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Pathology of Streptococcal Infections

Written By

Yutaka Tsutsumi

Submitted: 06 June 2022 Reviewed: 13 June 2022 Published: 15 July 2022

DOI: 10.5772/intechopen.105814

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Streptococcus pyogenes and Streptococcus pneumoniae, representative Gram-positive cocci, may cause both localized (skin and soft tissue) and systemic infections. Lobar pneumonia is a unique form of acute and severe lung infection of S. pneumoniae. Streptococcus viridans group, normal flora of the oral cavity, may lead not only to mucosal infection but also to aspiration pneumonia, infective endocarditis, and systemic infections. The severest and often lethal form of progressive and systemic infection includes fulminant streptococcal and pneumococcal infections. Autopsy is essentially important for the analysis of fulminant infections. Pathological features of varied streptococcal infections are illustrated and discussed. Immunohistochemical identification of the pathogen in formalin-fixed, paraffin-embedded sections is effective and valuable in confirming the type of infected pathogens.


  • Streptococcus
  • localized skin infection
  • tonsillitis
  • streptococcal mucosal infection
  • pneumonia
  • meningitis
  • fulminant streptococcal infection
  • fulminant pneumococcal infection

1. Introduction

Streptococcus is a classic and representative Gram-positive extracellular pathogen, occasionally being highly invasive and harmful for the patient. Strepto and coccus derive from ancient Greek words streptos and kokkos, respectively: Streptos means twisted or pliant, and coccus means grain or seed. The medical burden of streptococcal infections is among the greatest in the world. There are two major pathogenic species: group A beta-hemolytic streptococcus (Streptococcus pyogenes) and Streptococcus pneumoniae.

Staphylococci mainly colonize the skin, whereas streptococci are the resident of the oral, intestinal, and vaginal mucosa, where non-A group streptococci consistently colonize. Both of the Gram-positive facultative anaerobic cocci are resistant to both aerobic and anaerobic conditions, but streptococci relatively prefer anaerobic or microaerophilic conditions to aerobic conditions: They survive in the microaerophilic sites such as dental and tonsillar pits and can cause gangrenous lesions under anaerobic conditions.

Group A beta-hemolytic streptococcus or S. pyogenes provokes classic streptococcal infections, including tonsillitis and erysipelas, while non-A group streptococci are less pathogenic. Viridans group streptococci, a representative non-A streptococcus and normal flora of the oral cavity, may cause localized mucosal colonization and bacterial (infective) endocarditis. Viridans group streptococci are important as an etiological microbe of aspiration pneumonia and subacute bacterial (infective) endocarditis. Streptococcus mutans is known as a pathogenic bacterium causing dental caries. Group B streptococci, including Streptococcus agalactiae, a resident in the vagina and digestive tract, may cause localized vaginal infection and transvaginally transmitted neonatal meningitis. Systemic dissemination of group B streptococci may also happen. S. pneumoniae typically provokes severe pneumonia, pneumococcal lobar pneumonia, as well as purulent meningitis. It also provokes head and neck infections such as conjunctivitis, sinusitis, and otitis media. Traumatic skin and eye ball infections by S. pneumoniae may also be encountered.

Of note are lethal fulminant infections of group A Streptococcus and S. pneumoniae. In fulminant streptococcal infection, gangrenous change happens in the extremities, and it has been called as flesh-eating bacterial infection. Lethal infection without gangrene may also happen in both streptococcal pathogens. Splenectomy represents one of the representative risk factors for such fulminant infections. Infrequently, lethal infection of Streptococcus suis is experienced as an occupation-related infection among persons handling pigs and pork.

Regarding the treatment for infection of group A beta hemolytic Streptococcus, beta-lactam antibiotics such as penicillins and cephalosporines are chosen. The most common therapeutic drugs are penicillin and amoxicillin [1, 2]. Group A beta hemolytic Streptococcus revels no resistance to beta-lactam antibiotics. This is in sharp contrast to the frequent drug resistance in Staphylococcus aureus. If the patient is allergic to beta-lactam antibiotics, macrolides and lincomycins are chosen. Some strains (12–45%) are resistant to tetracyclin, erythromycin, clindamycin, and clarithromycin. Chloramphenicol resistance is infrequent.

Viridans group streptococci and group B streptococci also reveal similar drug resistance patterns [3, 4]. Resistance to amoxycillin is rare, whereas they are occasionally resistant to erythromycin and tetracyclin. In contrast, antibacterial resistance in S. pneumoniae is increasing worldwide, primarily against β-lactams and macrolides. At present, pneumonococci are frequently multidrug-resistant [5, 6].

It is noteworthy that virulent factors and the immune response are important for understanding the pathogenesis and prevention of the infections of streptococci. They may depend on the genetic variations between the strains [7]. Drug resistance of S. pneumoniae is caused by mutations in penicillin-binding protein genes [5, 6]. Alterations of innate immunity also play a key role in launching the immune response against group A Streptococcus [8]. Group A Streptococcus is equipped with a wide variety of virulence factors to invade human tissue and escape from immunity, including fibronectin-binding proteins: SPE-B (a streptococcal superantigen [9, 10, 11]) and C6-binding protein [12].

Pathological features of these streptococcal infections are described below. Microscopic pictures stained with hematoxylin and eosin (H&E), Gram, Grocott, and colloidal iron, as well as those immunostained for bacterial antigens, are presented. Regarding the pathological features of skin infections caused by various microorganisms, refer to the author’s previous publication [13]. Antibodies used in the present article are listed in the reference [14]. Immunohistochemical visualization of the pathogen may help the histopathological diagnosis, as reported previously [14, 15, 16].


2. Pyogenic streptococcal infection of the skin

Persistent and asymptomatic pharyngeal carriage of group A beta-hemolytic Streptococcus (S. pyogenes) is common in children [17]. Biofilm formation is closely related to the persistence of colonization of streptococci [18]. Droplet transmission may occur from such healthy carriers to other healthy individuals, particularly to the youth. Cocci on the pharyngeal mucosa may be activated to cause the subsequent localized or systemic infections in the carrier. Transient bacteremia originating from the pharyngeal mucosa may lead to the microbial seeding to the deep tissue [19].

2.1 Erysipelas

Erysipelas is non-ulcerating, diffuse cellulitis (phlegmonous inflammation) of the facial skin and soft tissue, caused by group A beta-hemolytic Streptococcus or S. pyogenes [20, 21]. Diffuse infiltration of neutrophils occasionally phagocytizing the cocci is seen within the lesion. The involved skin, showing sharply demarcated raised edges, is fiery red-swollen, hard, warm, and painful. High fever, shaking, headache, and vomiting are associated. It is noteworthy that Streptococcus causes either diffuse cellulitis or necrotizing inflammation, rather than abscess formation characteristic of staphylococcal infection. Gross and microscopic findings of erysipelas are shown in Figure 1.

Figure 1.

Erysipelas (left: gross features, right, H&E). A 74-year-old lady complained of high fever and painful facial swelling. The involved facial skin accompanies demarcated red and hard swelling. Biopsy reveals diffuse dermal infiltration of neutrophils, intermingled with lymphocytes. The epidermis remains intact. By courtesy of Prof. Daisuke Tsuruta at Department of Dermatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.

Subclinical lymphatic dysfunction and preexisting lymphedema caused by mastectomy and axillary nodal dissection for breast cancer are a clear-cut risk factor for erysipelas on the arm [22, 23]. Chronic recurrent erysipelas may be encountered under such predisposing factors as alcoholism and diabetes mellitus [24].

2.2 Streptococcal impetigo and pyoderma/ecthyma

Impetigo contagiosa is commonly caused by infection of S. aureus. This is a highly contagious infectious status among children [25]. S. pyogenes (group A beta-hemolytic Streptococcus) also provokes impetigo [26]. It is classified into two types: bullous and non-bullous. The non-bullous type impetigo is also called as “school sores.” A representative lesion of bullous type is displayed in Figure 2.

Figure 2.

Streptococcal impetigo of bullous type (left: H&E, right top: Gram, right bottom: Immunostaining for streptococcal antigens). The lesion was seen on the heel of an 83-year-old man. Biopsy reveals active colonization of Gram-positive cocci on the hyperkeratotic layer. Neutrophilic reactions are evident. The bacteria are immunoreactive for streptococcal antigens, whereas staphylococcal, pneumococcal, and enterococcal antigens are negative.

Occasionally, localized pyoderma or ecthyma is caused by group A streptococcal infection, rather than staphylococcal infection (Figure 3). Groups B and G Streptococcus may also cause streptococcal impetigo in cases of atopic dermatitis [27]. Ecthyma is a deep form of impetigo causing ulceration of the skin. Infection of S. aureus or S. pyogenes secondary to wounds or other skin lesions may be called as “impetiginization.”

Figure 3.

Streptococcal pyoderma seen in a man in his 60s (left: H&E, right: streptococcal antigens). Group A beta-hemolytic Streptococcus was cultured. Subcutaneous abscess is noted (asterisk). Infected Gram-positive cocci immunohistochemically express streptococcal antigens. The immunoreactive coccoid microbes are phagocytized by neutrophils. Staphylococcal antigens were scarcely detected.

Another rare form of localized and afebrile streptococcal infection is perianal streptococcal dermatitis, seen exclusively in children [28]. It presents as perianal erythema with a defined border, clinically followed by scaling and healing.


3. Streptococcal acute tonsillitis

Acute tonsillitis is inflammation of bilateral palatine tonsils, oval-shaped lymphoid tissue bilaterally located at the back of the throat (mesopharynx). It is commonly seen in children and the youth between the ages of 5 and 15 years. Occasionally, tonsillitis also happens in adults. Clinical signs and symptoms of tonsillitis include high fever, swollen tonsils, sore throat, coughing, running nose, difficulty in swallowing, and tender swelling of cervical lymph nodes.

Acute tonsillitis is commonly caused by infection of bacteria, most frequently by S. pyogenes [29]. Other bacteria such as S. aureus, Mycoplasma pneumonia, Bordetella pertussis, and Fusobacterium may also provoke tonsillitis. Polymicrobial infections are also encountered. Viral pathogens, such as common cold viruses, influenza virus, picorna virus (enterovirus), adenovirus, Epstein-Barr virus, and SARS coronavirus-2, also become sources of infection, particularly among young children. Treatment of tonsillitis depends upon the cause, so that prompt and appropriate confirmation of the causative agent is essentially important. Tonsillectomy, once a common choice of treatment, is performed only when tonsillitis occurs recurrently, resists to usual treatments, and/or causes a chronic illness lasting beyond 3 months.

Colonization of S. pyogenes to the tonsillar surface is mediated through bacterial M-protein and lipoteichoic acid, which bind to fibronectin molecules within the tonsillar tissue [29]. The bacterial invasion leads to an inflammatory response with upregulated cytokines. Grossly, multifocal erosions are seen on the surface of the swollen tonsils (Figure 4). Microscopically, small erosions with microabscess formation are observed, and Gram-positive coccal colonies are immunoreactive for streptococcal antigens (Figure 5). Streptococcal infection may extend upward into the nose, sinuses, and ears or downward into the larynx, trachea, and bronchi. The virulent bacteria may spread from the infected tonsil to the adjoining tissues, resulting in peritonsillar abscess.

Figure 4.

Gross appearance of acute tonsillitis (left: streptococcal tonsillitis, right: infectious mononucleosis). The palatine tonsils in juvenile patients are bilaterally swollen, and multiple erosions covered with white-colored inflammatory exudates (left). As a reference, viral tonsillitis in Epstein-Barr virus-provoked infectious mononucleosis is shown (right).

Figure 5.

Streptococcal acute tonsillitis (left: H&E, center: streptococcal antigens, right: Strep A). Microscopically, small abscess is formed at the site of erosion. Colonization of cocci is observed in the abscess (arrows). The colonies are immunoreactive for both streptococcal antigens and Strep A (group A streptococcal carbohydrate antigen), confirming the diagnosis of streptococcal tonsillitis.

The tonsillectomy specimens consistently reveal reactive lymphoid hyperplasia with enlarged germinal centers, but without abscess formation [30] (Figure 6). Plasma cells with CD138 immunoreactivity are activated and richly infiltrate into the tonsillar reticular mucosa, where a capillary network is formed [31] (Figure 7). Actinomycotic grains may be seen in the tonsillar pit as an incidental finding. The reason for these microscopic features of lymphoid hyperplasia is primarily related to the fact that the surgical treatment is done in a chronic phase of the recurrent infection. Repeated acute infections cause chronic inflammatory responses. Surface colonization of Gram-positive cocci is occasionally observed. With the enzyme-labeled antigen method, which is a novel histochemical technique for detecting plasma cells producing specific antibodies in tissue sections [32], plasma cells producing antibodies against group A streptococcal sugar antigen, Strep A, are consistently identified in the tonsillar lymphoid tissue (Figure 8) [33].

Figure 6.

Lymphoid hyperplasia in a tonsillectomy specimen from a teenager boy (H&E). Lymphoid follicle formation with enlarged germinal centers (GC) is evident. Numbers of lymphocytes and plasma cells are seen among the reticular mucosa covering the tonsillar surface (asterisks).

Figure 7.

Features of the reticular mucosa of the palatine tonsil (left: H&E, center: type 4 collagen, right: CD138). The reticular mucosa is very unique for dense infiltration of lymphocytes and plasma cells and intramucosal distribution of capillary vessels. Immunostaining for type 4 collagen demonstrates the basement membrane (arrows) of the reticular mucosa and capillary vessels (arrowheads). Immunostaining for CD138 identifies plasma cells densely accumulated within the reticular mucosa.

Figure 8.

Plasma cells producing antibodies against Strep A carbohydrate antigen in the hyperplastic palatine tonsil (left: IgG immunostaining, right: the enzyme-labeled antigen method using a paraformaldehyde-fixed frozen section). Numbers of plasma cells in the reticular mucosa produce IgG. Some of them are positive for antibody reactivity against Strep A (arrows). Immune reaction against group A Streptococcus is visualized with the enzyme-labeled antigen method.

