Respiratory Micro Infections PDF

Chapter 59 Infective Syndromes of Respiratory Tract...

Chapter 59 Infective Syndromes of Respiratory Tract Chapter Preview „„Upper Respiratory Tract Infections „„Oral Cavity Infections „„Lower Respiratory Tract Infections Introduction microorganisms and the respiratory tract occur several times a day. However, establishment of infection after such The respiratory tract is divided into two segments, the contact tends to be the exception rather than the rule. This is upper and the lower respiratory tract. due to the defense mechanisms provided by the respiratory ™™ The upper respiratory tract (URT) includes the nasal tract which prevent the establishment of infection. cavity, paranasal sinuses, pharynx (throat), epiglottis, ™™ Nasal cavity: Nasal hairs, convoluted passages, and the and larynx nasal turbinates capture larger inhaled particles before ™™ The lower respiratory tract (LRT) comprises of trachea, they reach the lower respiratory tract bronchi, which are divided into bronchioles and lungs, ™™ Secretory products: Secretory IgA and nonspecific with the surrounding pleura. antibacterial substances (lysozyme) in respiratory Normal Commensals secretion ™™ Tracheobronchial tree: The branching architecture of There are a number of bacteria that reside in upper the tracheobronchial tree traps particles on the airway respiratory tract (oral cavity and nasopharynx) as indigenous lining flora. Some of these organisms are potential pathogens ™™ Mucociliary clearance: Cilia and mucous lining of elsewhere in the body and may invade the respiratory tract the trachea helps in clearing or killing the potential under certain circumstances—previous damage by a viral pathogens infection, low host immunity, or physical damage to the ™™ Reflexes such as coughing, sneezing, and gag reflex offer respiratory epithelium (e.g. from smoking). critical protection from aspiration ™™ Normal flora of URT prevents colonization by pathogenic Respiratory Commensals Common examples of respiratory commensals are: organisms in the URT by several mechanisms such as— ‰‰ Streptococci (α and nonhemolytic) competing for space, nutrients and through production ‰‰ Neisseria (non-pathogenic species, other than N. of bacteriocins and other metabolic products that are gonorrhoeae and N. meningitidis) toxic to the invading organism (Chapter 7) ‰‰ Diphtheroids ™™ Alveolar macrophages: After escaping the above ‰‰ Moraxella catarrhalis described defense mechanisms, the pathogens of URT ‰‰ Coagulase negative staphylococci such as S. epidermidis can establish infection locally; whereas the pathogens ‰‰ Anaerobes: Prevotella, Peptostreptococcus, Fusobacterium of LRT can gain access into the lungs. In such a case, the ‰‰ Major pathogens of other body sites may colonize in the nasopharynx less frequently, such as Haemophilus, establishment of infection can be prevented by alveolar meningococcus, pneumococcus and S. aureus macrophages, which ingest and subsequently destroy ‰‰ In hospitalized patients on the ventilator, the organisms the organisms. present in the hospital environment, such as gram- negative rods Acinetobacter, Pseudomonas, Burkholderia Upper respiratory tract infections and Enterobacteriaceae may colonize the URT ‰‰ Yeasts such as Candida albicans. The various URT infections (URTI) and the common microbial pathogens implicated are listed in Table 59.1. The classification of microbial infections into URTI and LRTI is Defence Mechanisms of Respiratory Tract artificial, as many URTI pathogens can occasionally infect Respiratory tract serves as portal of entry for a number lungs such as B. pertussis, influenza, coronaviruses (e.g. of pathogenic organisms. Encounters between COVID-19), etc. 588 Section 8  Respiratory Tract Infections Table 59.1: Upper and lower respiratory tract infections and the Etiologic Agents major pathogens implicated. Pharyngitis has varied etiology; the most frequent Upper respiratory tract infections organisms involved are: Pharyngitis and tonsillitis Viral: Influenza, coronavirus ™™ Bacterial agents : Strepto co ccus p y og enes, Bacterial: S. pyogenes, C. diphtheriae Corynebacterium diphtheriae, other β-hemolytic Laryngitis Influenza and parainfluenza viruses Streptococcus (group C and G) are major agents. Other Acute laryngotracheo- Parainfluenza virus rare causes include: bronchitis (croup) „„ Arcanobacterium hemolyticum Epiglottitis Haemophilus influenzae b „„ Fusobacterium necrophorum Parapharyngeal infections „„ Mycoplasma pneumoniae (usually associated with Peritonsillar abscess S. pyogenes, S.aureus and anaerobes cough) (quinsy) „„ Neisseria gonorrhoeae (due to orogenital sexual Ludwig’s angina Polymicrobial and anaerobic contact). ™™ Viral agents: Respiratory viruses account for majority of Infections of nasal cavity and sinuses pharyngitis cases. Viral pharyngitis should be suspected Rhinitis Rhinoviruses and others if concurrent manifestations such as conjunctivitis, Atrophic rhinitis (ozena) Klebsiella ozaenae coryza, cough, skin rash, vesicles on pharynx, etc. are Rhinoscleroma Klebsiella rhinoscleromatis associated. Etiological agents include: Sinusitis S. pneumoniae, H. influenzae „„ Influenza and parainfluenza viruses Infections of the oral cavity „„ Coronaviruses including the virus causing COVID-19 Stomatitis Herpes simplex virus „„ Epstein-Barr virus (causes infectious mononucleosis) Oral thrush Candida albicans „„ Enteroviruses: Coxsackie A virus (vesicular pharyngi- Dental, periodontal infections Anaerobes and viridans streptococci tis or herpangina), echoviruses, enterovirus 71 „„ Less common agents: Adenovirus, rhinovirus, Salivary gland infections Mumps and others herpes simplex virus or HIV (as acute retroviral Vincent’s angina Borrelia vincentii and Fusobacterium syndrome). Lower respiratory tract infections Bronchitis Respiratory viruses Clinical Manifestations Bronchiolitis Respiratory syncytial virus Throat (pharyngeal) pain is the earliest symptom, Whooping cough (Pertussis) Bordetella pertussis recognized when the person complains of difficulty in Pneumonia swallowing or drinking. Pharynx becomes erythematous Lobar pneumonia Pneumococcus, H. influenzae, (red) and swollen. Depending on the causative micro­ S. aureus, K. pneumoniae, and other organism, different tissue response may be observed. gram-negative bacilli ™™ Enlarged and inflamed tonsil, a consistent finding in Atypical pneumonia Mycoplasma, Chlamydia, viruses children (Figs 59.1A and B) Pulmonary tuberculosis Mycobacterium tuberculosis ™™ Inflammatory exudate—fluid with protein, inflammatory Rare causes of LRTI cells, and cellular debris; seen in bacterial infection such Fungal pneumonia Pneumocystis jirovecii and others as S. pyogenes ™™ Membrane over the tonsils can be seen in diphtheria Parasitic lung disease Paragonimus, Ascaris and others (pseudomembrane); rarely in infectious mononucleosis Lung abscess Primary: Anaerobes Secondary: Gram-negative bacilli Pleural effusion and Bacterial (secondary to pneumonia), empyema tubercular and viral Note: The classification of microbial infections into URTI and LRTI is artificial; many pathogens causing URTI can occasionally infect lungs and cause LRTI; such as B. pertussis, influenza virus, coronavirus, etc. At the same time, many pathogens causing LRTI such as Mycoplasma pneumoniae and Chlamydophila pneumoniae may occasionally cause URTI like pharyngitis. Pharyngitis and Tonsillitis Pharyngitis (or sore throat) refers to the inflammation of the pharynx, is one of the most common upper respiratory tract infection; affecting both children and adults. In A B children, most often it presents with tonsillitis (inflamed Figs 59.1A and B: A. Healthy throat; B. Sore throat, showing tonsils). inflamed pharynx with enlarged and inflamed tonsils and uvula.  