcus mutans, Streptococcus bovis group; Chapter 14) are most common, followed by enterococci (eg, Enterococcus faecalis) and other streptococci. The streptococci usually cause endocarditis on abnormal heart valves. The proportion of causes attributed to staphylococci is increasing due to the decline in cases associated with rheumatic heart disease and the increase in health care–associated infections. S aureus causes 20–25% of community acquired cases but a much higher proportion of health care–associated disease (see reference Hoen et al) and likewise Staphylococcus epidermidis about 5% of community and 15% of health care–associated cases (Chapter 13). S aureus can infect normal heart valves, is common in intravenous drug abusers and patients who acquire their disease in the hospital, and produces more rapidly progressive disease than the streptococci. S epidermidis is a cause of endocarditis on prosthetic valves and only rarely infects native valves. Gram-negative bacilli (Chapters 15, 18) occur in about 5% and yeasts such as Candida albicans in about 3% of cases (Chapter 45). Emerging pathogens such as Bartonella sp. (Chapter 22) and Tropheryma whipplei (Chapter 22) have been reported with increasing frequency. Many other bacteria—indeed any species—can cause endocarditis; a small percentage are culture negative.

The history and physical examination are important diagnostic procedures. The diagnosis is strongly suggested by repeatedly positive blood cultures with no other site of infection. Echocardiography can be a very helpful adjunctive procedure; the presence of vegetations in a patient with unexplained fever strongly suggests endocarditis.

Antibiotic therapy is essential because untreated endocarditis is fatal. Bactericidal drugs should be used. The choice of antibiotics depends on the infecting organism: Penicillin G plus gentamicin for 2 weeks for viridans streptococci and for 6 weeks for susceptible enterococci is recommended. Vancomycin is the drug of choice for penicillin-resistant strains. Multidrug resistance among enterococci may require the use of newer agents such as linezolid and daptomycin based on susceptibility data. S aureus is treated with a penicillinase-resistant penicillin (eg, nafcillin) often with the addition of gentamicin for the first 5 days of therapy. Vancomycin is substituted for the β-lactam in cases of methicillin/oxacillin-resistant staphylococci. Daptomycin is recommended for MRSA infections of the right side of the heart and may be useful for left-sided disease as well. Treatment duration for staphylococcal endocarditis is 6 weeks. Bacteria other than the streptococci and staphylococci are treated with antibiotics of demonstrated activity based on local antibiograms. Surgery with valve replacement is necessary when valvular regurgitation (eg, aortic regurgitation) results in acute heart failure even when active infection is present and to control infection unresponsive to medical treatment (as may occur with fungi and gram-negative pathogens). Contiguous spread of infection to the sinus of Valsalva or resultant abscesses, and prevention emboli due to large vegetations are other important indications for surgery.

REFERENCES

Clinical Features

The temperature was 38°C, the pulse 100/min, and respirations 24/min. The blood pressure was 110/70 mm Hg.

Physical examination showed a normally developed young man who appeared acutely ill and complained of diffuse abdominal pain. The chest and heart examinations were normal. The abdomen was slightly distended. There was diffuse periumbilical and right lower quadrant tenderness to palpation with guarding (muscle rigidity with palpation). There was a suggestion of a right lower quadrant mass. Bowel sounds were infrequent.

Laboratory Findings and Imaging

The hematocrit was 45% (normal), and the white blood cell count was 20,000/μL (markedly elevated) with 90% PMN cells (markedly elevated) and 12% lymphocytes. The serum amylase (a test for pancreatitis) was normal. Electrolytes and tests of liver and renal function were normal. X-ray films of the chest and abdomen were normal, though several distended loops of small bowel were seen. CT scan of the abdomen showed a fluid collection in the right lower quadrant with extension into the pelvis.

Treatment

The patient was taken to the operating room. At surgery, a perforated appendix with a large periappendiceal abscess extending into the pelvis was found. The appendix was removed, about 300 mL of foul-smelling abscess fluid was evacuated, and drains were placed. The patient was treated with ertapenem for 2 weeks. The drains were advanced daily and totally removed 1 week after surgery. Culture of the abscess fluid revealed at least six species of bacteria, including E coli (Chapter 15), Bacteroides fragilis (Chapter 21), viridans streptococci, and enterococci (normal gastrointestinal microbiota). The patient recovered uneventfully.

Comment

Pain is the usual primary manifestation of peritonitis and intra-abdominal abscess formation. The localization and intensity of the pain are related to the primary disease of the abdominal viscera. Perforation of a peptic ulcer quickly yields epigastric pain that rapidly spreads throughout the abdomen with the spillage of gastric contents. A ruptured appendix or sigmoid colon diverticulum often produces more localized right or left lower quadrant pain, respectively, associated with the focal peritonitis and abscess formation. Nausea, vomiting, anorexia, and fever accompany the pain.

The signs and symptoms following acute spillage of bowel contents into the abdomen tend to take two phases. The first is the peritonitis stage, with acute pain associated with infection by E coli and other facultative anaerobic bacteria; this occurs over the first 1–2 days and if untreated is associated with a high mortality rate. The second stage is abscess formation associated with infection with B fragilis and other obligately anaerobic bacteria.

Physical examination during the acute phase shows abdominal rigidity and diffuse or local tenderness. Often the tenderness is pronounced when palpation of the abdomen is released, termed rebound tenderness. Later, abdominal distention and loss of bowel motility (paralytic ileus) occur.

The bacteria that make up the normal gastrointestinal microbiota (Chapter 10) are the causes of acute peritonitis and abscesses associated with bowel rupture: E coli and other enteric gram-negative rods, enterococci, viridans streptococci, B fragilis and other anaerobic gram-negative rods, and anaerobic gram-positive cocci and rods of many species.

The history and physical examination are the important initial steps in the diagnosis, to determine the acuteness and localization of the problem. Laboratory tests, such as white blood cell counts, yield nonspecific abnormal results or help rule out diseases such as pancreatitis, as in this case. X-ray films of the abdomen are very useful diagnostic adjuncts and may show gas and fluid collections in the large and small bowel. More definitive information indicating focal abnormalities is obtained using contrast enhanced CT scans. When fluid is present, needle aspiration and culture yield a diagnosis of infection but do not define the underlying disease process.

Surgery may be necessary to obtain a definitive etiologic diagnosis, while at the same time it provides the definitive step in therapy. The underlying disease process, such as a gangrenous bowel or ruptured appendix, can be corrected and the localized infection drained. Antimicrobial drugs are important adjunctive therapy. The selection of drugs might include an antimicrobial active against enteric gram-negative rods, one active against the enterococci and streptococci, and a third against the anaerobic gram-negative rods that are often resistant to penicillin G. Many regimens have been described; one regimen includes gentamicin, ampicillin, and metronidazole; more recently piperacillin/tazobactam and ertapenem have supplanted triple-drug regimens.

Clinical Features

On physical examination, the children had temperatures of 39–39.5°C and the parents 38°C. All had tachycardia and appeared acutely ill. Both children appeared dehydrated.

Laboratory Findings

White blood cell counts ranged from 12,000 to 16,000/μL, with 55–76% PMN cells. Multiple white blood cells were seen in the fecal stains. Stools from the children were grossly bloody and mucoid. Cultures of the stools from each of the patients subsequently grew Shigella flexneri (Chapter 15).

Treatment

Both children were admitted to the hospital and given intravenous fluids and ampicillin. The parents were treated as outpatients, with oral fluids and oral ciprofloxacin. All recovered uneventfully. Public health follow-up determined that the relative who prepared the food was responsible for the outbreak.

Comment

Nausea, vomiting, abdominal pain, diarrhea, and fever are the major clinical findings in gastrointestinal infections. The predominant symptoms are dependent on the etiologic agent and whether it is toxigenic or invasive or both. When preformed toxins are in food, they often are associated with nausea and vomiting. For example, S aureus (Chapter 13) and Bacillus cereus (Chapter 11) produce enterotoxins in food; nausea and vomiting—and to a much lesser extent diarrhea—occur a few hours following ingestion of the food. Organisms that produce enterotoxins affect the proximal small bowel and tend to cause watery diarrhea (eg, enterotoxigenic E coli [Chapter 15], Vibrio cholerae [Chapter 17]). Agents such as rotaviruses, Norovirus virus (Chapter 37), and Giardia lamblia (G duodenalis [Chapter 46]) cause watery diarrhea through the mechanism of mucosal irritation or destruction. Invasive or cytotoxin-producing bacteria infect the colon and cause abdominal pain, frequent diarrhea, often with blood and mucus, fever, and dehydration, as in this case; this group of signs and symptoms is called dysentery. Organisms that cause dysentery include salmonellae of many serotypes, shigellae, Campylobacter jejuni (Chapter 17), enteroinvasive E coli, Clostridium difficile (Chapter 11), and E histolytica (Chapter 46). Enteric fever is a life-threatening infection characterized by fever, headache, and variable abdominal symptoms; Salmonella typhi (Chapter 15) (and also Salmonella paratyphi A and B, and Salmonella Choleraesuis) and Yersinia enterocolitica (Chapter 19) cause enteric fever. The agents that commonly cause toxin-induced gastroenteritis, invasive, and noninvasive gastrointestinal infections are listed in Table 48-4.