3.1 Scarlet fever

Scarlet fever (scarletina) represents the secondary systemic manifestation of acute tonsillitis caused by group A beta-hemolytic Streptococcus or S. pyogenes [34, 35]. In rare cases, scarlet-like fever may be caused by S. aureus. Infants aged around 4–5 years are susceptible to droplet transmission of the microorganism. Two days after the abovementioned acute tonsillitis symptoms, generalized exanthema develops, particularly on the neck, chest wall, back, and extremities. The rash is fine, red, and rough-textured and blanches upon pressure. The rash tends to be accentuated along the skin folds (Pastia’s lines). Perioral skin, palms, and soles are spared. Strawberry tongue and red cheek are characteristic of scarlet fever (Figure 9). In 4–8 days, scaling occurs, particularly on the fingers and toes, and the disease subsides within 2–3 weeks.

Figure 9.

Scarlet fever (gross appearance). Fused but spotted fine exanthemas (left) and strawberry tongue (right) are characteristic of scarlet fever. Red cheek and perioral haloe are noted. Scarlet fever follows streptococcal acute tonsillitis.

Active production and secretion of streptococcal pyogenic exotoxin (SPE) by the infected bacteria are the main mechanism of illness [36]. SPE is categorized as a member of superantigens (see the Note). Late complications include acute (post-streptococcal) glomerulonephritis and rheumatic fever (rheumatic endocarditis) affecting mitral and/or aortic valves, as well as the heart muscle layer. Rheumatic fever may result in chronic valvular heart diseases.

Post-streptococcal glomerulonephritis is characterized by granular IgG deposition in the enlarged and cellular glomerulus by immunofluorescence and hump formation (subepithelial deposition of immune complexes) by electron microscopy (Figure 10). Figure 11 demonstrates Aschoff’s nodule formed in the heart muscle layer in rheumatic fever. Small granulomas consist of activated macrophages termed Anitschkow cells or caterpillar cells. Chromatins are aggregated in the central part of nuclei, resembling a catapillar.

Figure 10.

Post-streptococcal acute glomerulonephritis (left: H&E, right: electron microscopy, inset: immunofluorescence for IgG). Biopsy was taken from an adult case. The glomerulus is swollen with high cellularity due to endothelial growth. Electron microscopy demonstrates hump formation (arrow) outside the basement membrane (beneath the epithelial cells). Granular IgG deposition is evident by immunofluorescence analysis.

Figure 11.

Rheumatic carditis in rheumatic fever (autopsy case, left: H&E, right: electron microscopy). Aschoff’s node (small granuloma) is formed among the cardiac muscle layer. The epithelioid macrophages frequently show catapillar-like chromatin accumulation in the central part of the nucleus (arrows) and called as Anitschkow cells or catapillar cells. Electron microscopic appearance of Anitchkow cell is quite characteristic.

Note: Superantigen.

Superantigen is an exotoxin drastically activating T-lymphocytes polyclonally, through direct binding to the major histocompatibility complexes class II antigen (DR, DQ, and DP). As a result, cytokines such as interleukin-2 and -6 are overproduced (hypercytokinemia) and secondary B-lymphocyte activation leads to hypergammaglobulinemia. A representative superantigen is toxic shock syndrome toxin-1 (TSST-1), secreted by S. aureus. TSST-1 provokes toxic shock syndrome. S. aureus produces different superantigens, enterotoxins A and C, which may cause intractable diarrhea in case of Methicillin-resistant S. aureus (MRSA) enteritis. S. pyogenes secretes superantigens termed streptococcal pyrogenic exotoxin (SPE) A, B, C, and F and streptococcal superantigen (SSA). These may have roles in fulminant streptococcal myonecrosis or streptococcal toxic shock-like syndrome [9, 10, 11]

Skin rash is commonly associated with superantigen-related disorders. Superantigens are also secreted from Yersinia pseudotuberculosis (in Izumi fever), Clostridium perfringens (enterotoxin), and Epstein-Barr virus (virus-associated hemophagocytic syndrome). Superantigens are also involved in the pathogenesis of scarlet fever, Kawasaki disease (mucocutaneous lymph node syndrome), and neonatal toxic shock syndrome-like exanthematous disease.


4. Traumatic streptococcal infection

Necrotizing and non-necrotizing soft tissue infections of S. pyogenes may occur after minor, non-penetrating skin trauma [37]. Oral or dental trauma provokes severe necrotizing fasciitis in pediatric population [38].

Post-traumatic endophthalmitis is an uncommon but devastating complication of an open eye injury [39, 40]. Risk factors include the presence of an intraocular foreign bodies, crystalline lens disruption, delayed primary globe repair, rural trauma, and trauma with contaminated objects. Common causative microorganisms include Gram-positive cocci such as Streptococcus, Staphylococcus and Enterococcus species. Less commonly, it is caused by Gram-negative pathogens including Pseudomonas aeruginosa and Enterobacteriaceae. Polymicrobial infections are also not rarely encountered. In case of perforating trauma (the association with intraocular foreign bodies or the wound with soil contamination), Bacillus infections may occur [40]. Candida albicans causes endophthalmitis as a secondary contamination of hyperalimentation therapy [41]. Aspergillus and Fusarium are hypha-forming fungi causing trauma-related, subacute to chronic indolent infections [42].

Figure 12 demonstrates severe streptococcal endophthalmitis seen in an autopsy case (a man in his 30s) of Hansen’s disease. Eye complications are common in Hansen’s disease, often accompanying lagophthalmos, uveitis, and corneal neuropathy. The diseased eyes are susceptible to traumatic injuries [43].

Figure 12.

Streptococcal endophthalmitis (left: H&E, right: streptococcal antigens). Neutrophils are densely clustered within the eye ball. Bacterial colonies showing immunoreactivity of streptococcal antigens are observed in the purulent exudate. Asterisks indicate the iris having melanin pigmentation.


5. Necrotizing streptococcal infection

Streptococcus pyogenes may cause necrotizing soft tissue infections. These include necrotizing fasciitis, non-clostridial gas gangrene, fulminant streptococcal infection (streptococcal myonecrosis), Fournier’s gangrene, and fulminant streptococcal infection without gangrene of the extremities. Refer to the author’s previous publication on the pathology of gangrene [44].

5.1 Necrotizing fasciitis

Necrotizing fasciitis represents severe pyogenic infection (cellulitis) of the skin and underlying soft tissue [45, 46, 47, 48, 49]. Deep, painful, and intractable ulceration progresses predominantly on the extremities, associated with a subacute clinical course. Minor trauma may provide the entry for the pathogen. Uncommonly, the condition follows surgical procedures. Diabetes mellitus, immunosuppression, alcoholism, drug abuse, atherosclerosis-related hypoperfusion, and malnutrition can also be prodromal to this troublesome infectious disorder. It may occur in healthy persons [50]. Necrotizing fasciitis is etiologically categorized into two types: type I (with polymicrobial infection) and type II (with monobacterial infection).

Classic pathogens of cellulitis represent group A beta-hemolytic Streptococcus and less frequently Staphylococcus aureus, but a diverse range of microorganisms, including Pseudomonas aeruginosa, cause cellulitis. Stenotrophomonas maltophilia causes erythematous nodular lesions formed on the leg of neutropenic or leukemic patients [51]. Haemophilus influenzae infection may provoke facial cellulitis [52]. In Figure 13, streptococcal infection on the ulcer base of minor trauma-provoked necrotizing fasciitis on the thigh of a 61-year-old man is demonstrated.

Figure 13.

Necrotizing fasciitis on the thigh of a 61-year-old man (left: H&E, right top: Gram, right bottom: streptococcal antigens). The ulcer base of the necrotizing fasciitis is infected by Gram-positive cocci with streptococcal antigens. Arrow indicates bacterial colonies in H&E preparation. The intractable ulcer was provoked by minor trauma.

Figure 14 illustrates gross features of necrotizing fasciitis seen in a poorly controlled diabetic male patient. In the wintertime, the patient got a severe burn on his sole provoked by a fan heater, because he did not feel pain due to diabetic peripheral neuropathy. The doctor-shy patient did not visit a hospital for 1 week, and this hesitation accelerated the lesion to become progressed. Severe atherosclerosis had provoked dry gangrene on his toes. Diabetes-related neutrophilic dysfunction provided the vulnerability to infection. Polymicrobial (type I) necrotizing fasciitis resulted in septicemia, and emergency amputation saved his life. The importance of foot care for patients with diabetes mellitus should be emphasized.

Figure 14.

Gross appearance of necrotizing fasciitis on the sole, seen in a poorly controlled diabetic male patient. In the wintertime, fan heater-induced severe burn occurred on his sole because of the senselessness due to diabetic neuropathy. The lesion progressed to necrotizing fasciitis. Atherosclerosis had provoked dry gangrene in his toes (arrows).

5.2 Non-clostridial gas gangrene

Gas gangrene is typically provoked by infection of Clostridium perfringens, but non-clostridial bacteria may also cause gas gangrene mostly in the limbs [53, 54, 55]. Prompt diagnosis and treatment are requested, as the disease rapidly progresses to fatal toxemia. Dermatologic emergency of this type presents non-traumatic subcutaneous emphysema of the leg with or without association of erythema, tenderness, or bullous lesions. Non-clostridial gas gangrene most often results from polymicrobial infection, and it is mainly seen in diabetic patients [56, 57, 58]. The causative gas-producing bacteria include Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Pseudomonas aeruginosa, Aeromonas hydrophila, Bacteroides spp., and Streptococcus anginosus group (former S. milleri group) [59]. Groups A, B, and G streptococci also cause gas gangrene, as a form of fulminant streptococcal infection [60]. Figure 15 illustrates lethal gas-forming fulminant group A beta-hemolytic streptococcal infection, caused by a deeply ulcerated (pocket-forming) decubitus at the sacral region of a 72-year-old diabetic female patient. Extensive exudation and foul odor were associated.

Figure 15.

Fulminant streptococcal infection secondary to deep pocket-forming decubitus (left: gross appearance, right top: CT scan, right bottom: H&E, inset: Gram). A deeply ulcerated decubitus at the sacral region of a 72-year-old diabetic female showed extensive exudation and foul odor. The lesion progressed to lethal and gas-forming fulminant group A beta-hemolytic streptococcal infection. CT scan and biopsy specimen indicate gas formation (arrows). The cocci growing in the lesion are Gram-positive.

Gangrenous inflammation may occur in a wide variety of internal organs, such as the vermiform appendix, gallbladder, bile duct, pancreas, lung, kidney, eyeball, etc. The lesion may be localized within the organ, but it often fatally extends to the surrounding tissues. When the anaerobic pathogens produce gas, the serious condition is called as “emphysematous” inflammation (as a form of localized gas gangrene).

One representative example of gangrenous infection in the internal organ is acute gangrenous appendicitis. Inflammatory perforation is common, resulting in generalized abdominal tenderness and peritonism [61, 62, 63]. The blockage the appendiceal lumen (most commonly by fecalith impaction) results in increased luminal pressure, impaired blood flow, and invasive infection of bacterial flora. Mixed bacterial infection is proven. Streptococcus anginosus (or milleri) group is often co-infected with Escherichia coli, Bacteroides fragilis, B. splanchnicus, B. intermedius, Peptostreptococcus, Pseudomonas, Lactobacillus, Bilophila wadsworthia, Fusobacterium nucleatum, and Eggerthella lenta. An average of 10.2 different microorganisms have been isolated from the infected lesion. Microscopically, the appendiceal wall reveals marked transmural infiltration of neutrophils and massive necrosis with disappearance of the proper muscle layer. Colonization of cocci and rods is easily observed within the gangrenous lesion. Fibrinopurulent peritonitis is associated. Thrombosis in medium-sized blood vessels prompts the gangrenous change. Representative findings of perforated gangrenous appendicitis are displayed in Figure 16. Colonization of Gram-positive cocci is easily seen.

Figure 16.

Perforated gangrenous appendicitis (left: gross appearance, right top: H&E, right bottom: Gram). The surgically resected vermiform appendix reveals transmural necrotizing inflammation with perforation (a probe inserted). In the necrotic lesion, colony formation of Gram-positive cocci and Gram-negative rods is noted.

Lethal purulent pancreatitis with mixed infection of enterobacteriae and streptococci is demonstrated in Figure 17. Infection occurred in a woman in her 50s following extensive chemotherapy against pancreatic malignant lymphoma of B-cell type. Gas formation was not evident in this case. Immunostaining was quite effective for visualizing the microorganisms. Severe lung abscesses were associated in both lungs.

Figure 17.

Lethal purulent pancreatitis in a woman in her 50s after extensive chemotherapy against malignant B-cell lymphoma of the pancreas (left: H&E. right top: lipopolysaccharide of E. coli using a monoclonal antibody J5, right bottom: streptococcal antigens). Co-infection of enterobacteriae and streptococci is immunohistochemically proven along the lumen of severely inflamed pancreatic ducts. Asterisks indicate the pancreatic duct lumen. A = atherosclerotic artery.

5.3 Fulminant streptococcal infection (streptococcal myonecrosis)

Bacterial invasion may cause progressive and often lethal gangrenous lesions in the soft tissue, particularly on the extremities. This frightening and life-threatening condition is often called as “flesh-eating bacteria infection” by mass communication. There are three representative forms: fulminant streptococcal infection, Vibrio vulnificus infection, and A. hydrophila infection [44].