Chapter 59  Infective Syndromes of Respiratory Tract 589 ™™ Vesicles (small blisters), seen in herpes ™™ Manifestation: Illness is characterized by variable ™™ Mucosal ulceration, or enlarged nasopharyngeal swollen fever, inspiratory stridor (produced by turbulent airflow lymph nodes; seen in infectious mononucleosis. through a partially obstructed larynx), hoarseness, and a harsh barking nonproductive cough. In young infants, Pathogenesis severe respiratory distress and fever are common Pathogenic mechanisms differ and depend on the symptoms organism causing the pharyngitis; either toxin-mediated ™™ Treatment: Only symptomatic treatment is required; (C. diphtheriae) or through liberation of several virulence antimicrobial therapy is not indicated. factors (S. pyogenes) or by direct invasion (Arcanobacterium) Agents of bacterial pharyngitis are discussed in Chapter Epiglottitis 60 and agents of vial pharyngitis are discussed in Chapter Epiglottitis is an infection of the epiglottis and other soft 66 (influenza), 67 (coronaviruses) and 68 (other viral tissues above the vocal cords. It can lead to significant agents). edema and inflammation. ™™ Agents: In contrast to laryngitis which is primarily Laryngitis caused by viruses, epiglottitis is usually associated with Acute laryngitis (inflammation of the larynx) has an abrupt bacterial infections. Haemophilus influenzae type b is onset and is usually self-limited. The patient presents with the primary cause of epiglottitis; although its incidence hoarseness and lowering or deepening of the voice (Fig. is greatly reduced because of widespread vaccination. 59.2). Other commonly implicated organisms include ™™ Viral agents: Acute laryngitis is almost exclusively S. pyogenes, pneumococcus and S. aureus (>90%) associated with viral infections such as influenza ™™ Age: Children (2-6 years of age) are commonly infected and parainfluenza viruses, rhinoviruses, adenoviruses, ™™ Manifestations: Children typically present with fever, coronaviruses, and human metapneumovirus difficulty in swallowing because of pain, drooling, and ™™ Bacterial agents may rarely cause laryngitis; presence respiratory obstruction with inspiratory stridor. It can be of exudate or membrane on the laryngeal mucosa— life-threatening if patient’s airway gets obstructed streptococcal infection, mononucleosis, or diphtheria ™™ Diagnosis: Bacteriologic culture of the epiglottis is should be suspected contraindicated because swabbing of the epiglottis may ™™ Treatment: Only symptomatic treatment is required; lead to respiratory obstruction. Blood cultures may be antimicrobial therapy is not indicated. performed as H. influenzae bacteremia usually occurs Chronic laryngitis: Occasionally, symptoms last for in children with epiglottitis ™™ Treatment: Cefotaxime alone, or ceftriaxone + vancomycin >3 weeks. It is most often caused by vocal abuse; less frequently caused by infections. are the primary antibiotics given. Tracheostomy may be needed in case of respiratory obstruction. Acute Laryngotracheobronchitis (Croup) Parapharyngeal Infections Croup is a potentially more serious disease as the infection extends downward from the larynx to involve the trachea 1. Peritonsillar Abscess (or Quinsy) or even the bronchi. It is deep neck infection that occurs as a complication of ™™ Agents: Parainfluenza viruses are the major etiologic tonsillitis. It usually affects children (> 5 years age) and agents. Other causes include influenza viruses, young adults. respiratory syncytial virus, adenoviruses, rhinoviruses, ™™ Unless promptly managed, it can spread to adjacent and enteroviruses; and a bacterial agent such as tissues, as well as erode into the carotid artery to cause Mycoplasma pneumoniae an acute hemorrhage ™™ Age: It commonly occurs in young children (< 3 years ™™ Organisms: The common organisms implicated are S. age) pyogenes, S. aureus, viridans streptococci and nonsporing anaerobe such as Fusobacterium necrophorum ™™ Treatment: Includes surgical drainage plus antibiotic such as piperacillin-tazobactam to cover the common etiological agents. 2. Ludwig’s Angina Ludwig’s angina is a form of diffuse cellulitis of the mandibular space (bilateral) present in the floor of the mouth; subsequently may spread to sublingual and submental spaces. It was first described by the German Fig. 59.2: Normal and inflamed larynx. physician, von Ludwig in 1836. 590 Section 8  Respiratory Tract Infections ™™ Source: This infection most commonly arises from an ™™ Treatment: Ciprofloxacin or levofloxacin is given for adjacent dental infection; typically from an infected 2–3 months. second or third molar tooth ™™ Etiology: Often polymicrobial and anaerobic; Sinusitis some common organisms isolated include viridans Sinusitis is characterized by inflammation of the lining of streptococci, staphylococci, Peptostreptococcus, the paranasal sinuses. Prevotella, Porphyromonas and Fusobacterium ™™ Manifestations: It is aggressive, rapidly spreading Etiology cellulitis, without lymphadenopathy, with potential for ™™ Acute bacterial sinusitis: The common pathogens airway obstruction causing sinusitis are S. pneumoniae (most common, „„ Presents with bilateral lower facial swelling around 33%), H. influenzae (32%), and Moraxella catarrhalis the mandible and upper neck (9%); less commonly, S. aureus, anaerobes and S. „„ Elevation of the floor of mouth may be seen due to pyogenes are implicated. S. aureus is a common pathogen sublingual space involvement in sphenoid sinusitis „„ Posterior displacement of the tongue may occur, ™™ Viral sinusitis: Viruses account for 15% of sinusitis. The creating the potential for a compromised airway common URT viruses such as rhinovirus, influenza, „„ Other symptoms may include painful neck swelling, parainfluenza and coronaviruses are the primary viral tooth pain, dysphagia, shortness of breath, fever, and pathogens in acute sinusitis general malaise. ™™ Fungal sinusitis: Allergic fungal sinusitis, though rare ™™ Treatment: Comprises of—(i) sufficient airway may be seen in infection with fungi such as Aspergillus, management, (ii) early and aggressive antibiotic therapy, Alternaria, Bipolaris and Curvularia. (iii) incision and drainage of localized abscesses if any, Clinical Manifestations and (iv) adequate nutrition and hydration support. Common features are facial pressure and frontal headache, Infections of Nasal Cavity and Sinuses loss of smell, nasal congestion and postnasal drip. Rhinitis Additional findings depend upon the etiology. ™™ For bacterial sinusitis: Fever, maxillary toothache, Rhinitis (also called as common cold) is an inflammation purulent nasal discharge and unilateral facial pain. of the nasal mucous membrane. It clinically presents as Symptoms typically last for >10 days running nose, sneezing, inflammatory edema of the nasal ™™ Viral sinusitis: Improves by 7–10 days mucosa, and watery eyes with variable fever. Rhinitis is ™™ For allergic rhinosinusitis: Postnasal drip, sneezing, itchy typically associated with viral infections. eyes, headache, tearing, red eyes, etc. ™™ Viral agents (20–25%): Rhinoviruses are the most common cause. Others include coronaviruses, influenza Diagnosis viruses, adenoviruses, parainfluenza, respiratory Microbiological diagnosis is very difficult. Diagnosis is often syncytial virus and enteroviruses made clinically, in adjunction with radiological features. ™™ Bacterial agents (10–15%) associated with rhinitis include Chlamydophila pneumoniae, Mycoplasma T Reatment Sinusitis pneumoniae, and Streptococcus pyogenes. Treatment in most cases is empiric, targeting the common bacterial pathogens. Atrophic Rhinitis (or Ozena) ‰‰ Amoxicillin ± clavulanate is the first line treatment, given for It is caused by Klebsiella pneumoniae subspecies ozaenae, 5-7 days. Alternative drugs include clindamycin or levofloxacin characterized by chronic foul smelling mucopurulent nasal ‰‰ Sinusitis are common cause of overuse of antibiotics discharge; affecting elderly people. It is biochemically ¾¾ Antibiotics are indicated only when specific symptoms inactive organism. Ciprofloxacin or levofloxacin is given are present for bacterial sinusitis such as fever or purulent for 2 months. nasal discharge ¾¾ When sinus symptoms are suggestive of viral or allergic; Rhinoscleroma antibiotics must be avoided and wait and watch policy should be followed. It is caused by Klebsiella pneumoniae subspecies