Gastrointestinal infections are very common, especially in developing countries, where the associated mortality rate is high in infants and young children. Public health prevention through fostering good hygiene and providing sanitary water and food supplies is of the utmost importance.

In only a small percentage of cases is the etiologic agent demonstrated by means of stool culture or immunoassay. This is likely to change with the implementation of broad-based nucleic acid amplification panels that can simultaneously detect bacteria, viruses, and protozoan infections with enhanced sensitivity. Some of these panels detect pathogens that are not routinely sought in clinical laboratories such as ETEC and EPEC (Chapter 15). Finding white blood cells on fecal wet mounts is highly suggestive of infection with an invasive pathogen but can also be seen in noninfectious causes of colitis such as inflammatory bowel disease.

Maintaining adequate hydration is the most important feature of treatment, especially in infants and children. Antimicrobial therapy is necessary in treatment of enteric fever (typhoid fever) and shortens the duration of symptoms in Shigella, Campylobacter, and V cholerae infections, but it prolongs the symptoms and fecal shedding of Salmonella.

There is no specific therapy for infection due to rotaviruses, the most common viral cause of diarrhea; however, a vaccine is available for prevention.

REFERENCES

Clinical Features

The temperature was 37.5°C, pulse 105/min, and respirations 18/min. The blood pressure was 105/70 mm Hg.

On physical examination, the only abnormal finding was mild tenderness to deep palpation in the suprapubic area.

Laboratory Findings

Laboratory tests showed a slightly elevated white blood cell count of 13,000/μL; 66% were PMNs, also elevated. Blood urea nitrogen, serum creatinine and glucose, and serum electrolytes were normal. The urine sediment contained innumerable white cells, moderate numbers of red cells, and many bacteria suggestive of urinary tract infection. Culture yielded more than 10⁵ CFU/mL of E coli (diagnostic of a urinary tract infection). Antimicrobial susceptibility tests were not done.

Treatment

The patient was cured by 3 days of oral trimethoprim/sulfamethoxazole therapy.

Comment

See below.

Clinical Features

The temperature was 39°C, the pulse was 120/min, and the respirations were 24/min. The blood pressure was 90/40 mm Hg.

On physical examination, the patient knew his name but was disoriented to time and place. His heart, lungs, and abdomen were normal. There was mild costovertebral tenderness over the area of the left kidney.

Laboratory Findings

Laboratory tests showed a normal hematocrit and hemoglobin but an elevated white blood cell count of 18,000/μL; 85% were PMNs (markedly elevated). Blood urea nitrogen, serum creatinine, serum glucose, and electrolytes were normal. Urine was obtained from the catheter port using a needle and syringe. The urine sediment contained innumerable white cells, a few red blood cells, and numerous bacteria, indicating a urinary tract infection. Urine culture yielded more than 10⁵ CFU/mL of E coli (Chapter 15), confirming the diagnosis of urinary tract infection. Blood culture also yielded the E coli, which was susceptible to third-generation cephalosporins, but resistant to gentamicin, fluoroquinolones, and trimethoprim-sulfamethoxazole.

Treatment and Hospital Course

The patient had a urinary tract infection associated with the bladder catheter. The left kidney was presumed to be involved based on the left costovertebral angle tenderness. He also had secondary bacteremia with shock (sometimes termed gram-negative sepsis and shock). He was treated with intravenous fluids and antibiotics and recovered. The same strain of E coli had been isolated from other patients in the hospital, indicating nosocomial spread of the bacteria.

Comment

Urinary tract infections may involve just the lower tract or both the lower and upper tracts. Cystitis is the term used to describe infection of the bladder with signs and symptoms, including dysuria, urgency, and frequency, as in Case 8. Pyelonephritis is the term used to describe upper tract infection, often with flank pain and tenderness, and accompanying dysuria, urgency, and frequency, as in Case 9. Cystitis and pyelonephritis often present as acute diseases, but recurrent or chronic infections occur frequently.

It is generally accepted that 10⁵ or more CFU/mL of urine is significant bacteriuria, though the patients may be symptomatic or asymptomatic. Some young women have dysuria and other symptoms of cystitis with less than 10⁵ CFU/mL of urine; in these women, as few as 10³ CFU/mL of a gram-negative rod may be significant bacteriuria.

The prevalence of bacteriuria is 1–2% in school-age girls, 1–3% in nonpregnant women, and 3–8% during pregnancy. The prevalence of bacteriuria increases with age, and the sex ratio of infections becomes nearly equal. Over the age of 70 years, 20–30% or more of women and 10% or more of men have bacteriuria. Upper urinary tract infections routinely occur in patients with indwelling catheters even with optimal care and closed drainage systems: 50% after 4–5 days, 75% after 7–9 days, and 100% after 2 weeks. Sexual activity and use of spermicides increase the risk for urinary tract infections in young women.

E coli (Chapter 15) causes 80–90% of acute uncomplicated bacterial lower tract infections (cystitis) in young women. Other enteric bacteria and Staphylococcus saprophyticus (Chapter 13) cause most of the other culture-positive bladder infections in this patient group. Some young women with acute dysuria suggesting cystitis have negative urine cultures for bacteria. In these patients, selective tests for Neisseria gonorrhoeae (Chapter 20) and Chlamydia trachomatis (Chapter 27) and evaluation for herpes simplex infection should be considered.

In complicated upper tract infections, in the setting of anatomic abnormality or chronic catheterization, the spectrum in infecting bacteria is larger than in uncomplicated cases. E coli is frequently present, but other gram-negative rods of many species (eg, Klebsiella, Proteus, and Enterobacter [Chapter 15] and pseudomonads [Chapter 16]), enterococci, and staphylococci are also common. In many cases, two or more species are present, and the bacteria are often resistant to antimicrobials given in association with prior therapy as was the situation with Case 9. In that scenario, the patient was most likely infected with a global clone of ESBL-producing (CTX-M15) E coli, ST131 (Chapter 15).

The presence of white blood cells in urine is highly suggestive but not specific for bacterial upper tract infections. White blood cells can be detected by microscopic examination of urine sediment or, indirectly, by dipstick detection of leukocyte esterase. The presence of red blood cells also is found on microscopy of the urine sediment, or indirectly by dipstick detection of hemoglobin. Proteinuria also is detected by dipstick. The presence of bacteria on Gram stain of uncentrifuged urine is strongly suggestive of 10⁵ or more bacteria per milliliter of urine.

The presence of bacteriuria is confirmed by quantitative culture of the urine by any one of several methods. One frequently used method is to culture urine using a bacteriologic loop calibrated to deliver 0.01 or 0.001 mL followed by counting the number of colonies that grow.

Acute uncomplicated cystitis is usually caused by E coli susceptible to readily achievable urine concentrations of antibiotics appropriate for treatment of urinary tract infections. Thus, in the setting of the first such infection in a young woman, definitive identification and susceptibility testing of the bacteria are seldom necessary. Such cases can be treated by a single dose of appropriate antibiotic, based on local or regional antibiograms, but a 3- to 5-day course of therapy yields a lower relapse rate. Typical agents used include trimethoprim-sulfamethoxazole, nitrofurantoin, or fosfomycin. Pyelonephritis is treated with 10–14 days of antibiotic therapy. Recurrent or complicated upper tract infections are best treated with antibiotics shown to be active against the infecting bacteria; definitive identification and susceptibility testing are indicated. Therapy for 14 days is appropriate and for 14–21 days if there is recurrence. Patients with complicated upper tract infections should have evaluations for anatomic abnormalities, stones, and so forth.