Streptococcal myonecrosis, a fulminant form of necrotizing fasciitis, presents rapidly progressive gangrene of the extremities caused by infection of Streptococcus pyogenes (group A beta-hemolytic Streptococcus), a prototype of “flesh-eating bacteria infection” [64, 65]. The disease affects persons of any age. Groups B and G beta-hemolytic Streptococcus may also provoke such fulminant conditions [66, 67]. Protein S deficiency may be a hereditary factor responsible for the necrotizing inflammation. Streptococcal toxic shock-like syndrome leads to an aggressive lethal condition without any predisposing disease [68, 69]. It has been reported that vimentin, an intracellular intermediate filament of nonepithelial cells, is upregulated in the injured skeletal muscle cells and functions as the major skeletal-muscle protein binding to streptococci [70]. The life-threatening gangrene may follow a subacute form of necrotizing fasciitis or occurs suddenly without such preexisting ulceration. Figure 15 demonstrates an advanced, deep pocket-forming decubitus in the sacral region, secondarily causing a lethal, S. pyogenes-infected gangrenous lesion categorized in non-clostridial gas gangrene [71].

Clinical manifestations include high fever, pain at the site of infection, and skin necrosis (gangrene) with hemorrhagic bulla formation. Scarlatiniform rash may be associated. Eventually, massive gangrenous necrosis involves the extremity.

Microscopically, pronounced myonecrosis with foci of infection of Gram-positive cocci is noted. Gram-positive cocci grow within the lesion of advancing gangrenous necrosis of soft tissue. Neutrophilic reaction is minimal, because of the ischemic (anaerobic) state with poor blood flow (Figure 18). In addition, S. pyogenes produces neutrophil-suppressing factors: Streptococcal pyrogenic exotoxin (SPE)-B degrades neutrophil extracellular traps (NETs), and C6-binding protein (a cell-surface protein) contributes to S. pyogenes evasion of the complement system by inhibiting complement polymerization and bacteriolysis activity [12]. NETs, special spider’s web- or net-like fibrillar structures formed after neutrophilic cell death, locally capture and kill the microorganisms [72, 73]. In both the necrotic soft tissue and cultured blood, short chains of Gram-positive cocci, morphologically typical of Streptococcus, are demonstrated (Figure 19). Streptococcal septicemia provokes streptococcal toxic shock-like syndrome [74]. The bacterial exotoxins (superantigens) such as SPE-A, B, C, F, and streptococcal superantigen induce a severe cytokine storm [9, 10, 11]. Hypercytokinemia activates hemophagocytosis by macrophages in the bone marrow, liver, and spleen. Activation of NLRP3 inflammasome may be an essential event for the cytokine storm in streptococcal toxic shock-like syndrome [75].

Figure 18.

Fulminant streptococcal myonecrosis in a previously healthy man in his 40s (amputation specimen, H&E). Left: Striated muscle cells are totally necrotic. Right: Fibrin thrombosis is formed in an arteriole (arrow). The patient died next day.

Figure 19.

Identification of Streptococcus pyogenes in the patient shown in Figure 18 (Gram stain for the amputated arm [left] and May-Giemsa stain for the cultured peripheral blood [right]). Gram-positive cocci are colonized in the necrotic striated muscle tissue. Chained Gram-positive cocci were identified as group A beta-hemolytic Streptococcus.

The bacteria are commonly sensitive to penicillin and its derivatives, but the intravenous antibiotics administration is clinically ineffective, principally because of the absence of blood flow: The drug can never reach the site of infection.

5.4 Fournier’s gangrene

Fournier’s gangrene is a special form of fulminant cellulitis (fatal gangrene) involving the male scrotum and perineum [76, 77, 78, 79]. The scrotum is remarkably swollen and becomes reddish-black in color (Figure 20). The causative microorganism is most commonly S. pyogenes, but S. pneumoniae may also cause the disease. The necrotizing change rapidly progresses to the surrounding soft tissue, eventually resulting in septicemia. The prognosis is very poor. The penis is either involved or spared. The physiological lack of subcutaneous fat tissue in the scrotum and penis accelerates the bacterial spread. Gas production and malodor may be associated. It belongs to non-clostridial gas gangrene when gas production is observed. The preferred age ranges from 50 to 80 years. Male patients of Fournier’s gangrene often have a history of diabetes mellitus. Immunocompromised condition also triggers the disease. Perianal abscess is a representative risk factor of the disease. Masturbation-related minor penile skin injury may cause the disease in younger age [80].

Figure 20.

Gross appearance of Fournier’s gangrene. The scrotum of a diabetic man in his 60s is markedly swollen with massive hemorrhagic necrosis. The penis and anal region are also extensively involved.

Microscopically, massive necrosis of the skin tissue is evident. Mixed bacterial infection, including Streptococcus and anaerobic bacteria, is often proven. When streptococci are isolated, it is categorized in fulminant streptococcal infection. Biopsy specimen from the abovementioned diabetic man in his 60s revealed a gas-forming necrotizing lesion with infection of Gram-positive cocci, in which streptococcal antigens were proven (Figure 21).

Figure 21.

Microscopic appearance of Fournier’s gangrene shown in Figure 20 (left: H&E, right top: Gram, right bottom: pneumococcal antigens). Gas-forming gangrenous change is evident in the biopsied scrotal wall. The growing cocci in the lesion are Gram-positive and immunoreactive for pneumococcal antigens.

5.5 Fulminant streptococcal infection without gangrene of the extremities

Fulminant infection of group A beta-hemolytic Streptococcus (S. pyogenes) is typically featured by progressive gangrene in soft tissue of the extremities, as described above. It is noteworthy that fulminant group A streptococcal infection is also encountered in cases without gangrenous lesions of the extremity [81]. It should be noted that streptococcal infection in the internal organs may cause the fatal disease.

We experienced five cases of fulminant streptococcal infection without gangrene of the extremities (Table 1). Four of five cases were young and immunocompetent and encountered at forensic autopsy. Infectious foci were seen in internal organs such as the tonsil, bronchus, puerperal endometrium, and urinary bladder. The clinical course was very short ranging from 2 to 4 days.

CaseAge/sexClinical coursePDPrimary lesionBEMCAutopsy findings
186F3 days+Hemorrhagic cystitis+NDBilateral renal cortical necrosis, bilateral adrenal hemorrhage, DIC
230 M2 daysAcute tonsillitis+Bilateral renal cortical necrosis, bilateral adrenal hemorrhage, DIC (microthrombosis)
338F4 daysNecrotizing endometritis (puerperal fever)+*Hemophagocytic syndrome, bilateral renal cortical necrosis, leukostasis, DIC (microthrombosis), myocardial ischemia, liver congestion
424F3 days+Necrotizing bronchitisaNDHemophagocytic syndrome, acute renal tubular necrosis, DIC, myocardial ischemia, pulmonary edema, tonsillar hyperplasia
535 M3 daysNecrotizing bronchitis+Hemophagocytic syndrome, acute renal tubular necrosis, DIC, Myocardial ischemia, liver congestion, pulmonary edema

Table 1.

Summary of five autopsy cases of fulminant streptococcal infection without gangrene of the extremities (reference [81]).

Negative in the blood but positive from the uterine cervix.

Aspiration of coccal colonies into the alveolar space seen.

PD: preexisting disease (case 1: cerebral infarct and femoral neck fracture, case 4: Graves’ disease), BE: bacterial embolus formation in distant organs and tissues, MC: microbial culture (ND: not done).

Infective and hemorrhagic cystitis with systemic streptococcal dissemination was encountered in an aged female with a history of cerebral infarction and femoral neck fracture (Figure 22). Focal necrotizing endometritis in a puerperal woman was the cause of streptococcal toxic shock-like syndrome, and it is categorized into so-called puerperal fever (Figure 23). Pregnancy-associated lethal infection should be of particular note [82]. Artificial abortion may provoke septic shock caused by S. pyogenes infection [83].

Figure 22.

Fulminant streptococcal infection without gangrene of the extremities: I (gross appearance, left: urinary bladder, right; bilateral adrenal glands). An 86-year-old woman manifested extensive hemorrhagic cystitis and bilateral adrenal hemorrhage. Bilateral renal cortical necrosis was also associated. The total clinical course was 3 days.

Figure 23.

Fulminant streptococcal infection without gangrene of the extremities: II (left: gross appearance of the puerperal uterus, right; Gram stain for the endometrium). The puerperal endometrium was focally infected with Gram-positive and Strep A-immunoreactive cocci, resulting in fatal toxic shock-like syndrome with bilateral renal cortical necrosis. The total clinical course was 4 days.

The other cases accompanied acute tonsillitis in one and acute bronchitis in two. Group A Streptococcus infection was proven by microbial culture in two cases, and immunoreactivities of streptococcal antigens and Strep A were shown on the Gram-positive cocci in all five cases. Strep A is a carbohydrate antigen specific for group A Streptococcus [33]. It should be emphasized that the causative infective lesion in the internal organs were microscopic and focal mucosal erosions were the gross abnormality in four of five cases (except for diffuse hemorrhagic cystitis).

There are two different pathophysiological mechanisms in fulminant streptococcal infection without gangrene of the extremities [81]. One form with overwhelming bacterial growth is featured by systemic bacterial dissemination accompanying bacterial emboli with poor neutrophilic reaction. Bacterial embolism in the adrenal gland provokes bilateral adrenal hemorrhage (acute adrenocortical insufficiency), as categorized in Waterhouse-Friderichsen syndrome [84] (Figure 24). See also Figure 22. Another form without bacterial embolism was represented by bacterial toxin-induced hemophagocytosis by activated macrophages, reflecting a hypercytokinemic state [85] (Figure 25,left). Hypercytokinemia and disseminated intravascular coagulopathy (DIC) are common phenomena in both forms, and bilateral renal cortical necrosis is a severe sequela as an extreme manifestation of DIC (Figure 25,right) [86]. Hematopoiesis in the bone marrow appears to be normal, but neutrophilic reactions are limited in the primary and disseminated infective foci. Supposedly, neutrophilic functions are acutely suppressed through the two different mechanisms during the process of the fulminant disease. The disease is categorized in streptococcal toxic shock-like syndrome mediated by streptococcal superantigens [74, 75].

Figure 24.

Fulminant streptococcal infection without gangrene of the extremities III (adrenal gland, left: H&E, right; Strep A). The adrenal cortex in a case shown in Figure 22 shows marked fresh hemorrhage with mycotic embolism (arrow). The Gram-positive cocci are immunoreactive for Strep A carbohydrate antigen.

Figure 25.

Fulminant streptococcal infection without gangrene of the extremities IV (H&E; left: bone marrow, right: renal cortex, the same case as Figure 23). Activated macrophages reveal hemophagocytosis in the bone marrow (yellow arrows). The renal cortex (both renal tubules and glomeruli) reveals massive ischemic change. Fibrin thrombi are clustered in the glomerulus (green arrows).

Physicians should consider the possibility of fulminant streptococcal infection, particularly when they examine the patient manifesting progressive shock symptoms even without gangrene of the limbs. Autopsy prosecutors (diagnostic and forensic pathologists) must realize the difficulty in making an autopsy diagnosis, particularly when bacterial embolism is not identified under a microscope. The knowledge of these types of fulminant syndrome and the appropriate microscopic recognition of hemophagocytosis in the bone marrow, liver, and spleen must be key findings for the autopsy prosecutor. The correct autopsy diagnosis cannot be reached when the association of the hypercytokinemic state was not suspected clinically and/or microscopically. Immunohistochemical demonstration of streptococcal antigens in the infected lesion is of critical importance for the appropriate recognition of pathogenesis.


6. Infection of viridans group streptococci

Viridans group streptococci normally reside in the oral cavity. They may cause dental caries and localized infection on the mucosa of the oral cavity through the esophagus. Streptococcal crystalline sinusitis is a unique form of streptococcal infection of the paranasal cavity. Invasive diseases may also happen.

6.1 Viridans group streptococci as normal mucosal flora

Streptococci mainly proliferate on the diseased mucosa under microaerophilic or even anaerobic conditions, such as the oral cavity and the digestive tract. This is in sharp contrast to staphylococci, which are an inhabitant of the skin.

Viridans group Streptococcus (virido means green in Latin) is a general term used for alpha-hemolytic Streptococcus normally colonizing the oropharyngeal mucosa [87, 88]. It may cause dental caries, aspiration pneumonia, and infective endocarditis. The following species are known. (a) S. salivarius is the commonest flora in saliva and oral mucosal surface. (b) S. sanguis and S. mitis may cause infective endocarditis. (c) S. anginosus group (former S. milleri group) such as S. intermedius and S. constellatus is anaerobic and predominantly seen in the dental pit and thus called as aerotolerant or microaerophilic Streptococcus. They may cause sinusitis, lung abscess, aspiration pneumonia, and brain abscess. Oral hygiene is very important for preventing aspiration pneumonia. (d) S. mutans is a causative agent of dental caries to form dental plaques as a result of biofilm infection. It can produce glucose polymers (glucans) by consuming sucrose. (e) S. sobrinus produces gelatinous material (zooglea) by using sucrose on the dental plaques.

6.2 Dental caries as a sequela of Streptococcus mutans infection

In dental caries, the tooth surface is covered with a biofilm, a slime layer consisting of millions of bacteria among extracellular polysaccharides. Varied bacteria are involved in the process of dental caries, and S. mutans plays a central role in cariogenesis [89]. There are three steps for the formation of dental plaque [90]. First, the dental enamel is coated with a complex mixture of components including glycoproteins, acidic proline-rich proteins, and mucins. The second step includes biofilm formation by primary colonizers, mainly Streptococcus sanguis and Actinomyces viscosus [91]. In the third step, acid-secreting S. mutans and Lactobacillus, so-called carious bacteria, adhere to the primary colonizers by cell-to-cell interactions. S. mutans and Streptococcus sobrinus can also adhere to the enamel salivary pellicle [92]. S. mutans and Lactobacillus belong to strong acid producers. Acidogenic S. mutans and S. sobrinus can form extracellular polysaccharides (insoluble glucans or fructans) in the presence of sucrose or fructose [93]. The production of large quantities of extracellular polysaccharides from sucrose is an important factor for the cariogenicity of S. mutans [94]. Subsequent bacterial growth leads to formation of thick biofilm on the teeth, called as a dental plaque [95]. Tooth cavities are usually formed 6–24 months after the colonization of S. mutans [96]. Figure 26 demonstrates a microscopic picture of the decayed dental surface in an advanced stage: Colonization of Gram-positive long rods, representing Lactobacillus species, is discerned, whereas Gram-positive cocci are no longer seen.