rhinoscleromatis. Laboratory Diagnosis of URTI ™™ It is a rare form of chronic, granulomatous hypertrophy of the nose. It presents as tumor-like growth, may cause Specimen Collection and Transport prolonged nasal obstruction. Infection may spread to the ™™ Throat swab (oropharyngeal swab) containing fibrous sinuses and occasionally the pharynx and larynx exudates is the ideal specimen for pharyngitis. It should ™™ It is prevalent in Southeast Europe, India and in Central be collected by vigorous rubbing of sterile swab over the America posterior pharynx and both the tonsillar pillars. Two  Chapter 59  Infective Syndromes of Respiratory Tract 591 swabs may be collected, one for direct smear and the Oral cavity infections other for culture ™™ Specimens other than throat swabs include: Infections of the Oral Mucosa „„ In suspected diphtheria, a portion of pseudo­ Stomatitis membrane may be obtained Stomatitis is an inflammation of the mucous membranes of „„ Nasopharyngeal swab is preferred for B. pertussis or the oral cavity. It is caused by herpes simplex virus (HSV); viruses like influenza or coronavirus. It is collected characterized by multiple painful tiny vesicular lesions by inserting flexible swab through nose into posterior on the oral mucosa and in oropharynx. Recurrences are nasopharynx and then rotating for 5 seconds. common, but the lesions are less severe. HSV infection of ™™ Types of swabs: Dacron, or Rayon swabs are suitable for the oral cavity is more common in immunosuppressed collecting most URT microorganisms. Flocked swabs are patients. preferable. Cotton swabs can be used for S. pyogenes, but not suitable for viruses and B. pertussis Oral Thrush (Oral Candidiasis) ™™ Transport: For isolation of most URT bacterial Candida spp. can also invade the oral mucosa, especially in pathogens, swabs should be processed within 4 immunosuppressed patients (e.g. HIV). It is characterized hours. However for molecular diagnosis (bacteria or by whitish patches of exudate (the area of inflammation) viruses), the specimens can be stored at 4°C and can be which are observed on the buccal mucosa (Chapter 58, processed late. Special transport media such as Amies Fig. 58.11A). It may extend to the tongue, oropharynx or or Stuart’s media (charcoal based) may be preferred esophagus; especially in HIV-infected individuals. for B. pertussis. Dental and Periodontal Infections Diagnostic Methods Dental infections include infections of the tooth or its ™™ Direct smear: Gram staining is not useful for most of the supporting periodontal structures. URTI. Albert stain may be performed when diphtheria ™™ Dental infections most commonly occur when the is suspected bacteria invade the pulp and spread to surrounding Note: If oral thrush or Vincent’s angina is suspected, tissues. This can occur due to trauma, dental procedures, Gram staining can be performed. or dental caries (cavity formation in the tooth due to ™™ Culture: Specimens may be inoculated onto blood agar destruction of its mineralized tissues; caused by viridans and chocolate agar. Additional media may be used such streptococci) as potassium tellurite agar (for C. diphtheriae), Regan- ™™ Periodontal infections mostly result from poor or low media (for B. pertussis) ineffective dental hygiene leading to plaque formation ™™ Molecular diagnosis: This is the gold standard method and subsequent inflammation of tissues around the for detection for respiratory viruses such as influenza or teeth. coronaviruses and others „„ Real-time PCR is available for targeting genes Etiologic Agents specific for SARS CoV-2, influenza A H1N1 and other Common organisms implicated in dental infections are respiratory viruses primarily the anaerobic bacteria and viridans streptococci „„ BioFire FilmArray, an automated multiplex PCR is found in the oral cavity. commercially available. Its respiratory panel can ™™ Anaerobic bacteria: They account for up to 50% of dental simultaneously detect 22 most common pathogens infections, which include: involved in URTI (17 viruses and 3 bacteria) in a „„ Anaerobic cocci (Peptostreptococcus and Veillonella) turnaround time of 1 hour. It has an overall sensitivity „„ Anaerobic gram-negative bacilli such as Prevotella, and specificity of 95% and 99% respectively. Porphyromonas, Bacteroides fragilis, and Fusobacte- ™™ Antigen detection tests may be useful for detection of rium. certain URT pathogens ™™ Viridans streptococci: Streptococcus anginosus group are „„ Rapid antigen detection test for detection of Group A usually found in 20 to 30% of dental infections. carbohydrate antigen of S. pyogenes in throat swabs „„ Direct fluorescent antibody (DFA) staining for Common Dental Infections detection of B. pertussis in nasopharyngeal secretions Common dental and periodontal infections include: „„ Recently a rapid chromatographic immunoassay has ™™ Root canal infections, with or without periapical abscess been developed for detection of SARS CoV-2 from ™™ Dental (periapical) abscess: It is common in children; nasopharyngeal swabs. occurs secondary to dental caries ™™ Antibody detection in serum is less useful for URT „„ Dental caries erode the protective layers of the tooth pathogens. They only provide retrospective evidence of (i.e. enamel) which allows bacteria to invade the infection and are used for seroepidemiological purpose. pulp, producing pulpitis 592 Section 8  Respiratory Tract Infections „„ Pulpitis can progress to necrosis, with bacterial Bronchitis invasion of the alveolar bone, causing an abscess. Acute bronchitis is defined as self-limited inflammation of ™™ Periodontal abscess: It involves the supporting the bronchial tree due to infections. Most infections occur structures of the teeth (periodontal ligaments, alveolar during the winter. bone). This is the most common dental abscess in adults, ™™ Etiology: Most commonly caused by respiratory viruses but may also occur in children (20–50%) such as RSV, influenza and coronavirus. ™™ Spread: Dental infections have a potential of Bacterial causes include Mycoplasma pneumoniae spreading to the surrounding tissues such as gingivitis (5%), Chlamydophila pneumoniae (5%) and Bordetella (gums), orofacial infections, osteomyelitis of the jaw, pertussis perimandibular space infections, etc. ™™ Manifestations: Acute bronchitis presents with Salivary Gland Infections persisting cough, variable fever, and sputum production. The sputum is often clear at the onset but may become Parotitis (inflammation of the parotid gland) can be caused purulent as the illness persists. by both bacteria and viruses. ™™ Mumps is traditionally the most common virus to Chronic bronchitis: It is clinically defined as cough with cause parotitis (Chapter 66); although the cases are expectoration for at least 3 months/ year during a period significantly reduced since the advent of childhood of 2 consecutive years. It usually affects adults. vaccination. Influenza virus and enteroviruses may also ™™ In contrast to acute bronchitis (which typically has an cause parotitis infectious etiology) in chronic bronchitis, there occurs ™™ Acute suppurative parotitis: It is seen among severely chronic irritation of bronchial mucosa due to factors such sick malnourished, or elderly patients as cigarette smoking „„ Characterized by painful, tender swelling of the ™™ Smokers with underlying COPD (chronic obstructive parotid gland; purulent drainage may be evident at pulmonary disease) may suffer from acute bacterial the opening of the duct (of the gland) in the mouth exacerbation of chronic bronchitis—characterized „„ S. aureus is the major pathogen but occasionally by increased dyspnea, increased sputum viscosity/ Enterobacteriaceae, other gram-negative bacilli, and purulence, and increased sputum volume. oral anaerobes may also be implicated. T Reatment Bronchitis ™™ A chronic bacterial parotitis has been described involving Staphylococcus aureus. ‰‰ Acute bronchitis: Antibiotics are not effective and are not indicated except when bacterial cause is suspected Vincent’s Angina (e.g. pertussis). Symptomatic treatment is the mainstay of It is an acute necrotizing