REFERENCES

Comment

Osteomyelitis follows hematogenous spread of pathogenic bacteria from a distant site of infection to bone or, as in this case, direct inoculation of the bone and soft tissue, as can occur with an open fracture or from a contiguous site of soft tissue infection. The primary symptoms are fever and pain at the infected site; swelling, redness, and occasionally drainage can be seen, but the physical findings are highly dependent on the anatomic location of the infection. For example, osteomyelitis of the spine may present with fever, back pain, and signs of a paraspinous abscess; infection of the hip may present as fever with pain on movement and decreased range of motion. In children, the onset of osteomyelitis following hematogenous spread of bacteria can be very sudden, while in adults the presentation may be more indolent. Sometimes osteomyelitis is considered to be chronic or of long standing, but the clinical spectrum of osteomyelitis is broad, and the distinction between acute and chronic may not be clear either clinically or on morphologic examination of tissue.

S aureus (Chapter 13) is the primary agent of osteomyelitis in 60–70% of cases (90% in children). S aureus causes the infection after hematogenous spread or following direct inoculation. Community-acquired methicillin-resistant S aureus that contains the Panton-Valentine leukocidin causes acute hematogenous osteomyelitis affecting multiple sites, often in association with vascular complications. Streptococci, most commonly S pyogenes and S pneumoniae in children, cause osteomyelitis in about 10% of cases, and enteric gram-negative rods (eg, E coli) and other bacteria such as P aeruginosa (Chapter 16) in 20–30%. Kingella kingae (Chapter 16) is a common etiologic agent in infants and children younger than 4 years. Anaerobic bacteria (eg, Bacteroides species [Chapter 21]) are also common, particularly in osteomyelitis of the bones of the feet associated with diabetes and foot ulcers. Any bacteria that cause infections in humans have been associated with osteomyelitis.

Definitive diagnosis of the etiology of osteomyelitis requires culture of a specimen obtained at surgery or by needle aspiration of bone or periosteum through uninfected soft tissue. Culture of pus from the opening of a draining sinus tract or superficial wound associated with the osteomyelitis commonly yields bacteria that are not present in the bone. Blood cultures are often positive when systemic symptoms and signs (fever, weight loss, elevated white blood cell count, high erythrocyte sedimentation rate) are present.

Early in the course of osteomyelitis, x-ray films of the infected site are negative. The initial findings noted radiologically usually are soft tissue swelling, loss of tissue planes, and demineralization of bone; 2–3 weeks after onset, bone erosions and evidence of periostitis appear. Bone scans with radionuclide imaging are about 90% sensitive. They become positive within a few days after onset and are particularly helpful in localizing the site of infection and determining if there are multiple sites of infection; however, bone scans do not differentiate between fractures, bone infarction (as occurs in sickle cell disease), and infection. CT and MRI also are sensitive and especially helpful in determining the extent of soft tissue involvement.

Antimicrobial therapy and surgical debridement are the mainstays of treatment of osteomyelitis. The specific antimicrobial should be selected after culture of a properly obtained specimen and susceptibility tests and continued for 6–8 weeks or longer, depending on the infection. Surgery should be done to remove any dead bone and sequestra that are present. Immobilization of infected limbs and fixation of fractures are important features of care.

REFERENCES

Clinical Features and Course

The temperature was 40°C, the pulse 150/min, and respirations 28/min. The blood pressure was 80/40 mm Hg.

Physical examination showed an acutely ill young man who was in shock and delirious. The left thigh was markedly swollen and cool to touch. Large ecchymotic areas were present near the wound, and there was a serous discharge from the wound. Crepitus was felt, indicative of gas in the tissue of the thigh. An x-ray film also showed gas in the tissue planes of the thigh. Gas gangrene was diagnosed, and the patient was taken to the operating room for emergency extensive debridement of necrotic tissue. At the time of surgery, his hematocrit had fallen to 27% and his hemoglobin to 11 g/dL; his serum was red-brown in color, indicating hemolysis with free hemoglobin in his circulation. Anaerobic cultures of the specimen obtained at surgery grew Clostridium perfringens (Chapters 11, 21). The patient developed renal failure and heart failure and died 3 days after his injury.

Comment

Case 11 illustrates a classic case of clostridial gas gangrene. C perfringens (or occasionally other Clostridium species such as C septicum and C histolyticum) are inoculated into the traumatic wound from the environment; the clostridia are discussed in Chapters 11 and 21. The presence of necrotic tissue and foreign body material provides a suitable anaerobic environment for the organisms to multiply. After an incubation period usually of 2–3 days but sometimes only 8–12 hours, there is acute onset of pain, which rapidly increases in intensity associated with shock and delirium. The extremity or wound shows tenderness, tense swelling, and a serosanguineous discharge. Crepitus is often present. The skin near the wound is pale but rapidly becomes discolored, and fluid-filled blebs form in the nearby skin. Skin areas of black necrosis appear. In severe cases, there is rapid progression.

In patients such as this one, Gram stain of fluid from a bleb or of a tissue aspirate shows large gram-positive rods with blunt ends and is highly suggestive of clostridial infection. PMN leukocytes are rare. Anaerobic culture provides the definitive laboratory confirmation. The differential diagnosis of clostridial gas gangrene includes anaerobic streptococcal myonecrosis, synergistic necrotizing myonecrosis, and necrotizing fasciitis. These clinically overlapping diseases can be differentiated from clostridial gas gangrene by Gram stain and cultures of appropriate specimens.

X-ray films of the infected site show gas in the fascial planes. Abnormal laboratory tests include a low hematocrit. The hemoglobin may be low or normal even when the hematocrit is low, consistent with hemolysis and cell-free circulating hemoglobin. Leukocytosis is usually present.

Treatment

Extensive surgery with removal of all the dead and infected tissue is necessary as a lifesaving procedure. Penicillin G is the antibiotic of choice. Antitoxin is of no help. Hyperbaric oxygen can be used in centers that have experience and the appropriate equipment. When shock and circulating free hemoglobin are present, renal failure and other complications are common and the prognosis is poor.

REFERENCE

Clinical Features

Her temperature was 37.5°C; other vital signs were normal. Physical examination showed a yellowish mucopurulent discharge from the cervical os. Moderate left lower abdominal tenderness was present. The bimanual pelvic examination showed cervical motion tenderness and adnexal tenderness more severe on the left than on the right.

Laboratory Findings

A nucleic acid amplification test that detects both N gonorrhoeae (Chapter 20) and C trachomatis (Chapter 27) performed on a cervical swab specimen was positive for C trachomatis.

Treatment

A diagnosis of pelvic inflammatory disease (PID) was made. The patient was treated as an outpatient with a single intramuscular dose of ceftriaxone plus oral azithromycin. Both of her partners came to the clinic and were treated.

Comment

In men, urethral discharge is classified as gonococcal urethritis, caused by N gonorrhoeae, or nongonococcal urethritis, caused usually by C trachomatis (15–55% of cases), Ureaplasma urealyticum (20–40% of cases), Mycoplasma genitalium, and infrequently by Trichomonas vaginalis (Chapter 46). The diagnosis is based on the presence or absence of gram-negative intracellular diplococci on stain of the urethral discharge. All patients with urethritis should be tested using nucleic acid amplification methods for both C trachomatis and N gonorrhoeae. Ceftriaxone is frequently used to treat gonococcal urethritis, but quinolones may be used in areas that report low resistance. Doxycycline or azithromycin is used to treat nongonococcal urethritis. It is highly recommended that men with gonococcal infection also be treated for chlamydial infection because of the likelihood that both infections may be present.

In women, the differential diagnosis of endocervicitis (mucopurulent cervicitis) is between gonorrhea and C trachomatis infection. The diagnosis is made by culture of the endocervical discharge or nucleic acid amplification tests for simultaneous detection of N gonorrhoeae and C trachomatis. Treatment for both N gonorrhoeae and C trachomatis is recommended. Recommended treatments are the same as those mentioned for urethritis.