Figure 26.

Dental caries (left: H&E, right: Gram). Biofilm infection of long Gram-positive rods is evident on the carious teeth. At this advanced stage of dental caries, the adhesive growth of Lactobacillus remains, and Gram-positive cocci are no longer observed.

An increase in dietary sucrose and fructose, fermentable carbohydrates, accelerates acid production, resulting in dental caries formation, when the consistent formation of acid by the bacteria exceeds neutralizing power of the saliva [97]. Sucrose-containing diet definitely is the main reason for the high rate of dental caries in developed countries [98].

6.3 Secondary mucosal streptococcal colonization

Secondary streptococcal colonization preferentially occurs on the mucosa under locally altered conditions such as ulcerative or polypoid lesions formed on the oral through esophageal mucosa or vaginal cavity [99, 100]. In Figure 27, biofilm colonization of the oral commensal bacteria on the surface of the lip is demonstrated. Two types of bacteria are recognized: Gram-positive cocci (streptococci) are observed beneath a layer of Gram-negative bacteria, and both types of bacteria produce colloidal iron-positive mucosubstances. No inflammatory reaction is discerned. Figure 28 exhibits streptococcal colonization on the surface of the furred tongue (bacterial glossitis) seen at autopsy. Poor oral hygiene at the agonal stage of chronic diseases such as cancer prompted the bacterial colonization. The filiform papillae are densely infected with streptococci. Co-infection with C. albicans and long rods (Lactobacillus or Spirochaeta) is common. Transmission electron microscopic appearance of streptococci colonizing the tongue surface is presented in Figure 29.

Figure 27.

Biofilm colonization of the oral commensal bacteria on the surface of the lip (left: HE, center: Gram, right: colloidal iron). Two types of bacteria are focally recognized on the squamous mucosa: Gram-positive cocci (streptococci) are observed beneath a thick layer of Gram-negative bacteria, and both types of bacteria produce colloidal iron-positive acidic mucosubstances. No inflammatory reaction is noted.

Figure 28.

Furred tongue (bacterial glossitis) seen at autopsy (left: Gram, right: streptococcal antigens). The filiform papillae are densely infected with streptococci. Poor oral hygiene at the agonal stage of chronic illness accelerated infection of oral microbiota.

Figure 29.

Electron microscopy of Streptococcus growing on the tongue. Electron-dense cocci measuring around 600 nm in diameter are demonstrated. Arrow indicates a binary division (dichotomy). Bar = 200 nm.

In most instances, streptococci represent opportunistic microbes growing on the mucosa, but occasionally they become genuine pathogens responsible for locally invasive and/or systemic infectious diseases. Typical examples are demonstrated in Figure 30. The base of tonsillar ulcer seen in a 48-year-old woman is covered with Gram-positive cocci immunoreactive for streptococcal antigen and protein G (a streptococcal IgG Fc-binding protein) [101]. Co-infection of viridans group streptococci with C. albicans is quite common in candidal esophagitis [102] (Figure 31). Streptococcal adhesion to the esophageal mucosa may cause bacterial esophagitis without Candida infection [103]. Figure 32 illustrates a biopsy specimen accompanying streptococcal adhesion (colonization) onto the esophageal squamous mucosa, against which no inflammatory reaction is seen. Esophageal ulcers caused by alkali ingestion, drinking hot coffee, or by eating hot food are almost consistently associated with colonization of viridans group streptococci on the ulcerated surface. Aspirated streptococcal colonies are occasionally observed in the pit of folds of gastric polyps as a contaminant [104]. As shown in Figure 33, mixed colonization of oral mucosal flora (streptococci and Gram-negative rods) is discerned within the fold of a polypectomized gastric polyp, just adjacent to food debris.

Figure 30.

Secondary streptococcal colonization on tonsillar ulcer seen in a woman in her 40s (left top: H&E, right top: Gram, left bottom: immunostaining for streptococcal antigens, right bottom: immunostaining for protein G). Gram-positive cocci densely cover the eroded surface. They are immunoreactive for both streptococcal antigens and protein G, an IgG Fc-binding protein of Streptococcus.

Figure 31.

Co-infection of streptococci in candidal esophagitis (left top: Grocott, right top: Gram, left bottom: immunostaining for candidal antigens, right bottom: immunostaining for streptococcal antigens). Esophageal biopsy specimen reveals co-infection of Candida albicans and streptococci.

Figure 32.

Bacterial esophagitis (left: Gram, right; immunostaining for streptococcal antigens). In the esophageal biopsy specimen, a few cocci colonize the esophageal surface. The cocci are Gram-positive and immunoreactive for streptococcal antigens. Candidal infection is not seen. No neutrophilic reaction is associated.

Figure 33.

Co-colonization of streptococci and enterobacteriae in the pit of gastric hyperplastic polyp (left top: H&E, right top: Gram, left bottom: immunostaining for streptococcal antigens, right bottom: immunostaining for E. coli antigens). Colonies of streptococci and enterobacteriae are seen adjacent to the food debris (arrows). No inflammatory reaction is noted. This should be regarded as incidental contamination of oral flora.

Immunocompromised status facilitates opportunistic streptococcal infection [105]. Opportunistic esophagitis is frequently seen on the esophageal mucosa under the immunocompromised condition [106]. Figure 34 demonstrates severe green-colored erosive esophagitis seen in a female patient in her 40s who underwent bone marrow transplantation for acute myeloid leukemia. At autopsy, Gram-positive cocci densely and diffusely colonized the eroded esophageal surface. The color of the lesion may represent the production of green-colored pigments such as pyocyanin and fluorescein by the colonized bacteria, viridans group streptococci. Systemic dissemination of streptococci led to lethal septicemia in the patient.

Figure 34.

Severe erosive esophagitis in a female patient in her 40s after bone marrow transplantation for acute myeloid leukemia (left: gross appearance, center: H&E, right: Gram). At autopsy, Gram-positive cocci densely colonized the diffusely eroded and green-colored esophageal surface. The production of green-colored pigments by viridans group streptococci is indicated. Systemic dissemination of the pathogen followed. By courtesy of Dr. Yumiko Yasuhara at Department of Diagnostic Pathology, Sakai City Medical Center, Sakai, Osaka, Japan.


7. Streptococcal crystalline sinusitis

A unique lesion of “streptococcal crystalline sinusitis” is illustrated in Figures 35 and 36. A biopsy specimen was sampled from the maxillary sinus with inflammatory exudation. The patient was a 63-year-old Japanese woman suffering from chronic sinusitis. Microscopically, numbers of colonies of basophilic cocci were clustered in the eosinophilic inflammatory exudates. The colonies were clearly stained with Gram, Grocott, and colloidal iron. Colloidal iron positivity indicated the production of mucosubstances, namely the capsule formation. The cocci were immunoreactive for streptococcal antigens but negative for staphylococcal, pneumococcal, and enterococcal antigens. Neutrophilic reactions were focally associated, whereas eosinophils were scarcely noted. Characteristic was the deposition of needle-shaped, basophilic crystals around the coccal colonies and in the eosinophilic exudate matrix. Colloidal iron positivity indicated capsule formation by the bacteria. The crystals frequently formed rosette-like structures and consistently revealed Grocott reactivity. Streptococcal antigens and Gram/colloidal iron reactivities were negative in the crystals. Alpha-streptococci were cultured from the nasal exudates. The pathogen might belong to viridans group streptococci, though the species is unclear.

Figure 35.

Streptococcal crystalline sinusitis: I (left: H&E, center: Gram, right: colloidal iron). Biopsy from the paranasal cavity of a 63-year-old female patient microscopically shows the growth of Gram-positive and capsule-forming (colloidal iron-positive) cocci. The deposition of basophilic needle-shaped crystals is closely associated with the coccal growth, and crystals are devoid of colloidal iron reactivity (arrows). By courtesy of Dr. Hiroshi Ohashi at Department of Diagnostic Pathology, Ikeda City Hospital, Ikeda, Osaka, Japan.

Figure 36.

Streptococcal crystalline sinusitis: II (left: Grocott, right: streptococcal antigens). Streptococci are closely associated with basophilic crystal deposition as seen in Figure 35. The crystals frequently form rosette-like structures and consistently reveal Grocott reactivity. Streptococcal antigens are positive in the cocci but negative in the crystals (arrows).

In vitro crystal formation by S. pyogenes and biofilm-forming S. suis (a zoonotic pathogen) has been investigated, and zinc ions may stabilize the crystals [107, 108]. In the cornea, streptococcal infection may cause infectious crystalline keratopathy, an indolent infection showing needle-like branching crystalline opacities in the corneal stroma [109, 110]. S. viridans or S. pyogenes is cultured from the lesion. To the best of our knowledge, there has been no report describing streptococcal sinusitis with crystal formation. The author dares to term this unique infectious condition as streptococcal crystalline sinusitis.


8. Systemic dissemination of viridans group streptococci

Viridans group streptococci may cause systemic dissemination, such as pneumonia/pyothorax, infective endocarditis, and septicemia [111, 112].

8.1 Aspiration pneumonia

The most important causative bacterium of aspiration pneumonia is viridans group Streptococcus. Bronchiole-centered pneumonia (bronchopneumonia) is provoked by colonization of Gram-positive bacteria, in association with aspirated food debris (Figure 37). Multibacterial infection of the resident microbiota in the oral cavity (predominantly with anaerobic bacteria, including Peptostreptococcus) is a common phenomenon [113]. Candida infection may also be associated. The infection can progress to lung abscess. Purulent pleuritis or pyothorax is a serious complication of aspiration pneumonia (Figure 38). In children under 5 years of age, viridans group streptococci can be a causative microorganism for community-acquired pneumonia [114]. Viridans group streptococci occasionally cause community-acquired pneumonia in adults [115].

Figure 37.

Aspiration pneumonia (left and center: H&E, right: streptococcal antigens, inset: Grocott). Asterisk indicates aspirated food debris (dead striated muscle cells of meat). Gram-positive coccal colonies immunoreactive for streptococcal antigens are impacted in the terminal bronchiole, provoking acute inflammatory reactions. Co-infection of Candida is observed (inset).

Figure 38.

Pyothorax caused by S. anginosus (former S. milleri) group (Gram). In aspirated pleural effusion, rosette-like neutrophilic accumulation is seen around a colony of Gram-positive cocci. Some pathogens are phagocytized by neutrophils. The pyothorax was secondarily caused by aspiration pneumonia in a man in his 80s.

8.2 Infective endocarditis

Subacute bacterial endocarditis, a classical form of infective endocarditis accompanying persistent septicemia, is most frequently caused by viridans group streptococci [116, 117]. The presence of rheumatic and non-rheumatic chronic endocarditis involving the mitral or aortic valves is prone to provoke this septicemic condition. Tooth extraction or oral surgery induces the blood-borne infection of viridans group streptococci to the heart valves. Even at present time under advanced medical care, infective endocarditis remains as a life-threatening illness. Streptococcal endocarditis of the aortic valve of a man in his 60s is exhibited in Figure 39. The surgically removed infected valve reveals atherosclerotic valvulopathy with dystrophic calcification and fibrosis.

Figure 39.

Subacute bacterial endocarditis of the aortic valve (left: H&E, right: streptococcal antigens). A surgical specimen from a septicemic man in his 60s reveals a deformed and calcified aortic valve accompanying acute inflammatory reactions. The bacterial colonies are immunoreactive for streptococcal antigens. Arrow indicates dystrophic calcification of the valve.

Characteristic skin manifestation of infective endocarditis is called as Osler’s nodes, painful, red, raised lesions found on the hands and feet, particularly on finger tips: 10–25% of endocarditis patients have Osler’s nodes [118]. The skin lesion is caused by the deposition of immune complexes (as leukocytoclastic vasculitis without visible microorganisms) or septic emboli. When the lesion is non-tender, it is termed as Roth’s spots and Janeway lesions. Osler’s node caused by cutaneous septic embolism is demonstrated in Figure 40.

Figure 40.

Osler’s node on the skin of the finger (left: Gram, right: streptococcal antigens). Skin lesions (Osler’s node) are seen on the finger of an autopsy case of subacute bacterial endocarditis. Streptococcal embolism is evident in capillary vessels in the upper dermis. Inflammatory reaction is poor in this lesion.

8.3 Septicemic spread of viridans group streptococci

Viridans group streptococci are occasionally identified in the bloodstream of cancer patients with chemotherapy-related neutropenia. A toxic shock-like syndrome may happen. Most frequently, S. anginosus (former S. mitis) is the causative species, and the resistance to a variety of antimicrobial agents is clinically serious and problematic [105, 119].


9. Infection of group B streptococci

Group B streptococci are normal flora in the vagina and digestive tract. Occasionally, they show invasive growth to provoke purulent meningitis in the neonate and septicemic dissemination in the adult.

9.1 Colonization of group B streptococci on the female genital tract

Group B Streptococcus showing beta hemolysis on culture plates is normal flora in the vagina and digestive tract in one-third of individuals and may cause neonatal meningitis via transvaginal transmission [120]. Group B streptococci are classified into nine serotypes based on the polysaccharide of the capsule. A representative species is S. agalactiae. In pregnant and postpartum women, group B streptococci may cause urinary and genital tract infections, postpartum endometritis, and puerperal sepsis [121, 122]. Group B streptococci may provoke spontaneous abortion [123].

Figure 41 illustrates opportunistic streptococcal colonization on the polypoid vaginal mucosa. In Figure 42, spontaneous abortion complicated with streptococcal infection is presented. Regarding the streptococcal growth in gangrenous appendicitis, see Figure 16.

Figure 41.

Streptococcal colonization on the eroded vaginal polyp (left: H&E. right: streptococcal antigens). Streptococci grow on the eroded surface of the biopsied vaginal polyp. An abnormal status of the mucosa such as polyp formation allows localized growth of the commensal flora.