ulcerative gingivitis, also called as treatment such as antitussive ± inhaled bronchodilators. ‰‰ Chronic bronchitis: Antibiotic therapy is recommended only Trench mouth or Vincent’s stomatitis. if presented with acute bacterial exacerbations. Amoxicillin or ™™ Clinical manifestations: It presents as gingivitis with azithromycin is given for mild cases, whereas for hospitalized sudden onset of painful bleeding gums, foul breath, and patients with severe disease, anti-pseudomonas coverage a bad taste is also given such as levofloxacin, cefepime or piperacillin- „„ The gingival mucosa becomes ulcerated and may be tazobactam. covered by gray “pseudomembrane,” resembling diphtheria, but peels off easily Bronchiolitis „„ Patients may become systemically ill, mortality is Bronchiolitis (inflammation of bronchioles) is almost always high if not treated. caused by respiratory viruses. It usually affects infants and ™™ Agents: Organisms such as Prevotella, Borrelia vincentii young children; and most commonly during winter. and Fusobacterium species have been implicated. They ™™ Agents: Respiratory syncytial virus (RSV) is the most are normal flora in the mouth important etiology; others include influenza virus, ™™ Diagnosis: Demonstration of spirochetes and fusiform human metapneumovirus, parainfluenza viruses, bacilli in stained smears of exudate from the lesion adenovirus, rhinovirus and coronavirus remains the mainstay of diagnosis ™™ Manifestations: Characterized by respiratory distress ™™ Treatment consists of debridement and antibiotics with expiratory wheeze, tachypnea, nasal flaring, (metronidazole plus penicillin). retractions, and irritability. Lower respiratory tract infections T Reatment Bronchiolitis Various lower respiratory tract infections (LRTI) include Mainstay of therapy is symptomatic management such as bronchitis, bronchiolitis, whooping cough, pneumonia, hydration, oxygen supplement and suctioning to clear the airway. tuberculosis, fungal and parasitic lung disease, lung Antibiotics should not be used for bronchiolitis unless there is abscess, pleural effusion, and empyema (Table 59.1). clear evidence of a secondary bacterial infection.  Chapter 59  Infective Syndromes of Respiratory Tract 593 Whooping Cough (Pertussis) Table 59.3: Co-morbidities of community-acquired pneumonia It is a respiratory disease, caused by a gram-negative and possible etiological agents. bacterium Bordetella pertussis; clinically characterized Factors Possible etiological agents by paroxysmal cough. Each paroxysm consists of bursts Alcoholism Pneumococcus, anaerobes, coliforms of 5–10 repetitive violent spasmodic coughs, often within COPD and/or smoking Haemophilus influenzae, Moraxella a single expiration which ends with an audible sound or catarrhalis, pneumococcus, Legionella whoop (details described in Chapter 64). Post CVA-aspiration Oral flora, pneumococcus Post-obstruction of bronchi Pneumococcus, anaerobes Pneumonia Post-influenza Pneumococcus, S. aureus Pneumonia refers to infection of the pulmonary Neutropenia, low immunity P. aeruginosa parenchyma; which can be classified into: (1) community Injection drug use Staphylococcus aureus acquired—patients acquire infection in the community, Structural lung disease (e.g. P. aeruginosa, Burkholderia cepacia, (2) hospital acquired—patients acquire infection in the bronchiectasis) S. aureus healthcare facility. Decreased consciousness Oral anaerobes, gram-negative enteric bacteria Community-acquired Pneumonia (CAP) Abbreviations: CVA, cerebrovascular accident; COPD, chronic obstructive The etiology of CAP is different than that of HAP (Table pulmonary disease. 59.2); which vary depending upon the comorbidities present (Table 59.3). „„ Inhalation of pathogens through infected droplets ™™ Streptococcus pneumoniae followed by Mycoplasma „„ Via hematogenous spread, e.g. from tricuspid pneumoniae are the most common agents of CAP endocarditis (rare) ™™ Others include H. influenzae, Chlamydophila „„ Contiguous extension from an infected pleural or pneumoniae and viral pneumonia. mediastinal space (rare) 2. Microorganisms escape the defense mechanisms of the Pathogenesis host’s respiratory tract (as described at the beginning of Pathogenesis of CAP depends upon two factors: (i) this chapter, e.g. mucociliary clearance). microbial pathogens that gain access to the lungs, and (ii) Host immune response host’s response to those pathogens. Once the microorganisms reach lungs, they are engulfed by Microbial pathogens gain access to the lungs the resident alveolar macrophages and subsequently are 1. Microorganisms gain access to the lower respiratory tract either killed or eliminated by the mucociliary escalator, or in several ways— through the lymphatics. „„ By aspiration from the oropharynx (most common): ™™ Only when the capacity of the alveolar macrophages It occurs frequently during sleep (especially in the to ingest or kill the microorganisms exceeds, clinical elderly), or when consciousness is lowered pneumonia manifests ™™ In that situation, the inflammatory response is initiated Table 59.2: Agents of community-acquired and healthcare- by the alveolar macrophages rather than preventing the associated pneumonia. proliferation of microorganisms, triggers the clinical syndrome of pneumonia. They release a cascade of Community-acquired Healthcare-acquired pneumonia (CAP) 1 pneumonia (HAP) 1,2 cytokines, which act as inflammatory mediators causing Bacterial pneumonia: Includes Multidrug resistant (MDR) host tissue damage (cytokine storm) Streptococcus pneumoniae pathogens found in the hospital „„ Interleukin (IL)-1 and tumor necrosis factor (TNF) Mycoplasma pneumoniae environment induce fever Haemophilus influenzae Pseudomonas „„ Chemokines, such as IL-8 and granulocyte Chlamydophila pneumoniae Acinetobacter colony-stimulating factor, stimulate the release of Viral pneumonia: Includes Escherichia coli neutrophils. influenza, coronaviruses Klebsiella pneumoniae ™™ Subsequently the inflammatory mediators create an (including COVID-19), MRSA (methicillin resistant S. respiratory syncytial virus, aureus) alveolar capillary leak, as seen in the acute respiratory parainfluenza, adenoviruses distress syndrome (ARDS). The capillary leak results Note: in a radiographic infiltrate, rales are detectable on 1 The distinction between CAP and HAP is vague; many individuals auscultation, and hypoxemia results from alveolar filling. presenting to outpatient department with pneumonia have been found to be infected with the MDR-pathogens. Factors responsible for this Hospital-acquired Pneumonia (HAP) phenomenon include the widespread use of antibiotics in the community, earlier discharge of patients from hospitals to their homes, increased use of Hospitalized patients are at increased risk of developing outpatient IV antibiotic therapy. pneumonia; majority of which are attributed to the 2 VAP (ventilator-associated pneumonia) accounts for majority of HAP. presence of ventilator. 