Pelvic inflammatory disease (PID), also called salpingitis, is inflammation of the uterus, uterine tubes, and adnexal tissues that is not associated with surgery or pregnancy. PID is the major consequence of endocervical N gonorrhoeae and C trachomatis infections, and well over half of the cases are caused by one or both of these organisms. The incidence of gonococcal PID is high in inner city populations, while chlamydial PID is more common in college students and more affluent populations. Other common bacterial causes of PID are enteric organisms and anaerobic bacteria associated with bacterial vaginosis. Lower abdominal pain is the common presenting symptom. An abnormal vaginal discharge, uterine bleeding, dysuria, painful intercourse, nausea and vomiting, and fever also occur frequently. The major complication of PID is infertility due to uterine tubal occlusion. It is estimated that 8% of women become infertile after one episode of PID, 19.5% after two episodes, and 40% after three or more episodes. A clinical diagnosis of PID should be considered in any woman of childbearing age who has pelvic pain. Patients often have classic physical findings in addition to the presenting signs and symptoms, including lower abdominal, cervical motion, and adnexal tenderness. A clinical diagnosis can be confirmed by laparoscopic visualization of the uterus and uterine tubes, but this procedure is not practical and is infrequently performed; however, only about two-thirds of women with a clinical diagnosis of PID will have the disease when the uterine tubes and uterus are visualized. The differential diagnosis includes ectopic pregnancy and appendicitis as well as other diseases. In PID patients, hospitalization with intravenous therapy often is recommended to decrease the possibility of infertility. Inpatient drug regimens include cefoxitin and doxycycline or gentamicin and clindamycin. Outpatient regimens include cefoxitin or ceftriaxone in single doses plus doxycycline, or ofloxacin plus metronidazole.

REFERENCES

Clinical Features

Physical examination showed a thin, homogeneous, whitish gray discharge that was adherent to the vaginal wall. There was no discharge from the cervical os. The bimanual pelvic examination was normal, as was the remainder of the physical examination.

Laboratory Findings

The pH of the vaginal fluid was 5.5 (normal, <4.5). When KOH was added to vaginal fluid on a slide, an amine-like (“fishy”) odor was perceived. A wet mount of the fluid showed many epithelial cells with adherent bacteria (clue cells). No PMN cells were seen. The diagnosis was bacterial vaginosis.

Treatment

Metronidazole twice daily for 7 days resulted in rapid clearing of the disorder. The decision was made not to treat her male partner unless she had a recurrence of vaginosis.

Comment

Bacterial vaginosis must be differentiated from a normal vaginal discharge and from T vaginalis vaginitis and C albicans vulvovaginitis (Table 48-5). These diseases are very common, occurring in about one-fifth of women seeking gynecologic health care. Most women have at least one episode of vaginitis or vaginosis during their childbearing years.

Bacterial vaginosis is so named because no PMN cells are present in the vaginal discharge; that is, the disease is not an inflammatory process. In association with Gardnerella vaginalis (Chapter 22) infection, the lactobacilli of the normal vaginal microbiota decrease in number and the vaginal pH rises. Concomitantly, there is overgrowth of G vaginalis and vaginal anaerobic bacteria, producing the odorous amine-containing discharge. In addition to G vaginalis, curved gram-negative rods of the genus Mobiluncus have been associated with bacterial vaginosis. These curved bacteria can be seen on Gram stains of the vaginal discharge.

T vaginalis (Chapter 46) is a flagellated protozoan. T vaginalis vaginitis is usually diagnosed by a wet mount of the vaginal fluid showing the motile trichomonads that are slightly larger than PMN cells. Because trichomonads lose their motility when cooled, it is best to use warm (37°C) saline, slides, and coverslips when making the wet mount preparations and to examine the preparations promptly. Newer diagnostic methods are much more sensitive than wet mounts, and at least one nucleic acid amplification test is available in the United States.

Candidal vulvovaginitis frequently follows antibiotic therapy for a bacterial infection. The antibiotics decrease the normal genital microbiota, allowing the yeasts to proliferate and produce symptoms. Thus, candidal vulvovaginitis is not really a sexually transmitted disease.

REFERENCES

Clinical Features

The patient’s temperature was 37°C, pulse 80/min, respirations 16/min, and blood pressure 110/80 mm Hg. There was a 1-cm ulcer on the left side of the penile shaft. The ulcer had a clean base and raised borders with moderate induration. There was little pain on palpation. Left inguinal lymph nodes 1–1.5 cm in diameter were palpable.

Laboratory Findings

The penile lesion was gently cleaned with saline and gauze. A small amount of clear exudate was then obtained from the base of the lesion, placed on a slide, and examined by dark-field microscopy. Multiple spirochetes were seen. The rapid plasma reagin (RPR) screening serologic test for syphilis was positive at a 1:8 dilution. The confirmatory treponeme-specific fluorescent treponemal antibody-absorbed (FTA-ABS) test also was positive.

Treatment and Follow-Up

The patient was treated with a single dose of benzathine penicillin. Six months later, his RPR test had reverted to negative, but the FTA-ABS test was expected to stay positive for life.

The patient named five female sex partners for the month prior to his clinic visit. Three of these women were located by the public health investigators; two had positive serologic tests for syphilis and were treated. The two women who were not located had gone to unknown addresses in other cities.

Comment

The three major genital ulcer diseases are syphilis, genital herpes, and chancroid (Table 48-6).

Two much less common genital sore diseases are the initial lesion of lymphogranuloma venereum, caused by certain serovars of C trachomatis (Chapter 27), and the rare disease granuloma inguinale (donovanosis), caused by Klebsiella granulomatis. Lymphogranuloma venereum is a systemic illness with fever, malaise, and lymphadenopathy; inguinal buboes may be present. The diagnosis usually is made by serology and NAATs, but culture of pus aspirated from an inguinal bubo may yield C trachomatis. Some reference laboratories have developed multiplex polymerase chain reaction (PCR) assays for simultaneous detection of the pathogens that cause genital sore disease, but these are not widely available.

New approaches to syphilis diagnosis include implementation of “reverse” algorithms. This involves screening patients with one of the newer, more sensitive treponemal tests (newer ELISA or chemiluminescent assays) followed by testing positive samples with a non-treponemal assay like the rapid plasma regain test (RPR). If the RPR is negative then a second treponemal assay is performed. The advantages to the reverse algorithm are that it allows automation of the tests, thereby removing subjective interpretation and it is more accurate in detecting patients with early disease or late/latent syphilis (see Tong et al). Others cite the major disadvantage that more patients may screen positive that do not have disease which could lead to initial over-treatment or extensive medical follow-up (see review by Binnicker).

REFERENCES

Clinical Features

His temperature was 39°C, pulse 110/min, respirations 32/min, and blood pressure 120/80 mm Hg. He was a slender man. His dentition was poor, but the remainder of his head and neck examination was normal. On chest examination, many crackles were heard over the upper lung fields. The remainder of the physical examination was normal.

Laboratory Findings and Imaging

The hematocrit was 30% (low), and the white blood cell count was 9600/μL. Electrolyte concentrations and other blood tests were normal. The test for HIV-1 antibody was negative. A chest radiograph showed extensive cavitary infiltrates in both upper lobes. A tuberculin skin test was negative, as were skin tests with mumps and candida antigens, indicating anergy.

A sputum specimen was obtained immediately, and an acid-fast stain was done before the sputum concentration procedure. Numerous acid-fast bacteria were seen on the smear. Culture of the decontaminated and concentrated sputum was positive for acid-fast bacteria after 14 days’ incubation; M tuberculosis was identified by molecular probe 2 days later. Susceptibility tests of the organisms showed susceptibility to isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin.

Hospital Course and Treatment

The patient was treated with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by directly observed twice-weekly administration of isoniazid and rifampin for 7 months. Follow-up sputum cultures were negative for M tuberculosis.

At hospitalization, the patient had been placed in isolation and asked to wear a mask at all times. However, before the mask and isolation were implemented, a medical student and a resident physician were exposed to the patient. The resident physician converted her tuberculin skin test and received isoniazid prophylaxis for 9 months.

An attempt was made to trace the patient’s close contacts. A total of 34 persons were found to have positive tuberculin tests. Persons 35 years of age or younger were given isoniazid prophylaxis for 1 year; those older than 35 had periodic follow-up chest x-rays. Two cases of active tuberculosis also were diagnosed and treated. The M tuberculosis isolates from the two patients were identical to the index patient’s isolate by DNA fingerprinting.

Clinical Features

Her temperature was 39°C, pulse 100/min, respirations 20/min, and blood pressure 120/80 mm Hg. There were slightly enlarged cervical and axillary lymph nodes on physical examination. Lung auscultation appeared normal. The examiner was unable to palpate her spleen; the liver was of normal size to percussion.