Figure 42.

Abortion associated with streptococcal infection (H&E, inset: a higher power view). Dilatation and curettage specimen reveals coccal infection in massively necrotic decidual tissue. Supposedly, abortion was caused by infection of group B Streptococcus.

9.2 Systemic dissemination of group B streptococci

The most representative systemic dissemination of group B streptococci is neonatal meningitis. Infective embolism and infective arterial aneurysm formation are encountered in septicemic cases. Group B streptococci may cause flesh-eating bacterial infection, as described above [66].

9.2.1 Purulent meningitis in the neonate caused by group B Streptococcus

Streptococcus agalactiae, categorized in group B Streptococcus, is the most common microorganism causing purulent meningitis among neonates or infants younger than 90 days [124, 125, 126]. Figure 43 displays Gram-positive cocci phagocytized by neutrophils in the cerebrospinal fluid of a neonate. Maternal colonization of S. agalactiae in the vagina and/or gastrointestinal tract represents a primary risk factor for the neonatal invasive disease. The colonization of group B Streptococcus in pregnant women is asymptomatic. The risk is increased in case of protracted labor or premature rupture of the membrane. The disease is divided into two groups: early-onset cases (manifested in the first week of life) versus late-onset cases (manifested after 1 month of life). Devastating outcomes with complex neurological or neuropsychiatric sequelae are not rare among meningitis survivors.

Figure 43.

Neonatal meningitis caused by group B Streptococcus (aspirated cerebrospinal fluid, Gram). Chained Gram-positive cocci are phagocytized by clustered neutrophils. We should realize the clinical importance of group B Streptococcus as a cause of neonatal meningitis.

Group B streptococcal meningitis can be protected by screening tests (microbial culture or polymerase chain reaction analysis) using the specimen sampled from the vagina or rectum. When group B streptococci are detected, prophylactic antibiotics should be administered during delivery [127].

9.2.2 Group B Streptococcus-infected embolism and aneurysm of the cerebral artery

S. agalactiae may cause septic (mycotic) embolism in cerebral artery. An 86-year-old man manifested cerebral infarction with high fever. Embolectomy of right middle cerebral artery was performed, and the embolus was infected with Gram-positive cocci. Streptococcal antigens were positive (Figure 44), and S. agalactiae was cultured from the peripheral blood.

Figure 44.

Infected embolism in right middle cerebral artery (left: H&E, right; streptococcal antigens). A febrile 86-year-old man manifested cerebral infarction. Embolectomy specimen shows infection of Gram-positive cocci immunoreactive for streptococcal antigens. S. agalactiae was cultured from the peripheral blood.

Infected (mycotic) aneurysm is caused by bacterial invasion in a normal or previously damaged arterial wall [128]. The disease is commonly seen in patients older than 65 years. Femoral artery and abdominal aorta are prerequisite sites of infection [122]. Cerebral arteries are also occasionally involved [129]. It may or may not be associated with bacterial endocarditis. Classical pathogens for the infected aneurysm included Streptococcus pyogenes, Streptococcus pneumoniae, and Staphylococcus aureus in the pre-antibiotic era [130]. At present, Salmonella species (particularly S. gastroenteritis) and S. aureus comprise the main microorganisms [131]. Listeria monocytogenes, Bacteroides fragilis, and Campylobacter fetus may also cause arterial infection [132]. Group B streptococcus can be a rare pathogen provoking infective aneurysm [133, 134].

Figure 45 illustrates infected aneurysm of the cerebral artery seen in a male patient in his 60s [135]. Streptococcus agalactiae provoked infected aneurysm of the cerebral artery initially presented as atherothrombotic brain infarction followed by intracranial hemorrhage. Disruption of the elastic lamina of the arterial wall (corresponding to aneurysm formation) was proven. Infective endocarditis was not associated in this case.

Figure 45.

Infected aneurysm of the cerebral artery (left: Elastica van Gieson, right: streptococcal antigens). In a man in his 60s, Streptococcus agalactiae provoked cerebral embolism followed by intracranial hemorrhage. An infected aneurysm of the cerebral artery was surgically removed. Infective endocarditis was not associated. The elastic lamina is disrupted (arrows). Cocci immunoreactive for streptococcal antigens are seen in the acute inflammatory exudation.


10. Peptostreptococcus infection

Peptostreptococcus belongs to a family of Gram-positive obligate-anaerobic bacteria [136]. The spherical bacteria are smaller than Streptococcus, but form short chains or pairs. They typically move with cilia, grow slowly, and are resistant to antimicrobial drugs. Peptostreptococcus is a commensal organism in the human mouth, skin, vagina and urinary tract and is a member of the gut microbiota (hence, “pepto,” meaning digestion in Greek, was added to the scientific name as a prefix). Taxonomically, Peptostreptococcus is distinct from Streptococcus, but human infection of Peptostreptococcus is briefly commented here.

Based upon DNA homology and polypeptide expression analysis, many species of bacteria have been reclassified. While new species of Peptostreptococcus are added, other species are renamed. For example, Peptostreptococcus magnus is now called Finegoldia magna. Peptostreptococcus is the only genus among anaerobic Gram-positive cocci encountered in clinical infections. Capsule formation is an important virulence mechanism. Peptostreptococcal growth is often seen in cases of chronic infections. Predisposing factors for peptostreptococcal infection included trauma with the presence of foreign bodies, diabetes mellitus, steroid therapy, immunodeficiency, and ischemic vascular diseases. Most peptostreptococcal infections are synergistic. Peptostreptococcus has been cultured from subcutaneous and soft tissue abscesses, human and animal bites, chronic mastoiditis, osteoarthritis, decubitus, necrotizing fasciitis/gangrene, and diabetes-related foot ulcers [137, 138, 139]. Peptostreptococcus may cause aspiration pneumonia, lung abscess, peritonitis, pelvic abscess, endocarditis, pericarditis, subdural empyema, and brain abscess. Brain abscess can be caused by peptostreptococcal infection in acquired immunodeficiency syndrome [140].

Figure 46 illustrates peptostreptococci in a Gram-stained sputum smear preparation. Small-sized Gram-positive cocci are phagocytized by neutrophils. This may represent commensal flora in the oral cavity as a non-pathogenic phenomenon. Figure 47 exhibits a surgical case of brain abscess with peptostreptococcal infection. The bacteria are often co-cultured with other bacteria.

Figure 46.

Sputum smear preparation with Peptostreptococcus appearance (Gram). Small-sized Gram-positive cocci are phagocytized by neutrophils. This may represent commensal bacteria residing in the oral cavity as a physiological phenomenon.

Figure 47.

Peptostreptococcal brain abscess (left: H&E, right: Gram). This is a surgical case (a man in his 50s) of brain abscess caused by peptostreptococcal infection, Abscess cavity is formed in the brain parenchyma. Small-sized Gram-positive cocci are surrounded by neutrophils filling the abscess cavity.

11. Fulminant Streptococcus suis infection

Infection of S. suis is seen among pigs (suis: a Latin adjective referring to the pig). The bacterium colonizes the tonsil of pigs and may spread among pigs by nose-to-nose contact or by droplet transmission. It induces alpha-hemolysis on a sheep blood agar plate and beta-hemolysis on a horse blood agar plate. The infection may also happen in such animals as boars, horses, dogs, cats and birds as zoonotic infection. Human infection of S. suis occurs mainly in adults, particularly in pig breeders, abattoir workers, meat processing and transport workers, butchers and cooks, as an occupation-related disease [141, 142, 143]. It may infrequently be transmitted via ingestion of the meat. The disease most frequently provokes acute meningitis, and hearing loss is a frequent complication. Less commonly, septicemia with or without infective endocarditis is encountered. Individuals under immunocompromised condition or with diabetes mellitus, alcoholism, and cancer are susceptible to infection at a greater risk. This lethal disease is relatively common in Southeast Asia, where the pig density is high. The incubation period ranges from a few hours to 2 weeks.

Yang et al. described four autopsy cases of fulminant S. suis infection. All patients suffered septicemia with DIC and toxic shock with multi-organ failure [144]. An autopsy case of human S. suis infection is presented. A few cocci were identified on the Giemsa-stained peripheral blood smear preparation (Figure 48). Acute multiorgan failure with bilateral adrenocortical hemorrhage (Waterhouse-Friderichsen syndrome) was the cause of death in this Japanese abattoir worker in his 30s. He had been healthy without any predisposing disease. Macrophages in the bone marrow, liver, and spleen revealed activated hemophagocytosis, representing a state with hypercytokinemia (Figure 49). No bacterial emboli were observed in the internal organs and tissues.

Figure 48.

Lethal septicemia caused by S. suis infection (peripheral blood, May-Giemsa). Diplococci are observed in the peripheral blood smear preparation sampled from an abattoir worker in his 30s. The pathogen is not phagocytized by neutrophils. By courtesy of Dr. Tadakazu Okoshi, Department of Diagnostic Pathology, Fukui Red Cross Hospital, Fukui, Japan.

Figure 49.

Lethal septicemia caused by S. suis infection (H&E; left: adrenal cortex, right: liver). Bilateral adrenal cortex reveals acute hemorrhage, indicating Waterhouse-Friderichsen syndrome. Kupffer cells in the sinusoid of the liver show active hemophagocytosis (arrow), representing a state of hypercytokinemia. Bacterial embolism is not associated.

12. Infection of Streptococcus pneumoniae

Streptococcus pneumoniae or Pneumococcus, a capsule-forming Gram-positive diplococcus, causes varied types of infection [145]. Pneumococcal diseases range from localized infections on the head and neck mucosae such as conjunctivitis, sinusitis, and otitis media to serious progressive diseases such as lobar pneumonia and meningitis [145]. Septic arthritis, osteomyelitis, peritonitis, and endocarditis may also be caused by S. pneumoniae. Small children below 5 years of age and the elderly persons are at the highest risk. Reportedly, 60% of small children are asymptomatic pneumococcal carriers in the nasal and pharyngeal mucosa [146]. Virtually, all children will become carriers at one time or another. It is noteworthy that adults living with small children at home have a higher carriage rate. Pneumococcal infections may spread from person to person via droplets/aerosols transmission. However, pneumococcal diseases themselves are not contagious: close contact with the patient does not increase the risk of infection. Capsule formation by the bacteria is an important pathogenetic factor (Figure 50). The virulence of pneumococcal infections is dependent on the capsular polysaccharide serotypes. There are more than 93 different capsular serotypes, and certain serotypes such as 1 and 7F are frequently seen in invasive diseases [147].

Figure 50.

Electron microscopy of Streptococcus pneumoniae in lobar pneumonia. Filamentous capsule formation is evident on the surface of cocci (arrows). The nucleoid is indicated with a red arrowhead. The cocci measuring 600–800 nm floating in the alveolar space escape from phagocytosis. Bar = 200 nm.

12.1 Pneumococcal infection on the head and neck mucosae

Conjunctivitis, sinusitis, and otitis media are often caused by pneumococcal infection. The patients should be regarded as asymptomatic carriers of S. pneumoniae on the throat.

Bacterial conjunctivitis, occasionally seen in adults, is commonly caused by infection of S. pneumoniae, Staphylococcus epidermidis, Staphylococcus aureus (often with methicillin resistance), or Pseudomonas aeruginosa. Aged patients hospitalized for a long period are susceptible to conjunctivitis caused by MRSA. Pneumococcal keratitis and endophthalmitis may also happen [148]. It has been clarified that nonencapsulated S. pneumoniae may cause conjunctivitis [149]. Figure 51 illustrates Gram-stained eye discharge from a patient with pneumococcal conjunctivitis. Capsule formation is recognized in this case.

Figure 51.

Pneumococcal conjunctivitis (eye discharge, Gram stain). Capsule-forming Gram-positive diplococci are seen, not phagocytized by neutrophils. Transparent haloe around the coccus indicates the capsule. S. pneumoniae was cultured on the plate.

S. pneumoniae is an important pathogen in chronic sinusitis among children younger than 5 years: The median age is 24 months. Chronic otitis media represents a common comorbid condition. Co-infection with Haemophilus influenzae, Moraxella catarrhalis, or S. aureus may be encountered [150].

Bacterial triad causing otitis media includes S. pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. S. pyogenes may also provoke acute otitis media, which is common among infants under the age of 2 years. Secretory otitis media or otitis media with effusion, a chronic inflammatory condition, is seen among children aged 3–7 years [151].

12.2 Localized skin infection of S. pneumoniae

Infection of S. pneumoniae uncommonly occurs in the skin and soft tissue [152, 153]. Direct spread of the bacteria by autoinoculation from the nose to the skin through a minor trauma can be an explanation for the skin involvement. Superficial skin infection may occur in previously healthy children [154]. Reportedly, cases with connective tissue diseases such as systemic lupus erythematosus are vulnerable to pneumococcal skin/soft tissue infection [155]. Diabetes mellitus may accelerate pneumococcal skin infection [156]. Other risk factors include human immunodeficiency virus infection and corticosteroid treatment. Hematogenous spread of the microbe is speculated as a pathogenesis of cellulitis in the immunocompromised adults. The bacteria can be isolated not only from the infected tissue but also from the blood. Lethal Fournier’s gangrene (non-clostridial gas gangrene) can be caused by S. pneumoniae, as shown in Figure 20.

In Figure 52, ecthyma caused by S. pneumoniae is presented. A 94-year-old woman suffered from febrile cellulitis in her left lower leg. The lesion showed clustered skin ulceration and was intractable against medical treatment. The lesion was thus surgically removed. Colonies of Gram-positive cocci, distributed in the abscess lesion, were immunoreactive for pneumococcal antigens. Streptococcal, staphylococcal, and enterococcal antigens were undetectable. Pneumococcal genome was amplified by PCR analysis.

Figure 52.

Pneumococcal ecthyma (left: surgical specimen after formalin fixation, center: pneumococcal antigens, right: streptococcal antigens, inset: Gram stain). Intractable cellulitis (ecthyma) accompanying clustered ulceration was surgically resected from the left lower leg of a 94-year-old woman. Gram-positive cocci in the abscess lesion are immunoreactive for pneumococcal antigens but negative for streptococcal antigens. Pneumococcal genome was PCR-amplified.