594 Section 8  Respiratory Tract Infections ™™ The normal respiratory flora of hospitalized patient gets quickly replaced by multidrug resistant gram-negative organisms present in the hospital environment, such as Pseudomonas, Acinetobacter, etc. ™™ Endotracheal intubation damages the respiratory epithelium, and thus helps oropharyngeal bacteria to gain access directly into the lower respiratory tract. Ventilator-associated pneumonia is a major healthcare associated infection, has been discussed in detail in Chapter 22. Clinical Manifestations of Pneumonia Based on area of lungs involved, and the type of cough produced, pneumonia can be traditionally grouped into typical and atypical pneumonia. Fig. 59.4: A case of COVID-19 pneumonia with CT scan lungs Lobar (typical) pneumonia: It refers to infection of lung showing ground- glass opacity seen in both lungs, predominantly subpleural in distribution. Ground-glass opacity is a feature of parenchyma (alveoli). It is characterized by consolidation interstitial pneumonia. radiologically, which gives a dull note on percussion and Source: Dr Sunitha V, Department of Radiology, JIPMER, Puducherry (with productive cough with purulent sputum (Fig. 59.3). It is permission). mostly caused by pyogenic organisms such as: ™™ Pneumococcus (most common agent) However, there is considerable overlapping. The typical ™™ Haemophilus influenzae agents can be atypical in presentation and vice-versa. ™™ Staphylococcus aureus ™™ Gram-negative bacilli such Klebsiella pneumoniae. Clinical Features Interstitial or atypical pneumonia: It refers to Clinical features which may be found in both types of infection of interstitial space of lungs (Fig. 59.4). Cough pneumonia include: is characteristically non-productive. Radiologically, it ™™ Fever, with chills and/or sweats, tachycardia presents as patchy reticulonodular opacities (chest X-ray) ™™ Increased respiratory rate (tachypnea), with increased and ground glass opacities (CT scan). It is mostly caused by use of accessory muscles of respiration organisms such as: ™™ Dyspnea (shortness of breath) ™™ Chlamydophila pneumoniae ™™ If the pleura is involved, the patient may experience ™™ Mycoplasma pneumoniae pleuritic chest pain ™™ Viral agents causing pneumonia ™™ Gastrointestinal symptoms: may be seen up to 20% of ™™ Fungal agents causing pneumonia patients such as nausea, vomiting, and/or diarrhea ™™ Legionella species. ™™ Other symptoms may include fatigue, headache, myalgia, and arthralgia ™™ Severely ill patients may develop septic shock and multi- organ failure. T Reatment Community-acquired pneumonia Empiric regimen differs for inpatients and outpatients. Hospitalization in CAP is determined based on CURB-65 scoring system (Table 59.4). The prognosis of CAP can be predicted by a scoring system called CURB-65. If CURB-65 score is >1, prognosis is poor and requires hospitalization. CAP, hospitalized (if CURB65 score >1): ‰‰ IV ceftriaxone plus azithromycin or IV levofloxacin (not recommended for severe CAP) ‰‰ Add vancomycin if CA-MRSA is suspected ‰‰ Add piperacillin-tazobactam, if Pseudomonas is suspected CAP, outpatient (if CURB-65 score ≤1): Fig. 59.3: CT scan depicting lobar pneumonia, with consolidation For outpatients, empirical regimen is dependent on presence in both the lower lobes. upon comorbidities. ‰‰ If no comorbidity present: Oral amoxicillin or doxycycline is given Source: Dr Sunitha V, Department of Radiology, JIPMER, Puducherry (with permission). Contd...  Chapter 59  Infective Syndromes of Respiratory Tract 595 Table 59.4: Prediction of prognosis in community-acquired ™™ Ascaris lumbricoides: Causes Loeffler’s pneumonia pneumonia (CAP). ™™ Filarial nematodes: Causes hypersensitivity in lungs, The prognosis of CAP can be predicted by a scoring system called called tropical pulmonary eosinophilia (TPE) CURB-65. ™™ Parasites that infect elsewhere, rarely infect lungs such C (confusion of new onset) = 1 point as E. histolytica, Cryptosporidium and Echinococcus, etc. U (blood urea nitrogen >19 mg/dL) = 1 point R (respiratory rate >30 min) = 1 point Tuberculosis B (BP 1, patient should be hospitalized ™™ It spreads from an infected person by aerosol transmis- sion Contd... ™™ Although one-quarter of the world's population has been infected, most infections lead to latent tuberculosis—i.e. T Reatment Community-acquired pneumonia they do not develop the disease and are not capable of ‰‰ If comorbidity present (e.g. chronic heart, lung, liver or renal transmission diseases, diabetes, alcohol use disorder, neoplastic disease, ™™ About 5–15% of latent infections (especially who are asplenia): immunocompromised) progress to active disease which, ¾¾ Oral amoxicillin-clavulanate + Azithromycin or if left untreated, kills about half of those affected ¾¾ Oral levofloxacin. ™™ Every year about 100 lakh cases of TB occur worldwide Duration of treatment: 5-7 days (guided by clinical stability with nearly 15 lakh deaths such as afebrile >48h, normalization of vital signs). ™™ TB generally affects the lungs (pulmonary TB), but can also affect other parts of the body (extrapulmonary TB) Rare Etiological Agents of Pneumonia ™™ The classical symptoms of active pulmonary TB are Fungal Pneumonia chronic cough with blood-containing mucus, fever, Fungal pneumonia is uncommon, but occurs more night sweats, and weight loss; which last long (for commonly in individuals with weakened immune systems months) due to HIV/AIDS, immunosuppressive drugs, etc. (Chapter ™™ Early diagnosis and institution of appropriate anti- 69). tubercular therapy is the key to successful outcome. ™™ It is most often caused by Pneumocystis jirovecii (causes pneumocystis pneumonia or PCP) or due to Aspergillus Lung Abscess ™™ Fungal agents causing systemic mycoses; include Lung abscess represents necrosis and cavitation of the lung Histoplasma capsulatum, Blastomyces dermatitidis, following microbial infection. It usually presents as a single Coccidioides immitis, Paracoccidioides brasiliensis cavity of >2 cm size. ™™ Travel history gives an important clue about the disease; histoplasmosis is common in the Mississippi river basin Etiology and coccidioidomycosis is common in the Southwestern Lung abscess can present in two forms: primary or USA. secondary. ™™ Primary lung abscess: It accounts for ~80% of cases. Rare Bacterial Agents Causing Pneumonia It generally results from aspiration, mainly caused by Bacterial agents that rarely cause pneumonia include anaerobic bacteria (or microaerophilic streptococci) ™™ Burkholderia pseudomallei: Causes melioidosis present in the oral cavity. It usually occurs in the ™™ Coxiella burnetii : Causes Q fever absence of an underlying pulmonary or systemic ™™ Chlamydophila psittaci: Patients gives history of exposure condition to birds ™™ Secondary lung abscess arises in the setting of an ™™ Chlamydia trachomatis serotype D-K: Causes infant underlying condition, such as a bronchial foreign body pneumonia or tumor or immunocompromised condition such as ™™ Actinomyces and Nocardia HIV. Common organisms implicated are S. aureus, gram- ™™ Bacillus anthracis: Causes pulmonary anthrax or Wool negative rods (e.g. Pseudomonas, Enterobacteriaceae), Sorter’s disease Nocardia, Legionella and fungi such as Aspergillus, ™™ Yersinia pestis: Causes pneumonic plague. Mucorales, Cryptococcus, and Pneumocystis jirovecii. Parasitic Lung Disease Clinical Manifestations Parasitic agents that infect lungs (Chapter 69) include: Initially, lung abscess presents similar to that of pneumonia, ™™ Paragonimus westermani: Causes endemic hemoptysis with fever, productive cough, and chest pain. 596 Section 8  Respiratory Tract Infections ™™ In anaerobic etiology, progression is slow and indo- Microscopy lent; with features of night sweats, fatigue, and occa- ™™ Gram staining of the sputum or other specimens is done sionally foul-smelling sputum (in case of putrid lung for two purposes abscess) 1. Sputum quality: If pus cells are >25 and epithelial ™™ In cases with non-anaerobic etiology such as S. aureus, cells are 10 mm, a therapeutic low (~5–14% of CAP) thoracentesis (drainage of pleural effusion) should ™™ For lung abscess: When a primary lung abscess is be performed. suspected, lung aspirate is subjected for anaerobic ™™ Tuberculous pleuritis: It usually occurs in primary TB culture. Sputum is not a suitable specimen for anaerobic and is primarily due to a hypersensitivity reaction to culture. However for secondary lung abscess, sputum tuberculous protein in the pleural space and blood cultures can be performed „„ Patients present with fever, weight loss, dyspnea, ™™ For M. tuberculosis: Specimens should be inoculated and/or pleuritic chest pain onto LJ medium or automated MGIT (Mycobacteria „„ Elevated TB markers in the pleural fluid such as growth indicator tube) culture adenosine deaminase or interferon. ™™ For fungal pathogen isolation: Sabouraud dextrose agar ™™ Viral pleural effusion: Pleural effusion secondary to viral is used. infections is less common, usually gets undiagnosed. These effusions resolve spontaneously with no long- Serology (Antibody Detection) term residua. Antibody detection tests can be used for diagnosis of Laboratory Diagnosis of LRTI atypical pneumonia pathogens such as Mycoplasma, Chlamydia, Coxiella burnetii and viruses. Specimen Collection ™™ A fourfold rise in specific IgM antibody titer between Important specimens for LRTI include sputum, induced acute- and convalescent-phase serum samples is sputum, tracheal aspirate, bronchoalveolar lavage (BAL), generally considered diagnostics protected specimen brush (PSB), lung aspirate (collected ™™ They are less popular in recent days because of the time by transtracheal aspiration) and pleural fluid (collected by required to obtain a final result for the convalescent- thoracentesis) phase sample.  