Laboratory Findings and Imaging

The hemoglobin was 8.3 g/dL (normal, 12–15.5 g/dL), and the hematocrit was 27% (normal, 36–46%). The peripheral blood smear showed hypochromic, microcytic red blood cells compatible with chronic infection or iron deficiency anemia. The platelet count was 50,000/μL (normal, 140,000–450,000/μL). The white blood cell count was 7000/μL (normal), with a normal differential count. The prothrombin time was moderately prolonged and the partial thromboplastin time mildly prolonged, suggesting a coagulopathy of liver disease. The liver function tests were an aspartate aminotransferase (AST) of 140 units/L (normal, 10–40 units/L), alanine aminotransferase (ALT) 105 units/L (normal, 5–35 units/L), bilirubin 2 mg/dL (twice normal), and alkaline phosphatase 100 units/L (normal, 36–122 units/L). The serum albumin was 1.7 g/dL (normal, 3.4–5 g/dL). The creatinine, blood urea nitrogen, and electrolytes were normal. Urinalysis showed a few red and a few white blood cells. Two routine blood cultures were negative. Sputum and urine cultures grew small amounts of normal microbiota.

Serologic tests for HIV-1, hepatitis B virus antibody and antigen, coccidioidomycosis, leptospirosis, brucellosis, Mycoplasma infection, Lyme disease, and Q fever were negative. A tuberculin skin test was negative. A chest radiograph was normal. A CT scan of the abdomen was negative.

Hospital Course and Treatment

During the first few days of hospitalization, the patient developed progressive shortness of breath and respiratory distress. Repeat chest radiography showed bilateral interstitial infiltrates. Adult respiratory distress syndrome was diagnosed. The hemoglobin was now 10.6 g/dL and the white blood cell count 4900/μL. Arterial blood gases showed a pH of 7.38, a PO₂ of 50 mm Hg (low), and a PCO₂ of 32 mm Hg. The patient was placed on oxygen therapy and intubated (for 4 days). BAL was performed. The lavage fluid was negative on routine culture, and an acid-fast stain was also negative. A second abdominal CT scan showed a normal-appearing liver, but periaortic lymphadenopathy and mild splenomegaly were present. The patient underwent laparoscopy with a liver biopsy and a bone marrow biopsy.

The liver and bone marrow biopsies both showed granulomas with giant cells; acid-fast bacilli were also present. (There were abundant iron stores, indicating that the anemia was due to chronic infection and not iron deficiency.) The patient was started on isoniazid, rifampin, pyrazinamide, and ethambutol. The chest radiographs continued to show diffuse infiltrates, but improvement was evident. The patient’s fever decreased, and she showed general improvement.

Between 19 and 21 days of incubation, the liver and bone marrow biopsies and the lavage fluid all were culture-positive for acid-fast bacilli, identified as M tuberculosis by molecular probe. The mycobacteria were susceptible to all the drugs the patient was receiving. The four-drug regimen was continued for 2 months until the susceptibility test results were obtained. The patient was then continued on isoniazid and rifampin for 10 more months for a total of 1 year of therapy.

The patient’s relatives and the elderly persons who lived with them all had skin tests for tuberculosis. The persons with positive skin tests and those who had recent histories of cough or weight loss also had chest radiographs. Three tuberculin-positive persons were found. No one had active tuberculosis. Those living in the home with the patient and those persons who recently converted their skin tests were offered prophylaxis with isoniazid. The patient was thought to have had reactivation tuberculosis with hematogenous spread involving her lungs, liver, lymph nodes, and possibly her kidneys.

Comment

It is estimated that approximately one-third of the world’s population have tuberculosis and that each year about 1–3 million people die of the disease. In the United States, a low incidence of tuberculosis of 9.4 cases per 100,000 population was reached in the mid-1980s. The rate increased slightly in the late 1980s, but since 1992, the rates have again declined. The lowest (and most recently recorded) rate of 3.0 cases per 100,000 population (9582 cases) was recorded in 2013 representing a decline in the rate of 6.1% since 2012 (http://www.cdc.gov/tb/statistics/default.htm). Tuberculosis in the United States occurs most commonly among lower socioeconomic populations: the urban poor, homeless persons, migrant farm workers, alcoholics, and intravenous drug users as well as among foreign-born persons. Approximately half of the cases of tuberculosis occur in foreign-born individuals. The incidence of tuberculosis can be very high in selected groups and geographic areas (eg, HIV-positive intravenous drug abusers in the eastern United States, Haitian AIDS patients). Tuberculosis in elderly persons usually is due to reactivation of prior infection, while disease in children implies active transmission of M tuberculosis. About 80% of cases in children occur in ethnic minorities. However, active tuberculosis is most frequently diagnosed in young adults, often in association with HIV-1 infection. Concomitant tuberculosis and HIV-1 infections are especially important in developing countries; in Africa, millions of people have both infections. There is considerable concern about the spread of multidrug-resistant tuberculosis in Russia.

Spread of tuberculosis from a patient to another person occurs through infectious droplet nuclei generated during coughing, sneezing, or talking. The major factors in transmission of infection are the closeness and duration of contact and the infectiousness of the patient. Generally, less than 50% of contacts of active cases become infected as measured by conversion of tuberculin skin tests. Patients generally become noninfectious 2 weeks after beginning therapy. Once infected, 3–4% of persons develop active tuberculosis in the first year and about 10% at some later time. The ages when infection is most likely to yield active disease are infancy, age 15–25 years, and the elderly years.

The tuberculin skin test is performed by intracutaneous injection of 5 tuberculin units (TU) of purified protein derivative (PPD) using a number 26 or 27 needle. The reaction is read at 48–72 hours, and a positive test is induration of 10 mm or more; erythema is not considered in determining a positive test. Of persons with 10-mm induration, 90% have M tuberculosis infection, while essentially all persons with more than 15-mm induration are infected. False-positive tests are caused by infection with nontuberculous mycobacteria (eg, Mycobacterium kansasii). False-negative tests are due to generalized illness in tuberculosis patients or to immunosuppression. Alternatives to the tuberculin skin test are the interferon gamma release assays (Chapter 23). These assays are particularly helpful in assessing individuals who have received BCG vaccination. The use of these assays for diagnosing tuberculosis in patients who are immunocompromised or anergic is still under investigation.

Primary M tuberculosis infection in children includes mid or lower lung field infiltrates and hilar lymphadenopathy on chest films. Adolescents and adults may have a similar picture on primary infection, but infection will often quickly progress to apical cavitary disease. In the elderly, tuberculosis may present nonspecifically as a lower lobe pneumonia. When apical cavitary disease is present, it strongly suggests tuberculosis (the differential diagnosis includes histoplasmosis), but tuberculosis can mimic other diseases when parts of the lungs other than the apices are infected. Chronic pulmonary tuberculosis can be due to reactivation of endogenous infection or to exogenous reinfection.

Extrapulmonary tuberculosis occurs in less than 20% of cases, is more common in AIDS patients, and can be very serious and even life threatening. The most common method of spread is by hematogenous dissemination at the time of primary infection or, less commonly, from chronic pulmonary or other foci. Direct extension of infection into the pleural, pericardial, or peritoneal spaces can occur, as can seeding of the gastrointestinal tract by swallowing infected secretions. In AIDS patients, unlike other patients, concurrent pulmonary and extrapulmonary disease is common. The major extrapulmonary forms of tuberculosis—in approximately descending order of frequency—are as follows: lymphatic, pleural, genitourinary, bones and joints, disseminated (miliary), meningeal, and peritoneal. However, any organ can be infected with M tuberculosis, and tuberculosis must be considered in the differential diagnosis of many other diseases.

The two major drugs used to treat tuberculosis are isoniazid (INH) and rifampin (RIF). The other first-line drugs are pyrazinamide (PZA) and ethambutol (EMB). There are several second-line drugs that are more toxic or less effective, or both, and they should be used in therapy only when circumstances warrant their use (eg, treatment failure with standard drugs, multiple drug resistance). Several approved regimens exist for the treatment of susceptible M tuberculosis in children and adults. Most clinicians prefer 6-month regimens. The initial phase of a 6-month regimen for adults should consist of a 2-month period of INH, RIF, PZA, and EMB. Directly observed therapy 5 days per week is optimum. The continuation phase of treatment should consist of INH and RIF given for a minimum of 4 months. The continuation phase should be extended for an additional 3 months for patients who have cavitation on the initial or follow-up chest radiograph and are culture-positive at the time of completion of the initial phase of treatment (2 months).