12.3 Pneumococcal meningitis

Bacterial meningitis is caused by capsule-forming bacteria such as S. pneumoniae, Neisseria meningitidis (Meningococcus), Haemophilus influenzae, Klebsiella pneumoniae, and group B Streptococcus. S. pneumoniae is the most common etiology of bacterial meningitis in adults and the second most common cause of meningitis in children older than age 2. Transmission from person to person happens through coughing, sneezing, and intimate kissing. The bacteria reach the meninges via the bloodstream. Direct extension of the bacteria from otitis media to meningeal space may also happen. Pneumococcal meningitis may occur following head injury. Persons with uncontrolled diabetes mellitus or after splenectomy show an increased risk of this disease. To make a diagnosis, bacterial culture from both the spinal tap and blood is essential. Prompt diagnosis is requested to get the best therapeutic outcome. Pneumococcal vaccines are effective in preventing infection [157, 158].

Autopsy case analysis of pneumococcal meningitis revealed that in addition to purulent meningeal inflammation, medium to large-sized cerebral arteries were often involved, resulting in thrombosis, brain infarction, and cerebral hemorrhage [159].

Figure 53 illustrates lethal pneumococcal meningitis as a sequela of infected epidural hematoma [160]. A diabetic man in his 60s complained of sudden back pain, and subsequent imaging evaluation disclosed the formation of spinal epidural abscess as a sequela of secondary infection of epidural hematoma at L2-L4 levels. Ten days after hospitalization, back pain recurred, and coma followed. He died of multi-organ failure on the 12th day of hospitalization. Autopsy disclosed massive pus accumulation and hemorrhage both in the lumbar epidural space and brain, where pneumococcal antigens were demonstrated. The final anatomical diagnosis was fulminant pneumococcal meningoencephalitis evolving from infected lumbar epidural hematoma.

Figure 53.

Pneumococcal meningitis (left: gross appearance at autopsy, center: H&E, right: pneumococcal antigens). Yellow-colored purulent exudation is seen in the hyperemic meningeal space. Microscopically, neutrophils are clustered outside the brain parenchyma. Pneumococcal antigens are proven mainly in the cytoplasm of neutrophils.

12.4 Pneumococcal pneumonia

S. pneumoniae is the leading cause of community-acquired pneumonia, accompanying significant morbidity and mortality among adults. The incidence of pneumococcal pneumonia is highest in the elderly persons and in individuals with medical comorbidity. Immunodeficiency may increase a chance of getting pneumonia. Antimicrobial therapy and vaccination are central to the clinical approach to the pneumococcal disease [161, 162].

Classically, pneumococcal pneumonia produces lobar pneumonia, diffusely involving a whole lobe of the lung without necrosis and destruction of the preexisting lung structure [163]. Consolidation of the entire lobe of the lung is seen at autopsy. Gram-positive cocci are scattered among intra-alveolar exudation consisting of fibrin and neutrophils. Often times, the capsule-forming cocci are not phagocytized by neutrophils (Figure 54). At present in the antibiotics era, however, many cases are limited to acute non-necrotizing bronchopneumonia without progression to lobar involvement. In Figure 55, lethal pneumococcal lobar pneumonia in a pre-antibiotics era is demonstrated. Two lobes were massively involved, and cocci expressing pneumococcal antigens were actively phagocytized by neutrophils. Of note is that the antigenicity was preserved even after very long fixation in formalin for more than 70 years [16].

Figure 54.

Pneumococcal lobar pneumonia (left: H&E, right: Gram). Neutrophils are diffusely infiltrated in the alveolar space without destruction of the preexisting lung tissue structure. Gram-positive diplococci with capsule formation are seen outside neutrophils. The capsule prevents from phagocytosis.

Figure 55.

Lethal lobar pneumonia seen 70 years ago (left: gross appearance after formalin fixation, center: H&E, right: pneumococcal antigens). Both lobes of the lung are massively and homogeneously consolidated. Neutrophils reveal diffuse and nondestructive infiltration in the alveolar space. The cytoplasm of neutrophils contains pneumococcal antigens, which is tolerant to long fixation in formalin for 70 years.

12.5 Pneumococcal endocarditis

S. pneumoniae is responsible for <2% of infective endocarditis. It predominantly occurs in male patients aged 65 years or older. Alcoholism and smoking are predisposing factors for pneumococcal endocarditis. The disease causes rapidly progressive endocarditis, requiring life-saving early cardiac surgery. It is preventable by vaccination [164, 165].

Figure 56 demonstrates pneumococcal endocarditis involving the aortic valve of 63-year-old man. Surgical valvular replacement therapy was performed. Among the fibrinopurulent inflammatory lesions, Gram-positive cocci immunoreactive for pneumococcal antigens but not for streptococcal antigen were identified.

Figure 56.

Pneumococcal endocarditis (left: H&E, center: pneumococcal antigens, right: streptococcal antigens). The aortic valve surgically resected from a man in his 60s shows abscess formation with fibrinous exudation. Pneumococcal antigens are positive in the cytoplasm of neutrophils, whereas streptococcal antigens are undetectable.

12.6 Fulminant pneumococcal infection

Streptococcus pneumoniae may cause fulminant pneumococcal infection, a life-threatening progressive infectious disease accompanying multi-organ failure [166, 167]. “Purpura fulminans” represents an extreme skin manifestation of disseminated intravascular coagulopathy and Waterhouse-Friderichsen syndrome (caused by bilateral adrenal hemorrhage). The disease is often seen in splenectomized or immunosuppressed patients [168, 169, 170]. It is also seen in healthy patients without a history of splenectomy [171]. Splenectomy may also accelerate group A beta-streptococcal infection [172].

A term-pregnant woman in her 20s manifested high fever and systemic skin rash. She had a history of splenectomy by a traffic accident 10 years earlier. The total clinical course was just 2 days: septic shock provoked disseminated intravascular coagulopathy and generalized petechiae. The disease represented puerperal fever. At autopsy, a dead fetus was observed in the enlarged uterus. In the placenta, there were multifocal small abscesses infected with cocci with Gram-positivity and immunoreactivity of pneumococcal antigens (Figure 57). Alpha-hemolytic Streptococcus was isolated from the blood. Cytokine storm-activated hemophagocytosis was observed in the bone marrow and liver. Neither gangrene of the extremity nor pneumonia was complicated. The final diagnosis was fulminant pneumococcal infection as overwhelming postsplenectomy infection.

Figure 57.

Pneumococcal plancentitis, provoking fulminant pneumococcal infection (left: H&E, right: pneumococcal antigens). Abscess formation is observed in a term placenta of a woman in her 20s. Pneumococcal antigens are demonstrated in the abscess lesion. Her spleen had been resected 10 years earlier. Toxic shock-like syndrome killed her and her baby in 2 days.

Another case (60-year-old male patient) of fulminant pneumococcal infection is displayed in Figure 58. Total clinical course was 3 days. The small-sized spleen was observed. Neither limb gangrene nor pneumonia was observed. The entry of S. pneumoniae was unclear. Septic emboli were distributed throughout the body. The glomeruli showed bacterial microemboli caused by capsule-forming Gram-positive cocci immunohistochemically expressing pneumolysin (a pneumococcal hemolytic exotoxin). The capsule formation is evident with the colloidal iron method that stains acidic mucosubstances blue.

Figure 58.

Fulminant pneumococcal infection: septic embolus in the glomerulus (left: H&E, center: colloidal iron, right: pneumolysin). A 60-year-old male patient died in 3 days. At autopsy, septic emboli were seen throughout the body. The glomerulus shows coccal microembolism. Gram-positive cocci reveal capsule-formation evidenced by colloidal ion stain and immunoreactivity of pneumolysin, a pneumococcal hemolytic exotoxin. By courtesy of Dr. Etsuo Okazaki at Department of Diagnostic Pathology, Tachikawa General Hospital, Niigata, Japan.

13. Conclusions

Various aspects of pathological features of streptococcal infections were presented. Streptococcus is one of the most popular bacteria infectious to the human body. It is seen as normal flora, but localized or invasive infections may happen. Fulminant and lethal streptococcal infections belong to emergency disorders, and early diagnosis must be of critical importance. Immunohistochemical evaluation of streptococcal and pneumococcal antigens using formalin-fixed, paraffin-embedded sections can be a key technique to confirm the etiology of infection.


The author deeply thanks clinicians and diagnostic pathologists who provided him precious case samples as diagnostic consultations. There is no special funding for the present study.

Conflict of interest

The author declares no conflict of interest in the present article.