Chapter 59  Infective Syndromes of Respiratory Tract 597 The various antibody detection methods available are: Molecular Test ™™ Mycoplasma: Cold agglutination test, and ELISA formats Molecular methods are emerging as the most promising are available tool for diagnosis of LRTI. ™™ Chlamydial antibodies: Micro-immunofluorescence ™™ Multiplex PCR assays are available where multiple test can be performed primers targeting the genes specific for the common ™™ Q fever (Coxiella burnetii): Indirect immunofluorescence suspected agents of LRTI are used assay (IFA)is available ™™ BioFire FilmArray is an automated multiplex PCR ™™ Viral infections: Antibody detection methods are commercially available available for influenza or COVID-19. However, antibodies „„ Its pneumonia panel can simultaneously detect 33 usually appear late, therefore not of much use in clinical diagnosis, although useful for estimating seroprevalence. pneumonia pathogens; including both bacterial and viral agents from sputum or BAL specimen with a Antigen Detection Tests turnaround time of 1 hour Various antigen detection methods available for lower „„ For common bacterial pathogens which are usually respiratory tract pathogens include: the colonizers in the respiratory tract; it gives semi- ™™ Immunochromatographic test (ICT) is available for quantitative results (genome copies/mL), therefore detection of pneumococcal antigens in urine helps in differentiating colonization and disease. ™™ Enzyme immunoassay is available to detect L. pneu- ™™ Real time PCR is the gold standard diagnostic method mophila serogroup 1 specific soluble antigens in urine for detection of the agents of viral pneumonia such as ™™ Direct fluorescent antibody tests are available for influenza and SARS-CoV-2 influenza virus and respiratory syncytial virus, and ™™ Automated Real time PCR such as GeneXpert and B. pertussis, but are poorly sensitive and technically Truenat can be used for identification of M. tuberculosis in challenging. sputum. In addition, it also detects rifampicin resistance. EXPECTED QUESTIONS I. Write essay on: b. Discuss the pathogenesis, clinical presentation, 1. A 16-month-old boy was admitted with fever, laboratory diagnosis and treatment of this lethargy, productive cough with purulent sputum clinical condition. and shortness of breath. On examination, dull note II. Write short notes on: on percussion and consolidation on auscultation 1. Acute laryngotracheobronchitis (Croup). were noted. Sputum and blood specimens were 2. Vincent’s angina. obtained, and sent for bacteriological culture. 3. Pleural effusion. a. What is the clinical diagnosis and the etiological agents?  Chapter Bacterial Pharyngitis 60 Chapter Preview „„Streptococcal Pharyngitis „„Diphtheria „„Rare Causes of Bacterial Pharyngitis Introduction Pharyngitis (or sore throat) is one of the most common upper respiratory tract infections (URTI). Viral pharyngitis accounts for the vast majority of cases, and is usually self- limited. Bacteria are also important etiologic agents of pharyngitis, require specific antibiotic treatment; if not given, can lead to serious complications and sequelae. The common etiological agents of bacterial pharyngitis include: ™™ Streptococcus pyogenes (most common) ™™ Corynebacterium diphtheriae ™™ Other rare causes include: „„ Other β-hemolytic streptococci (group C and G) „„ Arcanobacterium hemolyticum „„ Fusobacterium necrophorum „„ Mycoplasma pneumoniae „„ Neisseria gonorrhoeae. Fig. 60.1: Streptococcal sore throat, with enlarged tonsils covered with white fibrinous exudate. Streptococcal Pharyngitis Source: James Heilman, Wikipedia (with permission). Streptococcus pyogenes (or group A Streptococcus) is the ™™ Non-suppurative complications may develop 2–3 most common bacterial cause of pharyngitis in children weeks following streptococcal sore throat, mediated by and accounts for 5 to 15% of all sore throats in adults. autoimmune mechanism Infection occurs through respiratory droplets. In addition, „„ ARF: Acute rheumatic fever (ARF) is the most common it causes skin and soft tissue infections (Chapter 52). non-suppurative complication developed following streptococcal pharyngitis; involves cardiac valves, Clinical Manifestations joints and other sites (Chapter 28) Streptococcal sore throat presents as either localized „„ PSGN: Post streptococcal glomerulonephritis (tonsillitis) or diffuse (pharyngitis). (PSGN) is another sequela that usually develops ™™ Symptoms: Manifests as erythema and swelling of pharyn- following streptococcal pyoderma, but can rarely geal mucosa with purulent exudate formation (Fig. 60.1) occur following streptococcal sore throat (Chapter ™™ Younger children (95%), a positive result can be irregularly stained and frequently shows club-shaped relied upon for definitive diagnosis and eliminates the swellings (Fig. 60.2A) (Greek word koryne, meaning club) need for throat culture ™™ It has several species; the most important pathogenic ™™ However, the sensitivity of this test is variable (55–90%), being C. diphtheriae. The other Corynebacterium species therefore a negative result should always be confirmed (called as diphtheroids) are usually found as commensals by throat culture. of throat and skin in man, can occasionally cause infections ASO Titer ™™ Corynebacterium diphtheriae typically shows two Anti-streptolysin O (ASO) antibodies appear late; therefore, characteristic features, which differentiates it from other a retrospective diagnosis of streptococcal infection may be Corynebacterium species A B C Figs 60.2A to C: Corynebacterium diphtheriae: A. Club-shaped bacilli in methylene blue-stained smear; B. Gram-stained smear shows V- or L-shaped bacilli with cuneiform arrangement; C. Albert’s stain shows dark blue metachromatic granules at the ends of the green bacilli (schematic). Source: Public Health Image Library, A. ID# /7323/P.B. Smith; B. ID# /1943, Centers for Disease Control and Prevention (CDC), Atlanta (with permission). 600 Section 8  Respiratory Tract Infections 1. Chinese letter or cuneiform arrangement: They Factors Regulating Toxin Production appear as V- or L-shaped in smear, because the The production of diphtheria toxin is dependent on various bacterial cells divide and daughter cells tend to lie at factors. acute angles to each other. This type of cell division is ™™ Phage coded: DT is coded by a bacteriophage called called snapping type of division (Fig. 60.2B) β-corynephage, carrying tox gene. C. diphtheriae remains 2. Metachromatic granules: They are present at ends toxigenic as long as the phages are present inside the or poles of the bacilli. bacilli (lysogenic conversion) ™™ Iron concentration: The toxin production depends on Metachromatic Granules the optimum concentration of iron (0.1 mg per liter) Also called polar bodies or Babes–Ernst bodies or volutin ™™ Other species: DT is also produced by C. ulcerans and granules). ‰‰ They are storage granules of the organism, composed of C. pseudotuberculosis. polymetaphosphates ‰‰ Granules are stained strongly gram-positive compared to Toxoid is used for Vaccination remaining part of the bacilli. The granules take up bluish Diphtheria toxin is antigenic and antitoxins are protective purple metachromatic color when stained with Loeffler’s in nature. However, as it is virulent, it cannot be given methylene blue directly for vaccination. ‰‰ However, they are better stained with special stains, such as ™™ Toxin can be converted to toxoid, which is used for Albert’s, Neisser’s and Ponder’s