Nine months of treatment is recommended if PZA cannot be included in the initial regimen, or if the isolate is determined to be resistant to PZA. A treatment course consisting of INH, RIF, and EMB should be given for the initial 2 months followed by INH and RIF for 7 months given either daily or twice weekly. INH and RIF susceptibility or resistance are important factors in choosing appropriate drugs and establishing the duration of treatment. In noncompliant patients, directly observed therapy is important as well.

REFERENCES

Clinical Features

His temperature was 38°C, pulse 90/min, respirations 18/min, and blood pressure 110/70 mm Hg. He did not appear to be acutely ill. The tip of the spleen was palpable in the left upper abdominal quadrant 3 cm below the ribs (suggesting splenomegaly). Hepatomegaly and lymphadenopathy were not present, and there were no neurologic or meningeal signs. The balance of the physical examination was normal.

Laboratory Findings and Imaging

The patient’s white blood cell count was stable at 3000/μL (below normal). The hematocrit was 29% (below normal). A CD4 T helper–inducer cell count was 75 cells/μL (normal, 425–1650/μL).

The chemistry panel was notable only for the liver enzyme alkaline phosphatase concentration of 210 units/L (normal, 36–122 units/L). Further evaluation of the cause of the patient’s fever showed a normal urinalysis, negative routine blood cultures, and a normal chest radiograph. A serum cryptococcal antigen test was negative. Two blood cultures for mycobacteria were obtained. These turned positive 10 and 12 days after they were drawn. Three days later, the organism was identified by molecular probe as M avium complex (MAC).

The patient was tested using the fourth generation HIV1/2 immunoassay that incorporates combined antibody/antigen tests. The assay was positive and a reflex RT-PCR viral load test was performed and the value was high at 300,000 copies/mL.

Treatment and Follow-Up

The patient was started on a three-drug regimen for MAC: clarithromycin, ethambutol, and ciprofloxacin. He noted an increased sense of well-being, a marked decrease in his fever and sweats, and an increased appetite. Concomitantly, the patient was started on highly active antiretroviral therapy (HAART). The drugs used were efavirenz, tenofovir, and emtricitabine (all 3 are nonnucleoside reverse transcriptase inhibitors) formulated together in a single tablet. At follow-up 4 months after initiating antiretroviral therapy, the patient’s HIV RNA viral load assay showed undetectable levels of the virus; the CD4 T-cell count was 250 cells/μL.

Comment on HIV-1 Infection and AIDS

The incubation period from exposure to onset of acute HIV disease is typically 2–4 weeks. Most persons develop acute illness that lasts 2–6 weeks. The common signs and symptoms are fever (97%), adenopathy (77%), pharyngitis (73%), rash (70%), and myalgia or arthralgia. The rash is erythematous and nonpruritic, and consists of maculopapular (slightly raised) lesions 5–10 mm in diameter, usually on the face or trunk—but the rash can be on the extremities or the palms and soles or may be generalized. Ulcers in the mouth are a distinctive feature of primary HIV infection. The acute illness has been described as “mononucleosis-like,” but it truly is a distinct syndrome.

Anti-HIV-1 IgM antibodies appear within 2 weeks after the primary infection and precede the appearance of IgG antibodies, which are detectable within another few weeks. Detection of HIV-1 RNA early in the course of infection is a major concern for blood banks to prevent transfusion of antibody-negative HIV-1-positive blood.

AIDS is the major complication of HIV infection. According to the CDC, it is defined as CD4 cell count of less than 200 cells/microL or the presence of serious opportunistic infections, neoplasms, or other life-threatening manifestations regardless of the CD4 count. The AIDS-defining infections are listed in Table 48-7. AIDS-defining tumors include primary lymphoma of the brain, Burkitt or immunoblastic lymphoma, and invasive cervical carcinoma in women, in addition to Kaposi sarcoma. HIV encephalopathy with disabling cognitive or motor functions and HIV wasting disease (>10% weight loss and over 1 month of either diarrhea or weakness and fever) also are AIDS-defining.

HIV-infected patients may present with signs and symptoms referable to one or more organ systems. The common opportunistic infections are listed by anatomic site in Table 48-8. Typically, the evaluation of patients who may have HIV infection or AIDS is based on a clinical and epidemiologic history of possible exposure coupled with a diagnostic evaluation of the presenting illness according to the site involved.

The status of knowledge about anti-HIV drug therapy changes very rapidly, and for that reason, anti-HIV therapy recommendations should be considered interim ones. Postexposure prophylaxis with anti-HIV drugs is effective, and treatment of primary HIV infection may also have favorable prognostic implications. Many factors influence the decision to begin anti-HIV treatment, including the rate of decrease of the CD4 cell count and the blood level of HIVRNA. The drugs used to treat HIV infection are discussed in Chapter 30. A variety of different regimens may be chosen. This highly active antiretroviral therapy has significantly improved the lives and prognosis for many AIDS patients. Response to treatment should be monitored by following viral load measurements and by testing for resistance when clinical response is poor. When the CD4 cell count is less than 200/μL, prophylaxis for P jirovecii infection should be started. Prophylaxis for other opportunistic infections (see Table 48-7) also may be appropriate.

REFERENCES

Orthotopic liver transplantation was accomplished without difficulty. Biliary reconstruction was by choledochocholedochostomy (primary anastomosis of the donor’s to the recipient’s common bile duct) with placement of a T-tube for external drainage of bile during healing of the anastomosis. A hepatocellular carcinoma was found incidentally on examination of the explant. The patient was started on intravenous tacrolimus (to reduce rejection) as a continuous infusion over 24 hours and corticosteroids for immunosuppression (also to help prevent rejection). The tacrolimus was changed to oral therapy on day 2. Intravenous ganciclovir was given on days 1–7 for prophylaxis against cytomegalovirus infection (hepatitis and pneumonia); after the ganciclovir was stopped, high-dose oral acyclovir was given four times daily for 3 months as continued prophylaxis against cytomegalovirus infection. Oral trimethoprim-sulfamethoxazole also was given twice weekly as prophylaxis against pneumocystis pneumonia.

Allograft function was established immediately after transplantation. On day 7 the AST was 40 units/L, alkaline phosphatase 138 units/L (normal, 36–122 units/L), and bilirubin 6.2 mg/dL. The differential diagnosis of the abnormal liver function was injury during liver preservation between donation and transplantation, hepatic artery thrombosis, and, rarely, herpes simplex hepatitis. Liver biopsy on day 7 showed injury during preservation.

The patient was discharged on day 12 on oral tacrolimus and prednisone to help prevent rejection. On day 21, a liver biopsy showed no evidence of cellular rejection and the liver tests were excellent: AST 18 units/L, alkaline phosphatase 96 units/L, and bilirubin 2 mg/dL. The serum creatinine was 2.2 mg/dL (normal, 0.5–1.4 mg/dL), and the dose of oral tacrolimus was decreased. On day 28, liver function tests rose to AST 296 units/L, alkaline phosphatase 497 units/L, and bilirubin 7 mg/dL. The differential diagnosis of abnormal liver function was acute cellular rejection and biliary obstruction. Cytomegalovirus hepatitis was possible, but this generally occurs after day 35, and the patient had been receiving prophylaxis for cytomegalovirus. A liver biopsy showed acute cellular rejection.

The patient was treated with two intravenous doses of methylprednisolone followed by oral prednisone. The tacrolimus blood level was in the therapeutic range. A follow-up liver biopsy 2 weeks later showed mild fatty change but no rejection. The AST was 15 units/L, alkaline phosphatase 245 units/L, and bilirubin 1.6 mg/dL.

One month later, 2.5 months post-transplantation, the AST again rose to 155 units/L, but the alkaline phosphatase was unchanged at 178 units/L. Biopsy showed moderate fatty change, lobular hepatocyte necrosis, and mild portal inflammation consistent with post-transplant hepatitis C infection or resolving rejection. A polymerase chain reaction assay for HCV RNA was not done because it would have been positive and would have had limited prognostic value. The clinical impression was recurrent hepatitis C. The tacrolimus and prednisone were continued. Over the next month, liver function tests returned to normal.

At 6 months post-transplantation, the T-tube was removed from the bile drainage system. The patient immediately experienced severe diffuse abdominal pain. Culture of the bile grew E coli and vancomycin-resistant Enterococcus faecium. The clinical impression was bile drainage into the abdomen. The patient was treated with ceftriaxone and linezolid. Endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy was performed to improve the bile flow. The patient was discharged 2 days later.