  1. 1. Okuno R, Sadamasu T, Ogata K, Tominaga K, Katsukawa C, Shima T, et al. Antibiotic resistance of group A β-hemolytic streptococcus (Streptococcus pyogenes) isolates collected from 14 prefectures in Japan, 2007–2010. Infectious Agents Surveillance Report. 2012;33:214-215 (in Japanese)
  2. 2. Brook I. Treatment challenges of group a beta-hemolytic streptococcal pharyngo-tonsillitis. International Archives of Otorhinolaryngology. 2017;21(03):286-296. DOI: 10.1055/s-0036-1584294
  3. 3. Kim Y-H, Lee SY. Antibiotic resistance of viridans group streptococci isolated from dental plaques. Biocontrol Science. 2020;25(3):173-178. DOI: 10.4265/bio.25.173
  4. 4. Raabe VN, Shane AL. Group B streptococcus (Streptococcus agalactiae). Microbiology Spectrum. 2019;7(2):10.1128. DOI: 10.1128/microbiolspec.GPP3-0007-2018
  5. 5. Reinert RR. The antimicrobial resistance profile of Streptococcus pneumoniae. Clinical Microbiology and Infection. 2009;15(3):7-11. DOI: 10.1111/j.1469-0691.2009.02724.x
  6. 6. Cherazard R, Epstein M, Doan TL, Salim T, Bharti S, Smith MA. Antimicrobial resistant Streptococcus pneumoniae: Prevalence, mechanisms, and clinical implications. American Journal of Therapeutics. 2017;24(3):e361-e369. DOI: 10.1097/MJT.0000000000000551
  7. 7. Brooks LRK, Mias GI. Streptococcus pneumoniae's virulence and host immunity: Aging, diagnostics, and prevention. Frontiers in Immunology. 2018;9:1366. DOI: 10.3389/fimmu.2018.01366
  8. 8. Fieber C, Kovarik P. Responses of innate immune cells to group A Streptococcus. Frontiers in Cellular and Infection Microbiology. 2014;4:140. DOI: 10.3389/fcimb.2014.00140
  9. 9. McCormick JK, Yarwood JM, Schlievert PM. Toxic shock syndrome and bacterial superantigens: An update. Annual Review of Microbiology. 2001;55:77-104
  10. 10. Llewelyn M, Cohen J. Superantigens: Microbial agents that corrupt immunity. The Lancet Infectious Diseases. 2002;2:156-162. DOI: 10.1016/s1473-3099(02)00222-0
  11. 11. Alouf JE, Muller-Alouf H. Staphylococcal and streptococcal superantigens: Molecular, biological and clinical aspects. International Journal of Medical Microbiology. 2003;292:429-440. DOI: 10.1078/1438-4221-00232
  12. 12. Terao Y. The virulence factors and pathogenic mechanisms of Streptococcus pyogenes. Journal of Oral Biosciences. 2012;54(2):96-100. DOI: 10.1016/j.job.2012.02.004
  13. 13. Tsutsumi Y. Pathology of skin infections. In: Series: Dermatology—Laboratory and Clinical Research (BISAC: HEA039130). NY, USA: Nova Science Publishers; 2013. 394 p. ISBN: 978-1-62808-518-1
  14. 14. Tsutsumi Y. Low-specificity and high-sensitivity immunostaining for demonstrating pathogens in formalin-fixed, paraffin-embedded sections. In: Streckfus CF, editor. Immunohistochemistry: The Ageless Biotechnology. London, UK: IntechOpen; 2019. 46 p. DOI: 10.5772/intechopen.85055
  15. 15. Tsutsumi Y. Cytological diagnosis of infectious diseases: Identification of pathogens and recognition of cellular reactions. In: Saxena SK, Prakash H, editors. Innate Immunity in Health and Disease, IntechOpen. London: UK; 2021. 63 p. DOI: 10.5772/intechopen.95578
  16. 16. Tsutsumi Y. Pitfalls and caveats in applying chromogenic immunostaining to histopathological diagnosis. Cell. 2021;10(6):1501. 57 p. DOI: 10.3390/cells10061501
  17. 17. Zacharioudaki ME, Galanakis E. Management of children with persistent group A streptococcal carriage. Expert Review of Anti-Infective Therapy. 2017;15(8):787-795. DOI: 10.1080/14787210.2017.1358612
  18. 18. Fiedler T, Köller T, Kreikemeyer B. Streptococcus pyogenes biofilms-formation, biology, and clinical relevance. Frontiers in Cellular and Infection Microbiology. 2015;5:15. DOI: 10.3389/fcimb.2015.00015
  19. 19. Cravez EM, Nasreddine AY, Halim A. Persistent Streptococcus pyogenes infection of the forearm following blunt trauma. Case Reports in Plastic Surgery and Hand Surgery. 2020;7(1):139-144. DOI: 10.1080/23320885.2020.1858715
  20. 20. Stulberg DL, Penrod MA, Blatny RA. Common bacterial skin infections. American Family Physician. 2002;66:119-124. PMID: 12126026
  21. 21. Bonnetblanc JM, Bedane C. Erysipelas: Recognition and management. American Journal of Clinical Dermatology. 2003;4:157-163. DOI: 10.2165/00128071-200304030-00002
  22. 22. Damstra RJ, van Steensel MA, Boomsma JH, Nelemans P, Veraart JC. Erysipelas as a sign of subclinical primary lymphedema: A prospective quantitative scintigraphic study of 40 patients with unilateral erysipelas of the leg. The British Journal of Dermatology. 2008;158:1210-1215. DOI: 10.1111/j.1365-2133.2008.08503.x
  23. 23. Joseph M, Camilon M, Kang T. A woman with unilateral rash and fever: Cellulitis in the setting of lymphedema. Case Reports in Emergency Medicine. 2015;2015:252495. DOI: 10.1155/2015/252495
  24. 24. Koster JB, Kullberg BJ, van der Meer JW. Recurrent erysipelas despite antibiotic prophylaxis: An analysis from case studies. The Netherlands Journal of Medicine. 2007;65:89-94
  25. 25. Harman-Adams H, Banvard C, Juckett G. Impetigo: Diagnosis and treatment. American Family Physician. 2014;90(4):229-235
  26. 26. Stevens DL, Bryant AE: Impetigo, Erysipelas and cellulitis. Streptococcus pyogenes: Basic Biology to Clinical Manifestations [Internet]. 2016. Available from:
  27. 27. Adachi J, Endo K, Fukuzumi T, Tanigawa N, Aoki T. Increasing incidence of streptococcal impetigo in atopic dermatitis. Journal of Dermatological Science. 1998;17(1):45-53. DOI: 10.1016/s0923-1811(97)00072-8
  28. 28. Brilliant LC. Perianal streptococcal dermatitis. American Family Physician. 2000;61(2):391-393
  29. 29. Bartlett A, Bola S, Williams R. Acute tonsillitis and its complications: An overview. Journal of the Royal Naval Medical Service. 2015;101(1):69-73. DOI: 10.1136/jrnms-101-169
  30. 30. Ikram M, Khan AA, Ahmed M, Siddiqui T, Mian MY. The histopathology of routine tonsillectomy specimens: Results of a study and review of literature. Ear, Nose, & Throat Journal. 2000;79(11):880-882
  31. 31. Tang X, Hori S, Osamura RY, Tsutsumi Y. Reticular crypt epithelium and intraepithelial lymphoid cells in the hyperplastic human palatine tonsil. An immunohistochemical analysis. Pathology International. 1995;45(1):34-44. DOI: 10.1111/j.1440-1827.1995.tb03377.x
  32. 32. Mizutani Y, Shiogama K, Onouchi T, Sakurai K, Inada K, Tsutsumi Y. Enzyme-labeled antigen method: Development and application of the novel approach for identifying plasma cells locally producing disease-specific antibodies in inflammatory lesions. Acta Histochemica et Cytochemica. 2016;49(1):7-19. DOI: 10.1267/ahc.15030
  33. 33. Onouchi T, Mizutani Y, Shiogama K, Inada K, Okada T, Naito K, et al. Application of an enzyme-labeled antigen method for visualizing plasma cells producing antibodies against Strep A, a carbohydrate antigen, of Streptococcus pyogenes in recurrent tonsillitis. Microbiology and Immunology. 2015;59:13-27. DOI: 10.1111/1348-0421.12213
  34. 34. Basetti S, Hodgson J, Rawson TM, Majeed A. Scarlet fever: A guide for general practitioners. London Journal of Primary Care (Abingdon). 2017;9(5):77-79. DOI: 10.1080/17571472.2017.1365677
  35. 35. Pardo S, Perera TB. Scarlet fever. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. Available from:
  36. 36. Hurst JR, Brouwer S, Walker MJ, McCormick JK. Streptococcal superantigens and the return of scarlet fever. PLoS Pathogens. 2021;17(12):e1010097. DOI: 10.1371/journal.ppat.1010097
  37. 37. Lamb L, McDonald W, Scudamore C, Tan L, Lynskey N, Sriskandan S. The effect of trauma on invasive group A streptococcal disease. Lancet. 2015;385(Suppl. 1):S60. DOI: 10.1016/S0140-6736(15)60375-0
  38. 38. Goldberg BE, Sulman CG, Chusid MJ. Group A beta streptococcal infections in children after oral or dental trauma: A case series of 5 patients. Ear, Nose, & Throat Journal. 2015;94(1):e1-e6
  39. 39. Bhagat N, Nagori S, Zarbin M. Post-traumatic infectious endophthalmitis. Survey of Ophthalmology. 2011;56(3):214-251. DOI: 10.1016/j.survophthal.2010.09.002
  40. 40. Verbraeken H, Rysselaere M. Post-traumatic endophthalmitis. European Journal of Ophthalmology. 1994;4(1):1-5. DOI: 10.1177/112067219400400101
  41. 41. Henderson DK, Edwards JE Jr, Montgomerie JZ. Hematogenous Candida endophthalmitis in patients receiving parenteral hyperalimentation fluids. The Journal of Infectious Diseases. 1981;143(5):655-661. jstor: stable/30113284
  42. 42. Gupta A, Srinivasan R, Kaliaperumal S, Saha I. Post-traumatic fungal endophthalmitis—A prospective study. Eye (London, England). 2008;22(1):13-17. DOI: 10.1038/sj.eye.6702463
  43. 43. Sekhar GC, Vance G, Otton S, Kumar SV, Stanley JN, Rao GN. Ocular manifestations of Hansen's disease. Documenta Ophthalmologica. 1994;87(3):211-221. DOI: 10.1007/BF01203851
  44. 44. Tsutsumi Y. Pathology of gangrene. In: Kırmusaoğlu S, Bhardwaj SB, editors. Pathogenic Bacteria. 2020. 52 p. DOI: 10.5772/intechopen.93505
  45. 45. Kotrappa KS, Bansal RS, Amin NM. Necrotizing fasciitis. American Family Physician. 1996;53:1691-1697
  46. 46. Shimizu T, Tokuda Y. Necrotizing fasciitis. Internal Medicine. 2010;49:1051-1057. DOI: 10.2169/internalmedicine.49.2964
  47. 47. Machado NO. Necrotizing fasciitis: The importance of early diagnosis, prompt surgical debridement and adjuvant therapy. North American Journal of Medical Sciences. 2011;3:107-118. DOI: 10.4297/najms.2011.3107
  48. 48. Schwartz RA. Dermatologic Manifestations of Necrotizing Fasciitis. 2011. Available from:
  49. 49. Lancerotto L, Tocco I, Salmaso R, Vindigni V, Bassetto F. Necrotizing fasciitis. Classification, diagnosis, and management. Journal of Trauma and Acute Care Surgery. 2012;72:560-566. DOI: 10.1097/TA.0b013e318232a6b3
  50. 50. Center for Disease Control and Prevention. Necrotizing fasciitis: A rare disease, especially for the healthy. 2012. Available from:
  51. 51. Stens O, Wardi G, Kinney M, Shin S, Papamatheakis D. Stenotrophomonas maltophilia necrotizing soft tissue infection in an immunocompromised patient. Case Reports in Critical Care. 2018;2018:1475730. DOI: 10.1155/2018/1475730
  52. 52. Arnold CJ, Garrigues G, St Geme JW 3rd, Sexton DJ. Necrotizing fasciitis caused by Haemophilus influenzae serotype f. Journal of Clinical Microbiology. 2014;52:3471-3474. DOI: 10.1128/JCM.01460-14
  53. 53. Bessman AN, Wagner W. Nonclostridial gas gangrene. Report of 48 cases and review of the literature. Journal of the American Medical Association. 1975;233:958-963. DOI: 10.1001/jama.1975.03260090024014
  54. 54. Hubens G, Carly B, De Boeck H, Vansteenland H, Wylock P. "Spontaneous" non clostridial gas gangrene: Case report and review of the literature. Acta Chirurgica Belgica. 1989;89:25-28
  55. 55. Weisenfeld LS, Luzzi A, Picciotti J. Nonclostridial gas gangrene. The Journal of Foot Surgery. 1990;29:141-146
  56. 56. Jain AKC, Viswanath S. Non-clostridial gas gangrene in diabetic lower limbs with peripheral vascular disease. OA Case Reports. 2013;2(9):83. DOI: 10.13172/2052-0077-2-9-794
  57. 57. Takazawa K, Otsuka H, Nakawaga Y, Inokuchi S. Clinical features of non-clostridial gas gangrene and risk factors for in-hospital mortality. The Tokai Journal of Experimental and Clinical Medicine. 2015;40:124-129
  58. 58. Shigemoto R, Anno T, Kawasaki F, Irie S, Yamamoto M, Tokuoka S, et al. Non-clostridial gas gangrene in a patient with poorly controlled type 2 diabetes mellitus on hemodialysis. Acta Diabetologica. 2018;55:99-101. DOI: 10.1007/s00592-017-1038-2
  59. 59. Li CM, Chen PL, Ho YR. Non-clostridial gas gangrene caused by Klebsiella pneumoniae: A case report. Scandinavian Journal of Infectious Diseases. 2001;33:629-630. DOI: 10.1080/00365540110026728
  60. 60. Overcamp M, Pfohl M, Klier D, Domres B, Schmülling RM. Spontaneous gas-forming myonecrosis caused by group B streptococci and peptostreptococci. The Clinical Investigator. 1992;70:441-443. DOI: 10.1007/BF00235529
  61. 61. Carr NJ. The pathology of acute appendicitis. Annals of Diagnostic Pathology. 2000;4:46-58. DOI: 10.1016/s1092-9134(00)90011-x
  62. 62. Bhangu A, Søreide K, Di Saverio S, Assarsson JH, Drake FT. Acute appendicitis: Modern understanding of pathogenesis, diagnosis, and management. Lancet. 2015;386:1278-1287. DOI: 10.1016/S0140-6736(15)00275-5
  63. 63. Nordin AB, Diefenbach K, Sales SP, Christensen J, Besner GE, Kenney BD. Gangrenous appendicitis: No longer complicated. Journal of Pediatric Surgery. 2019;54:718-722. DOI: 10.1016/j.jpedsurg.2018.10.064
  64. 64. Cunningham MW. Pathogenesis of group A streptococcal infections. Clinical Microbiology Reviews. 2000;13:470-511. DOI: 10.1128/cmr.13.3.470-511.2000
  65. 65. Fox KL, Born MW, Cohen MA. Fulminant infection and toxic shock syndrome caused by Streptococcus pyogenes. The Journal of Emergency Medicine. 2002;22:357-366. DOI: 10.1016/s0736-4679(02)00436-5
  66. 66. Overkamp D, Pfohl M, Klier R, Domres B, Schmülling R-M. Spontaneous gas-forming bacterial myonecrosis caused by group B streptococci and peptostreptococci. The Clinical Investigator. 1992;70:441-443. DOI: 10.1007/BF00235529
  67. 67. Humar D, Datta V, Bast DJ, Beall B, De Azavedo JC, Nizet V. Streptolysin S and necrotising infections produced by group G streptococcus. Lancet. 2002;359:124-129. DOI: 10.1016/S0140-6736(02)07371-3
  68. 68. Stevens DL. Streptococcal toxic-shock syndrome: Spectrum of disease, pathogenesis, and new concepts in treatment. Emerging Infectious Diseases. 1995;1:69-78. DOI: 10.3201/eid0103.950301
  69. 69. Tajiri T, Tate G, Miura K, Masuda S, Ohike N, Kunimura T, et al. Sudden death caused by fulminant bacterial infection: Background and pathogenesis of Japanese adult cases. Internal Medicine. 2008;47:1499-1504. DOI: 10.2169/internalmedicine.47.1160