stain (Fig. 60.2C) vaccination. Toxoid is a form of toxin, where the virulence ‰‰ Granules are well developed on enriched media, such as is lost, retaining its antigenicity blood agar or Loeffler’s serum slope ™™ Toxoid formation is promoted by formalin, acidic pH and ‰‰ Volutin granules can also be possessed by other organisms such as—by Corynebacterium xerosis and Gardnerella prolonged storage vaginalis. ™™ Park William 8 strain of C. diphtheriae is used as a source of toxin for the preparation of vaccine ™™ LF unit: DT is expressed as Limit of flocculation (Lf) unit. History 1 Lf unit is the amount of toxin which flocculates most Diphtheria is an ancient disease, known since the time of rapidly with one unit of antitoxin. Hippocrates. ™™ Diphtheria was first recognized by Pierre Bretonneau Pathogenicity and Clinical Manifestations (1826). He used the term diphthérite (Greek word diph- Pathogenesis of diphtheria is toxin mediated. theros—meaning leather like) to describe the charac- ™™ Diphtheria is toxemia but never a bacteremia teristic manifestation, i.e. leathery pseudomembrane ™™ Bacilli are noninvasive, present only at local site (pharynx), formation over the tonsil secrete the toxin which spreads via bloodstream to ™™ C. diphtheriae was first observed by Klebs (1883) and various organs first cultivated by Loeffler (1884); hence, it is known as ™™ It is the toxin which is responsible for all types of Klebs-Loeffler bacillus. manifestations including local (respiratory) and systemic complications (except the skin lesions, which is caused Virulence Factors (Diphtheria Toxin) due to the organism, not toxin). Diphtheria toxin (DT) is the primary virulence factor responsible for diphtheria. Respiratory Diphtheria ™™ Toxin is a polypeptide chain, comprises of two This is the most common form of diphtheria. Tonsil and fragments—A (active) and B (binding) pharynx (faucial diphtheria) are the most common sites ™™ Fragment B binds to the host cell receptors (such as followed by nose and larynx. Incubation period is about epidermal growth factor) and helps in entry of frag- 3–4 days. ment A ™™ Faucial diphtheria: Diphtheria toxin elicits an ™™ Fragment A gets internalized into the cell and then acts inflammatory response, that leads to necrosis of the by the mechanism given below. epithelium and exudate formation „„ This leads to formation of mucosal ulcers, lined by Mechanism of Diphtheria Toxin (DT) a tough leathery greyish white pseudomembrane ‰‰ Fragment A is the active fragment, which causes ADP coat ; composed of an inner band of fibrin ribosyla­tion of elongation factor 2 (EF-2) → leads to surrounded by neutrophils, RBCs and bacteria (Fig. inhibition of EF-2 → leads to inhibition of translation step 60.3A) of protein synthesis „„ It is so named as it is adherent to the mucosal base and ‰‰ Exotoxin A of Pseudomonas has a similar mechanism like that of DT. bleeds on removal, in contrast to the true membrane which can be easily separated.  Chapter 60  Bacterial Pharyngitis 601 L aboratory diagnosis Diphtheria Isolation of the Corynebacterium diphtheriae ‰‰ Specimen: Throat swab and a portion of pseudomembrane ‰‰ Direct smear ¾¾ Gram stain: Club shaped gram-positive bacilli with Chinese letter arrangement ¾¾ Albert’s stain: Green bacilli with bluish black metachromatic granules ‰‰ Culture media ¾¾ Enriched medium: Blood agar, chocolate agar and Loeffler’s serum slope ¾¾ Selective medium: Potassium tellurite agar and Tinsdale A B medium, produces black colonies ‰‰ Identification Figs 60.3A and B: A. Pseudomembrane covering the tonsils ¾¾ Biochemical tests such as sugar fermentation tests using classically seen in diphtheria; B. Bull neck appearance (arrow Hiss’s serum sugar media showing). ¾¾ Automated identification systems such as MALDI-TOF Source: A. Department of Microbiology, JIPMER, Puducherry; B. Public Health or VITEK Image Library/ID#5325, Centers for Disease Control and Prevention (CDC), Atlanta (with permission). Diphtheria toxin demonstration ‰‰ In vivo tests (Guinea pig inoculation): Subcutaneous and intracutaneous tests ™™ Extension of pseudomembrane: In severe cases, it may ‰‰ In vitro tests: ¾¾ Elek’s gel precipitation test extend into the larynx and bronchial airways, which may ¾¾ Detection of tox gene-by PCR result in fatal airway obstruction leading to asphyxia. ¾¾ Detection of toxin-by ELISA or ICT This mandates immediate tracheostomy ¾¾ Cytotoxicity on cell lines. ™™ Bull-neck appearance: It is characterized by massive tonsillar swelling and neck edema. Patients present with Laboratory Diagnosis foul breath, thick speech, and stridor (noisy breathing) (Fig. 60.3B). The diagnosis of diphtheria is based on the clinical signs and symptoms plus laboratory confirmation. Cutaneous Diphtheria ™™ Because of the risk of respiratory obstruction, specific It presents as punched-out ulcerative lesions with necrosis, treatment should be instituted immediately on clinical or rarely pseudomembrane formation; most commonly suspicion without waiting for laboratory reports occurs on the extremities. ™™ Laboratory diagnosis is necessary only for: ™™ Cutaneous diphtheria is due to the organism itself and „„ Confirmation of clinical diagnosis is not toxin-mediated. Hence, it is possible that, the skin „„ Initiating the control measures lesions may also be caused by non-toxigenic strains „„ Epidemiological purposes. ™™ There is increasing trend of cutaneous diphtheria Laboratory diagnosis consists of isolation of the bacilli nowadays, especially in vaccinated children; because and toxin demonstration. antitoxins present in vaccinated people cannot prevent the disease. Isolation of Diphtheria Bacilli Specimen Systemic Complications Useful specimens include: (1) throat swab (one or two) Polyneuropathy and myocarditis are the late toxic containing fibrinous exudates, (2) a portion of pseudo­ manifestations of diphtheria, occurring after weeks of membrane, (3) nose or skin specimens (if infected). infection. Other complications of diphtheria include pneumonia, renal failure, encephalitis, cerebral infarction, Direct Smear Microscopy and pulmonary embolism. ™™ Gram stain: C. diphtheriae appear as irregularly stained ™™ Neurologic manifestations: It is a toxin mediated non- club-shaped gram-positive bacilli of 3–6 µm length, inflammatory demyelinating disorder; presented with: typically arranged in Chinese letter or cuneiform „„ Cranial nerve involvement arrangement (V- or L-shaped). It is difficult to differentiate „„ Peripheral neuropathy them from other commensal coryneforms found in the „„ Ciliary paralysis. respiratory tract (see Fig. 60.2B) ™™ Myocarditis: It is typically associated with arrhythmias ™™ Albert’s stain: It is more specific for C. diphtheriae; they and dilated cardiomyopathy. appear as green bacilli with bluish black metachromatic 602 Section 8  Respiratory Tract Infections granules at the poles. Details of Albert’s staining ™™ Automated identification systems such as MALDI-TOF procedure is given in Chapter 3.3 (see Fig. 60.2C). or VITEK. Culture Media Toxin Demonstration Enriched Medium As the pathogenesis is due to diphtheria toxin, mere C. diphtheriae is fastidious, aerobe and facultative anaerobe; isolation of bacilli does not complete the diagnosis. Toxin does not grow on ordinary medium. It grows best in enriched demonstration should be done following isolation, which medium such as blood agar, chocolate agar and Loeffler’s can be performed by in vivo and in vitro methods. serum slope. Plates are incubated at 37oC aerobically. ™™ Blood agar: Colonies are small circular, white and In Vivo Tests (Animal Inoculation) sometimes hemolytic (mitis biotype) In vivo toxin demonstration can be done by inoculation ™™ Loeffler’s serum slope: Colonies appear as small, of culture broth into guinea pig. With the advent of other circular, glistening, and white with a yellow tinge in 6–8 techniques, this method is rarely followed nowadays. hours (Fig. 60.4A) „„ Advantages: (1) Growth can be detected as early In Vitro Test as 6–8 hours. (2) Best medium for metachromatic ™™ Elek’s gel precipitation test: This is a