Eight months after the transplant, the patient presented with generalized subcutaneous edema (anasarca) and a lower extremity rash. His liver tests were mildly abnormal. The hematocrit and white blood cell count were normal. The blood urea nitrogen was 54 mg/dL (normal, 10–24 mg/dL), and serum creatinine was 2.8 mg/dL (normal, 0.6–1.2 mg/dL). Urinalysis showed 4+ protein and more than 50 red blood cells per high-power field. Skin biopsy showed a leukocytoclastic vasculitis. Cryoglobulinemia was diagnosed.

Four years post-transplant, the patient’s liver tests have remained normal with the exception of intermittent mild AST and ALT elevations. Follow-up liver biopsies have shown moderate to severe fatty change with mild mononuclear cell portal inflammation. The patient remains an insulin-dependent diabetic. Renal function is mildly abnormal, with a serum creatinine of about 1.4 mg/dL. His quality of life is good. He is currently maintained on tacrolimus and prednisone. Compared with other liver transplant recipients, the patient is at increased risk for developing cirrhosis and suffering graft loss.

Comment

Transplant patients have their most important and life-threatening infections during the first few months following transplantation. Factors present prior to the transplant may be important. Underlying disease may contribute to susceptibility to infection. The patient may not have specific immunity (eg, may never have been exposed to cytomegalovirus) but the transplanted organ may be from a cytomegalovirus-positive donor or a blood transfusion may transmit the virus. The patient may have a latent infection that can become active during the period of immunosuppression following transplantation; examples include infections with herpes simplex virus, varicella-zoster virus, cytomegalovirus, and others, including tuberculosis. The patient may have received immunosuppressive drugs prior to transplantation.

A major factor determining infection is the type of transplantation: liver, heart, lung, kidney, and so on. The duration and complexity of the surgical procedure also are important. Infections tend to involve the transplanted organ or to occur in association with the organ. In liver transplant patients, the surgery is complex and can take many hours. The type of biliary drainage that is established is an important determinant of abdominal infection. Direct connection of the donor biliary tract to the small bowel of the recipient (choledochojejunostomy) predisposes to biliary tract infection more so than does connection of the donor biliary tract to the recipient’s existing biliary tract (choledochocholedochostomy). Liver transplant patients with surgery lasting 5–10 hours average one episode of infection post-transplant, while those whose surgery takes over 25 hours average three episodes. Liver transplant patients are prone to development of cytomegalovirus hepatitis and pneumonia. Heart–lung transplant recipients are prone to cytomegalovirus pneumonia. Ganciclovir given early in the post-transplant period is effective in reducing the impact of post-transplant cytomegalovirus disease. Other drugs often given as prophylaxis for post-transplant infection include the following: acyclovir for herpes simplex and varicella-zoster; trimethoprim-sulfamethoxazole for Pneumocystis pneumonia; amphotericin B or other antifungal agent for fungal infections, primarily candidiasis and aspergillosis; isoniazid for tuberculosis; and a third-generation cephalosporin or other antibiotics for bacterial infections. The antibiotics often are given before, during, and shortly after operation to prevent wound infections and other infections directly associated with the procedure.

Immunosuppressive therapy in transplant patients also predisposes to infections. Corticosteroids in high doses used to help prevent rejection or graft-versus-host disease, inhibit T-cell proliferation, T-cell–dependent immunity, and the expression of cytokine genes and thus have major effects on cellular immunity, antibody formation, and inflammation. Patients receiving high doses of corticosteroids are increasingly prone to fungal and other infections. Cyclosporine, a peptide, and tacrolimus, a macrolide, act on T-cell function to prevent rejection. Other immunosuppressive drugs and anti-lymphocyte serum also are used. Collectively, the immunosuppressive agents can provide a setting where infections occur in transplant recipients.

Case 19 presents a patient with bone marrow transplantation and includes comments on the infections that occur in that setting.

REFERENCES

The first infectious complication appeared at 10 days post-transplantation, before engraftment had occurred. The patient had mucositis, enteritis, and severe neutropenia with a white blood cell count of 100 cells/μL (normal, 3400–10,000 cells/μL). He was receiving prophylactic ceftazidime, fluconazole, acyclovir, and trimethoprim-sulfamethoxazole. However, he became febrile to 39°C and looked sick. The clinical impression was probable bacterial sepsis related to the neutropenia, with the likely source being either his mouth or his gastrointestinal tract. Another possibility was infection of the central line used for his intravenous therapy. A fungal infection, either with Candida in the blood or Aspergillus pneumonia, would also be possible; however, these infections generally occur later following allogeneic bone marrow transplantation. The patient had been started on cyclosporine and low-dose prednisone therapy shortly after the bone marrow transplant to prevent graft-versus-host disease, which predisposed him to other opportunistic infections, but these also were less likely in the first few weeks following transplant.

When his condition worsened on post-transplant day 10, he was thought to have a bacterial infection. A blood culture was obtained, and the gram-negative antibiotic coverage was changed from ceftazidime to meropenem. Vancomycin was added pending the result of the blood culture. The fluconazole was changed to voriconazole. On day 12, the blood culture was reported positive for viridans streptococci. The patient improved. The antibiotic therapy was continued until his white blood cell count increased to over 1000/μL.

On day 30 post-transplant, the patient was discharged to home care. He was engrafted and was no longer neutropenic but was receiving cyclosporine and prednisone therapy for mild graft-versus-host disease.

On day 60 post-transplant, the patient developed fever, nausea, marked epigastric pain, and diarrhea. The clinical impression was cytomegalovirus enteritis or worsening graft-versus-host disease involving the gastrointestinal tract. Between day 30 and 60, the cyclosporine and prednisone therapy had gradually been decreased as his graft-versus-host disease had been stable. On day 60, the patient was admitted to hospital and examined by upper and lower gastrointestinal endoscopy. Mucosal lesions consistent with cytomegalovirus infection were seen and biopsied. On histologic examination, large intranuclear inclusion bodies consistent with cytomegalovirus infection were seen. Cultures were positive for cytomegalovirus. The patient was treated with ganciclovir and recovered.

The patient did well until day 120, when he developed abnormal liver function tests and diarrhea. Colonoscopy yielded a diagnosis of worsening graft-versus-host disease. His cyclosporine and prednisone dosages were increased.

On day 150 post-transplant, he developed fever and cough and was found to have multiple pulmonary infiltrates. The most likely diagnosis was fungal pneumonia, probably due to Aspergillus species, although P jirovecii and viral pneumonia were also possible. The patient underwent bronchoscopy with lavage and transbronchial biopsy. Cultures of the biopsy tissue grew Aspergillus fumigatus. The patient was treated with voriconazole. This therapy was continued for 2 weeks in the hospital and then daily on an outpatient basis for 3 more weeks. The cyclosporine and prednisone dosages were decreased also.

By day 300, the patient was free of opportunistic infections. His graft-versus-host disease subsided, and his cyclosporine and prednisone dosages were tapered and then the drugs were discontinued. His chronic myelogenous leukemia remained in remission. He returned to work full time 330 days after his bone marrow transplant.

Comment

Patients who undergo bone marrow transplantation receive ablative chemotherapy and radiation therapy to destroy their hematopoietic and immune systems. The result is severe neutropenia and abnormal cellular immunity until the transplanted marrow engrafts. Because of the neutropenia, bone marrow transplantation patients are at especially high risk for infection compared with patients who receive solid organ transplants and are not neutropenic. Patients who have allogeneic bone marrow transplantation are also at risk for graft-versus-host disease, which does not occur in persons who have autologous bone marrow transplantation (ie, receive their own previously harvested bone marrow or stem cells). The immunosuppressive therapy used to control the graft-versus-host disease also helps provide a setting where patients are at high risk for infection.

The infections and the times they are likely to occur are shown in Figure 48-1. During the first month post-transplant, before engraftment occurs, there is severe neutropenia and damaged mucosal surfaces because of the pre-transplant chemotherapy and radiation therapy. The patients are at greatest risk for infections caused by gram-negative and gram-positive bacteria that often are part of the normal microbiota of the skin, gastrointestinal tract, and respiratory tract. Recurrent herpes simplex virus infection may also occur at this time.

In the second and third months, after engraftment has occurred, the patients have continued impairment of humoral and cellular immunity. This impairment is more severe and persistent in patients with acute graft-versus-host disease. The major infections are interstitial pneumonia (about 50% caused by cytomegalovirus), Aspergillus pneumonia, bacteremia, candidemia, and viral respiratory infections.