type of immuno­ granules production diffusion in gel described by Elek (1949) „„ Disadvantages: Being an enriched medium, if „„ The strain isolated is streaked onto a media containing incubated beyond 6–8 hours, it supports growth of a filter paper soaked with antitoxin other throat commensals also. „„ If the strain is toxigenic, it liberates the toxin which Selective Medium diffuses in the agar and meets with the antitoxin to Selective media are best for isolation of C. diphtheriae from produce an arrow-shaped precipitation band „„ This test can also be used to know the relatedness cases as well as from carriers, as the normal flora will be inhibited. between the strains isolated during an outbreak. The precipitate bands of outbreak isolates (streaked Potassium tellurite agar (PTA): C. diphtheriae reduces adjacent) when meet with each other, three patterns tellurite to metallic tellurium which gets incorporated may be observed (Fig. 60.5) into the colonies giving them black color (Fig. 60.4B). C. 1. Cross-over with each other—indicates unrelated ulcerans and C. pseudotuberculosis can also grow on PTA strain producing black colored colonies. ™™ Advantage: Throat commensals are inhibited ™™ Disadvantage: Colonies appear only after 48 hours of incubation. Identification Species identification of C. diphtheriae is made by: ™™ Biochemical tests such as—(i) Sugar fermentation test using Hiss’s serum sugar media, (ii) Pyrazinamidase test, and iii) Urease test. The latter two tests are negative for C. diphtheriae Fig. 60.5: Elek’s gel precipitation test. I solates 1 to 4 are toxigenic strains (as precipitation bands are formed due to binding of toxin produced by the strains with antitoxin released by the filter paper) Isolates 1 and 2: The precipitation bands crossed over, indicates the toxins are not-identical and therefore strains are unrelated Isolate 2 and 3: There is partial fusion of precipitation bands, indicates the A B toxins are partially identical and therefore strains are partially related to each other Figs 60.4A and B: A. Loeffler’s serum slope; B. Potassium tellurite Isolates 3 and 4: The precipitation bands fused with each other, indicates agar shows black colonies. the toxins are identical to each other and therefore strains are completely related Source: A. Department of Microbiology, JIPMER, Puducherry; B. Department of Micro­ Isolate 5 is non-toxigenic strain (no precipitation band is formed). biology, Pondicherry Institute of Medical Sciences, Puducherry (with permission).  Chapter 60  Bacterial Pharyngitis 603 2. Spur formation—indicates partially related strain T Reatment Diphtheria 3. Fused with each other—indicates identical strain. ™™ Other in vitro tests include: Treatment should be started immediately on clinical suspicion „„ Detection of Tox gene by PCR of diphtheria. ‰‰ Antidiphtheritic serum or ADS (antitoxin): Passive immuni­ „„ Detection of diphtheria toxin by ELISA or immuno­ zation with antidiphtheritic horse serum is the treatment of chromatographic test (ICT) choice as it neutralizes the toxin. „„ Cytotoxicity produced on cell lines. ¾¾ A test dose should be given to check for hypersensitivity ¾¾ It is given either IM or IV and the dose depends on stage Typing of C. diphtheriae of illness: Typing methods are useful for epidemiological studies, to  Early stage (< 48 hours): 20,000–40,000 units know the relatedness between the isolates. Biotyping was  If pharyngeal membranes present: 40,000–60,000 units in use in the past, based on which there are four biotypes  Late stage (> 3 days, with bull neck): 80,000–120,000 of C. diphtheriae—gravis, intermedius, mitis and belfanti. units. Human antitoxin therapy is under development. They vary in virulence and toxin production; gravis being ‰‰ Antibiotics: Penicillin or erythromycin is the drug of choice. 100% toxigenic and more virulent. Antibiotic plays a minor role as it is of no use once the toxin is secreted. However, antibiotics are useful: Epidemiology ¾¾ If given early (95% over last erythromycin (7–10 days) is recommended. 3 decades. However, there is global resurgence of diphtheria in recent years; 16,648 cases were reported Vaccination in 2018 Diphtheria toxoid is used for vaccination as it induces ™™ Russian epidemic: An epidemic of adult diphtheria antitoxin production in the body. A protective titer of more occurred in Russia during 1990–97 with > 1.1 lakh than 0.01 Unit/mL of antitoxin can prevent all forms of cases and 3,000 deaths. It was controlled by improved diphtheria. However, vaccine is not effective for: vaccination of children and adults ™™ Prevention of cutaneous diphtheria ™™ Situation in India: India still accounts for the highest ™™ Elimination of carrier state. burden (60–70%) of diphtheria cases in the world (8,788 cases were reported in 2018) Types of Vaccine ™™ Resurgence of diphtheria in recent years is a public ™™ Single vaccine: Diphtheria toxoid (DT) is prepared health problem in India by incubating toxin with formalin and then the toxoid „„ In 2019, outbreaks have been reported from Tamil is adsorbed on to alum. Alum acts as adjuvant and Nadu, Kerala and Karnataka and few other states increases the immunogenicity of toxoid „„ Majority (>70%) of cases are from children 5–10 years ™™ Combined vaccine: Various vaccines available are: or more; which explains low coverage of diphtheria „„ DPT: Contains DT (diphtheria toxoid), Pertussis. vaccine especially the booster doses, as the primary (whole cell) and TT (tetanus toxoid). Pertussis cause of its resurgence component acts as adjuvant and increases the „„ Waning immunity in adults may be a minor cause immunogenicity of DT and TT which contributes to adult diphtheria cases. „„ DaPT: Contains DT, TT and acellular pertussis (aP) 604 Section 8  Respiratory Tract Infections „„ Td: It contains tetanus toxoid and adult dose (2 Lf ) of „„ Therefore, for children >7 years age who have not diphtheria toxoid received primary vaccination, DaPT comprising „„ Pentavalent vaccine: DPT can also be given along acellular pertussis vaccine is recommended. with hepatitis B and Haemophilus influenzae type b. ™™ Absolute contraindication to DPT include: „„ Hypersensitivity to previous dose Administration of Diphtheria Vaccine „„ Progressive neurological disorder. ™™ Schedule: Under National Immunization Schedule (NIS) of India 2020 (Chapter 20, Table 20.4): Schick Test „„ Children: Total seven doses are given; three doses It is a toxin-antitoxin neutralization test, was used long of pentavalent vaccine at 6, 10 and 14 weeks of back, to test the susceptibility of individual to diphtheria birth, followed by two booster doses of DPT at 16–24 before starting immunization. It is obsolete now. months and 5 years and another two booster doses of Td at 10 years and 16 years Diphtheroids „„ Pregnant woman also should receive two doses of Td Diphtheroids or coryneforms are the nondiphtherial at one month interval corynebacteria, that usually exist as normal commensals in „„ The introduction of Td boosters in place of TT at 10 the throat, skin, conjunctiva and other areas. However, they and 16 years and also in pregnancy is an attempt have been associated with invasive disease, particularly in made to reduce the resurgence of diphtheria in immunocompromised patients. They can be differentiated adults. from C. diphtheriae by many features such as: ™™ Site: DPT is given deep intramuscularly (IM) at antero- ™™ Stains more uniformly than C. diphtheriae lateral aspect of thigh, (gluteal region is not preferred as ™™ Palisade arrangement: Arranged in parallel rows rather fat may inhibit DPT absorption) than cuneiform pattern (Fig. 60.6) ™™ Thiomersal (0.01%) is used as preservative ™™ Absence of metachromatic granules (except C. xerosis). ™™ Storage: DPT should be kept at 2–8oC; if accidentally Coryneforms that are rarely pathogenic to man are: frozen then it has to be discarded ™™ Clinically resembling diphtheria: C. ulcerans and C. ™™ Dose: The usual dose (given to children) of diphtheria pseudotuberculosis produce diphtheria toxin and cause toxoid contains 25 Lf units, whereas the adult dose localize