After 3 months post-transplant, there is gradual recovery of both humoral and cellular immunity. This reconstitution takes 1–2 years and can be significantly impaired by chronic graft-versus-host disease. Patients are at risk for varicella-zoster infections and for respiratory tract infections, usually with encapsulated bacteria such as S pneumoniae (Chapter 14) and H influenzae (Chapter 18).

Prophylactic antimicrobial therapy is routinely used in bone marrow transplantation patients. Trimethoprim-sulfamethoxazole is given for 6 months or the duration of immunosuppression to prevent Pneumocystis pneumonia. Acyclovir is given from the time of transplantation until engraftment occurs to prevent herpes simplex infection. Intravenous ganciclovir often is given early after transplantation and followed by oral acyclovir or oral ganciclovir to help prevent severe cytomegalovirus disease; the use of this prophylaxis varies depending on whether the donor, the recipient, or both have evidence of prior cytomegalovirus infection. Fluoroquinolones or third-generation cephalosporins may be given during the engraftment period to help prevent bacterial infections. Antifungal agents—fluconazole, posaconazole, or voriconazole (depending on whether graft-versus-host disease is present)—may be used as prophylaxis for fungal disease. The use of vancomycin to prevent infections by gram-positive bacteria is controversial, in part because of potential selection for vancomycin-resistant enterococcal infection. After the immune system has returned to normal function, reimmunization with tetanus and diphtheria toxoids, pneumococcal and H influenzae polysaccharide vaccines, and killed viral vaccines (eg, polio, influenza) should be considered.

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EMERGING INFECTIONS

The following cases discuss novel emerging infections. In such events, priority is placed on the diagnosis, isolation and treatment of infected individuals, and on the monitoring of spread, containment and control within the population at risk.

On February 26, a man who had traveled in mainland China and Hong Kong was hospitalized in Hanoi, Vietnam with a respiratory illness; he later died. Health care providers in Hanoi subsequently developed a similar illness. In late February a second cluster was reported in Hong Kong linked to a patient who had traveled to southern China.

Most patients with SARS presented with upper respiratory viral symptoms leading to pneumonia. Mortality rates were approximately 10%, with higher mortality in patients older than 65 years.

On March 12, WHO issued a global alert about the outbreak and instituted worldwide surveillance. By March 19, 264 patients from 11 countries were reported. Intensive containment efforts were instituted, including airport screening, isolation, and large-scale quarantine.

Testing of samples by electron microscopy and virus microarray demonstrated a novel coronavirus, named SARS-CoV. The virus was spread by respiratory droplets and close person-to-person contact. The natural host of SARS-CoV is thought to be bats, with civet cats as intermediate hosts causing human infections in animal markets.

During the SARS epidemic, more than 8000 probable cases and 774 deaths were reported from 29 countries. Since 2004, there have not been any known cases of SARS reported anywhere in the world.

REFERENCES

Since November 2003, more than 600 sporadic cases of human infection with highly pathogenic avian influenza A (H5N1) have been reported, primarily by 15 countries in Asia, Africa, the Pacific, Europe, and the Near East. Indonesia, Vietnam, and Egypt have the highest number of reported cases to date. On January 8, 2014, the first case of human infection with H5N1 in the Americas was reported in Canada. Approximately 60% of cases have died.

Human infections with H7N9 avian influenza were reported in China in March 2013, with 132 cases and 44 deaths. Most patients have had severe respiratory illness, with about one-third resulting in death. New reports of human H7N9 infection were less frequent during May–December 2013. The decrease in cases was likely due to closure of live bird markets along with the change in weather. Since January 2014 the frequency of reported cases has increased, coinciding with the arrival of cooler weather.

The majority of infected persons have close contact with sick or dead poultry or wild birds, but there is evidence that limited nonsustained human-to-human transmission after prolonged close contact has occurred in some clusters.

The primary concern about avian influenza is the emergence of a novel strain with sustained human-to-human transmissibility that maintains high virulence for naïve individuals. Gain-of-function experiments have demonstrated that five substitutions are sufficient to transform H5N1 virus into an airborne-transmissible pathogen. Performing these gain-of-function experiments is controversial, and they are highly regulated to ensure that the strains are not accidentally released, or that the information can be used by terrorist groups to engineer highly pathogenic viruses.

REFERENCES

The park visitors had stayed at Curry Village tent cabins, which had insulation between the exterior canvas and interior walls. Deer mice infestations were detected in the insulation, exposing the guests to rodent urine and droppings, which contain infectious virus.

Patients developed fever, chills, myalgia, headache, and gastrointestinal symptoms, progressing to respiratory distress and shock. Approximately 26,000 visitors were notified of their potential exposure. The cabins were extensively decontaminated and reconstructed to eliminate areas that could serve as mouse habitats.

REFERENCE

On September 20, 2012, a physician in Saudi Arabia sent a respiratory virus culture from a patient with pneumonia to the laboratory of Dr. Fouchier in the Netherlands for identification. The virus was identified by next-generation sequencing as a novel coronavirus, related to severe acute respiratory syndrome coronavirus (SARS-CoV). Over the next several months, hundreds of cases were documented, with over 250 deaths by July 1, 2014. Cases were found in countries in or near the Arabian Peninsula and travelers returning from these countries. Most patients with severe disease were elderly or had medical comorbidities, overall mortality is about 30% for reported cases but is likely lower due to the absence of reporting of mild cases.

MERS-CoV presents with acute respiratory illness and fever, progressing to pneumonia. The virus has been shown to spread from person to person through close contact, but there is no evidence of sustained community spreading.

MERS-CoV is thought to be originally derived from bats. Camels in affected areas were found to be seropositive, and may be an intermediate host for transmission to humans. Cases and clusters of MERS infection are continuing to be investigated. PCR is used for diagnosis, and there is no specific treatment, though supportive care substantially improves case outcomes.

REFERENCE

By March 30, cases were reported in neighboring Liberia, and cases were identified in Sierra Leone in May. As of June 18, this had become the largest Ebola virus disease outbreak ever documented, with a combined 528 cases and 337 deaths (64% case-fatality rate).

Cases were characterized by sudden onset of fever and malaise with headache, myalgia, vomiting, and diarrhea. Around 30–50% of the patients experienced hemorrhagic symptoms. The incubation period is typically 8–10 days, but can range from 2 to 21 days. Patients with severe disease develop thrombocytopenia, bleeding, and multiorgan failure leading to shock and death.

While the definitive host species has not been identified, evidence supports fruit bats as one reservoir. The virus initially transfers to humans upon contact with infected wildlife, and is then spread person-to-person through direct contact with body fluids such as blood, urine, sweat, semen, and breast milk. Viral particles can be found in semen up to 61 days after illness onset from recovered cases. Many patients in Africa are thought to have become infected after handling of deceased relatives through customary burial practices.

Diagnosis is made through detection of Ebola virus antigen, RNA, or antibodies in blood. Patient care is supportive, with aggressive fluid and electrolyte replacement. Novel vaccines and treatments are currently being developed and tested on a case basis.

As of April 2015, there were a total number of over 25,000 suspect and confirmed cases, with over 10,000 deaths. Outbreak control measures have been enhanced with mandatory quarantine and disposal of infected bodies, intensive tracking and monitoring efforts, and international provision of medical supplies and training. International flights from the outbreak region have instituted passenger screening for fever and associated symptoms. These measures have substantially reduced the number of new cases, particularly in the most affected areas in Liberia and Sierra Leone.

Imported cases have been identified in Nigeria, Senegal, the United States, Spain, Mali and the United Kingdom. In Nigeria, localized transmission led to 20 cases, but subsequent spread in the country was stopped. While the risk of additional infected patients entering the United States is low, health care workers are advised to be alert for signs and symptoms of Ebola virus disease in travelers returning from the outbreak regions. These patients are to be strictly isolated while diagnostic tests are pending.

The combination of a novel highly virulent viral disease with an immunologically naïve population and sustained person-to-person spread is extremely concerning and poses a substantial risk to global health. The limited medical resources of the affected countries make it extremely difficult to treat patients and halt transmission. Response to this outbreak requires high-level regional and international cooperation with provision of outbreak response experts, trained health care workers, and personal protective equipment and other medical supplies. Failure to contain this or similar outbreaks could lead to a widespread epidemic with devastating consequences.