  70. 70. Bryant AE, Bayer CR, Huntington JD, Stevens DL. Group A streptococcal myonecrosis: Increased vimentin expression after skeletal-muscle injury mediates the binding of Streptococcus pyogenes. The Journal of Infectious Diseases. 2006;193:1685-1689. DOI: 10.1086/504261
  71. 71. Shibuya H, Terashi H, Kurata S, Ishii Y, Takayasu S, Murakami I, et al. Gas gangrene following sacral pressure sores. The Journal of Dermatology. 1994;21:518-523. DOI: 10.1111/j.1346-8138.1994.tb01786.x
  72. 72. Shiogama K, Onouchi T, Mizutani Y, Sakurai K, Inada K, Tsutsumi Y. Visualization of neutrophil extracellular traps and fibrin meshwork in human fibrinopurulent inflammatory lesions. I. Light microscopic study. Acta Histochemica et Cytochemica. 2016;49(4):109-116. DOI: 10.1267/ahc.16015
  73. 73. Onouchi T, Shiogama K, Matsui T, Mizutani Y, Sakurai K, Inada K, et al. Visualization of neutrophil extracellular traps and fibrin meshwork in human fibrinopurulent inflammatory lesions. II. Ultrastructural study. Acta Histochemica et Cytochemica. 2016;49(4):117-123. DOI: 10.1267/ahc.16016
  74. 74. Spaulding AR, Salgado-Pabón W, Kohler PL, Horswill AR, Leung DY, Schlievert PM. Staphylococcal and streptococcal superantigen exotoxins. Clinical Microbiology Reviews. 2013;26:422-447. DOI: 10.1128/CMR.00104-12
  75. 75. Lin L, Xu L, Lv W, Han L, Xiang Y, Fu L, et al. An NLRP3 inflammasome-triggered cytokine storm contributes to Streptococcal toxic shock-like syndrome (STSLS). PLoS Pathogens. 2019;15(6):e1007795. DOI: 10.1371/journal.ppat.1007795
  76. 76. Lamerton AJ. Fournier's gangrene: Non-clostridial gas gangrene of the perineum and diabetes mellitus. Journal of the Royal Society of Medicine. 1986;79:212-215. DOI: 10.1177/014107688607900408
  77. 77. Eke N. Fournier's gangrene: A review of 1726 cases. The British Journal of Surgery. 2000;87:718-728. DOI: 10.1046/j.1365-2168.2000.01497.x
  78. 78. Thwaini A, Khan A, Malik A, Cherian J, Barua J, Shergill I, et al. Fournier's gangrene and its emergency management. Postgraduate Medical Journal. 2006;82:516-519. DOI: 10.1136/pgmj.2005.042069
  79. 79. Erol B, Tuncel A, Hanci V, Tokgoz H, Yildiz A, Akduman B, et al. Fournier's gangrene: Overview of prognostic factors and definition of new prognostic parameter. Urology. 2010;75:1193-1198. DOI: 10.1016/j.urology.2009.08.090
  80. 80. Heiner JD, Eng KD, Bialowas TA, Devita D. Fournier's gangrene due to masturbation in an otherwise healthy male. Case Reports in Emergency Medicine. 2012;2012:Article ID 154025. DOI: 10.1155/2012/154025
  81. 81. Kato S, Yanazaki M, Hayashi K, Satoh F, Isobe I, Tsutsumi Y. Fulminant group A streptococcal infection without gangrene in the extremities: Analysis of five autopsy cases. Pathology International. 2018;68:419-424. DOI: 10.1111/pin.12678
  82. 82. Ooe K, Udagawa H. A new type of fulminant group A streptococcal infection in obstetric patients: Report of two cases. Human Pathology. 1997;28:509-512. DOI: 10.1016/s0046-8177(97)90043-5
  83. 83. Tardieu SC, Schmidt E. Group A Streptococcus septic shock after surgical abortion: A case report and review of the literature. Case Reports in Obstetrics and Gynecology. 2017: Article ID 6316739. DOI: 10.1155/2017/6316739
  84. 84. Tormos LM, Schandl CA. The significance of adrenal hemorrhage: Undiagnosed Waterhouse-Friderichsen syndrome, a case series. Journal of Forensic Sciences. 2013;58:1071-1074. DOI: 10.1111/1556-4029.12099
  85. 85. Fujiwara F, Hibi S, Imashuku S. Hypercytokinemia in hemophagocytic syndrome. The American Journal of Pediatric Hematology/Oncology. 1993;15:92-98. DOI: 10.1097/00043426-199302000-00012
  86. 86. Prakash J, Singh VP. Changing picture of renal cortical necrosis in acute kidney injury in developing country. World Journal of Nephrology. 2015;4(5):480-486. DOI: 10.5527/wjn.v4.i5.480
  87. 87. Coykendall AL. Classification and identification of the viridans streptococci. Clinical Microbiology Reviews. 1989;2(3):315-328. DOI: 10.1128/CMR.2.3.315
  88. 88. Maeda Y, Goldsmith CE, Coulter WA, Mason C, Dooley J, Lowery C, et al. The viridans group streptococci. Reviews in Medical Microbiology. 2010;21(4):69-79. DOI: 10.1097/MRM.0b013e32833c68fa
  89. 89. Tanzer JM, Livingston J, Thompson AM. The microbiology of primary dental caries in humans. Journal of Dental Education. 2001;65:1028-1037
  90. 90. Forssten SD, Björklund M, Ouwehand AC. Streptococcus mutans, caries and simulation models. Nutrients. 2010;2(3):290-298. DOI: 10.3390/nu2030290
  91. 91. Lamont RJ, Demuth DR, Davis CA, Malamud D, Rosan B. Salivary-agglutinin-mediated adherence of Streptococcus mutans to early plaque bacteria. Infection and Immunity. 1991;59(10):3446-3450. DOI: 10.1128/iai.59.10.3446-3450.1991
  92. 92. Marsh PD. Are dental diseases examples of ecological catastrophes? Microbiology-Sgm. 2003;149:279-294. DOI: 10.1099/mic.0.26082-0
  93. 93. Zero DT. Sugars—The arch criminal? Caries Research. 2004;38:277-285. DOI: 10.1159/000077767
  94. 94. Shellis RP, Dibdin GH. Analysis of the buffering systems in dental plaque. Journal of Dental Research. 1988;67:438-446. DOI: 10.1177/00220345880670020101
  95. 95. Davey ME, O'toole GA. Microbial biofilms: From ecology to molecular genetics. Microbiology and Molecular Biology Reviews. 2000;64(4):847-867. DOI: 10.1128/MMBR.64.4.847-867.2000
  96. 96. Mayooran B, Robin S, John RT. Dental caries is a preventable infectious disease. Australian Dental Journal. 2000;45:235-245. DOI: 10.1111/j.1834-7819.2000.tb00257.x
  97. 97. Trahan L, Bareil M, Gauthier L, Vadeboncoeur C. Transport and phosphorylation of xylitol by a fructose phosphotransferase system in Streptococcus mutans. Caries Research. 1985;19:53-63. DOI: 10.1159/000260829
  98. 98. Sheiham A. Dental caries in developed and developing countries. Caries Research. 1990;24:43. DOI: 10.1159/000261324
  99. 99. Law V, Seow WK, Townsend G. Factors influencing oral colonization of mutans streptococci in young children. Australian Dental Journal. 2007;52:93-100. DOI: 10.1111/j.1834-7819.2007.tb00471.x
  100. 100. Nobbs AH, Lamont RJ, Jenkinson HF. Streptococcus adherence and colonization. Microbiology and Molecular Biology Reviews. 2009;73(3):407-450. DOI: 10.1128/MMBR.00014-09
  101. 101. Rispens T, Vidarsson G. Chapter 9: Human IgG Subclasses. In: Ackerman ME, Nimmerjahn F, editors. Antibody Fc. Linking Adaptive and Innate Immunity. Academic Press; 2014. pp. 159-177. ISBN: 978-0-12-394802-1. DOI: 10.1016/B978-0-12-394802-1.00009-1
  102. 102. Xu H, Sobue T, Thompson A, Xie Z, Poon K, Ricker A, et al. Streptococcal co-infection augments Candida pathogenicity by amplifying the mucosal inflammatory response. Cellular Microbiology. 2014;16(2):214-231. DOI: 10.1111/cmi.12216
  103. 103. Howlett SA. Acute streptococcal esophagitis. Gastrointestinal Endoscopy. 1979;25(4):150-151. DOI: 10.1016/S0016-5107(79)73406-7
  104. 104. Ren R, Wang Z, Sun H, Gao X, Sun G, Peng L, et al. The gastric mucosal-associated microbiome in patients with gastric polyposis. Scientific Reports. 2018;8(1):13817. DOI: 10.1038/s41598-018-31738-2
  105. 105. Tunkel AR, Sepkowitz KA. Infections caused by Viridans streptococci in patients with neutropenia. Clinical Infectious Diseases. 2002;34:1524-1529. DOI: 10.1086/340402
  106. 106. Walsh TJ, Belitsos NJ, Hamilton SR. Bacterial esophagitis in immunocompromised patients. Archives of Internal Medicine. 1986;146(7):1345-1348. DOI: 10.1001/archinte.1986.00360190119016
  107. 107. Kang HJ, Coulibaly F, Proft T, Baker EN. Crystal structure of Spy0129, a Streptococcus pyogenes class B sortase involved in pilus assembly. PLoS One. 2011;6(1):e15969. DOI: 10.1371/journal.pone.0015969
  108. 108. Wang Y, Yi L, Wang S, Fan H, Ding C, Mao X, et al. Crystal structure and identification of two key amino acids involved in AI-2 production and biofilm formation in Streptococcus suis LuxS. PLoS One. 2015;10(10):e0138826. DOI: 10.1371/journal.pone.0138826
  109. 109. Sutton GL, Miller RC, Robinson LP. Infectious crystalline keratopathy. Australian and New Zealand Journal of Ophthalmology. 1990;18(2):151-153. DOI: 10.1111/j.1442-9071.1990.tb00606.x
  110. 110. Sharma N, Vajpayee RB, Pushker N, Vajpayee M. Infectious crystalline keratopathy. The CLAO Journal. 2000;26(1):40-43
  111. 111. Doern CD, Burnham CA. It's not easy being green: The viridans group streptococci, with a focus on pediatric clinical manifestations. Journal of Clinical Microbiology. 2010;48(11):3829-3835. DOI: 10.1128/JCM.01563-10
  112. 112. Parks T, Barrett L, Jones N. Invasive streptococcal disease: A review for clinicians. British Medical Bulletin. 2015;115(1):77-89. DOI: 10.1093/bmb/ldv027
  113. 113. Finegold SM. Aspiration pneumonia. Reviews of Infectious Diseases. 1991;13(Suppl. 9):S737-S742. DOI: 10.1093/clinids/13.supplement_9.s737
  114. 114. Freitas M, Castelo A, Petty G, Gomes CE, Carvalho E. Viridans streptococci causing community acquired pneumonia. Archives of Disease in Childhood. 2006;91(9):779-780. DOI: 10.1136/adc.2006.094847
  115. 115. Choi SH, Cha SI, Choi KJ, Lim JK, Seo H, Yoo SS, et al. Clinical characteristics of community-acquired viridans streptococcal pneumonia. Tuberculosis and Respiratory Diseases. 2015;78(3):196-202. DOI: 10.4046/trd.2015.78.3.196
  116. 116. Desimone DC, Tleyjeh IM, Correa de Sa DD, Anavekar NS, Lahr BD, Sohail MR, et al. Mayo cardiovascular infections study group. Incidence of infective endocarditis caused by viridans group streptococci before and after publication of the 2007 American Heart Association's endocarditis prevention guidelines. Circulation. 2012;126(1):60-64. DOI: 10.1161/CIRCULATIONAHA.112.095281
  117. 117. Chamat-Hedemand S, Dahl A, Østergaard L, Arpi M, Fosbøl E, Boel J, et al. Prevalence of infective endocarditis in streptococcal bloodstream infections is dependent on streptococcal species. Circulation. 2020;142:720-730. DOI: 10.1161/CIRCULATIONAHA.120.046723
  118. 118. Gunson TH, Oliver GF. Osler's nodes and Janeway lesions. The Australasian Journal of Dermatology. 2007;48(4):251-255. DOI: 10.1111/j.1440-0960.2007.00397.x
  119. 119. Haslam DB, Geme JWS III. Viridans Streptococci, Abiotrophia and Granulicatella species, and Streptococcus bovis group. In: Long SS, Prober CG, Fischer M, editors. Principles and Practice of Pediatric Infectious Diseases. fifth ed. Amsterdam, the Netherlands: Elsevier; 2018. pp. 732-735. ISBN 9780323401814. DOI: 10.1016/B978-0-323-40181-4.00121-3
  120. 120. Eichenwald EC. Perinatally transmitted neonatal bacterial infections. Infectious Disease Clinics of North America. 1997;11(1):223-239. DOI: 10.1016/s0891-5520(05)70350-0
  121. 121. Kubota T. Relationship between maternal group B streptococcal colonization and pregnancy outcome. Obstetrics and Gynecology. 1998;92:926-930. DOI: 10.1016/s0029-7844(98)00309-3
  122. 122. Krohn MA, Hillier SL, Baker CJ. Maternal peripartum complications associated with vaginal group B streptococci colonization. The Journal of Infectious Diseases. 1999;179(6):1410-1415. DOI: 10.1086/314756
  123. 123. Ahmadi A, Farhadifar F, Rezaii M, Zandvakili F, Seyedoshohadaei F, Zarei M, et al. Group B Streptococci and Trichomonas vaginalis infections in pregnant women and those with spontaneous abortion at Sanandaj, Iran. Iranian Journal of Microbiology. 2018;10(3):166-170
  124. 124. Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC. MMWR—Recommendations and Reports. 2002;51(RR-11):1-22
  125. 125. Coni E, Marcialis M, Pintus M, Irmesi R, Masile V, Fanos V. Group B streptococcal meningitis: A description of six case reports. International Journal of Clinical Pediatrics. 2015;4(1):127-136. DOI: 10.14740/ijcp179w
  126. 126. Tavares T, Pinho L, Bonifácio AE. Group B streptococcal neonatal meningitis. Clinical Microbiology Reviews. 2022;35(2):e0007921. DOI: 10.1128/cmr.00079-21
  127. 127. Verani JR, McGee L, Schrag SJ, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC). Prevention of perinatal group B streptococcal disease: Revised guidelines from CDC, 2010. MMWR Recommendations and Reports. 2010;59(RR-10):1-36
  128. 128. Brown SL, Busuttil RW, Baker JD, Machleder HI, Moore WS, Barker WF. Bacteriologic and surgical determinants of survival in patients with mycotic aneurysms. Journal of Vascular Surgery. 1984;1(4):541-547
  129. 129. Yuan S-M, Wang G-F. Cerebral mycotic aneurysm as a consequence of infective endocarditis: A literature review. ScienceDirect. 2017;59(3):e257-e265. DOI: 10.1016/j.crvasa.2016.11.004
  130. 130. Stengel A, Wolferth CC. Mycotic (bacterial) aneurysms of intravascular origin. Archives of Internal Medicine. 1923;31(4):527-554. DOI: 10.1001/archinte.1923.00110160074005
  131. 131. Davies OG Jr, Thorburn JD, Powell P. Cryptic mycotic abdominal aortic aneurysms: Diagnosis and management. American Journal of Surgery. 1978;136(1):96-101. DOI: 10.1016/0002-9610(78)90207-6
  132. 132. Gomes MN, Choyke PL, Wallace RB. Infected aortic aneurysms. A changing entity. Annals of Surgery. 1992;215(5):435-442
  133. 133. Thawait SK, Akay A, Jhirad RH, El-Daher N. Group B streptococcus mycotic aneurysm of the abdominal aorta: Report of a case and review of the literature. The Yale Journal of Biology and Medicine. 2012;85(1):97-104
  134. 134. Achilli P, Guttadauro A, Bontanti P, Terragni S, Fumagelli L, Cioffi U, et al. Streptococcus agalactiae infective endocarditis complicated by multiple mycotic hepatic aneurysms and massive splenic infarction: A case report. BMC Gastroenterology. 2017;17:170. DOI: 10.11861s12876-017-0728-0
  135. 135. Kanai R, Shinoda J, Irie S, Inoue K, Sato T, Tsutsumi Y. A case of embolic stroke imitating atherothrombotic brain infarction before massive hemorrhage from an infectious aneurysm caused by Streptococci. Journal of Stroke & Cerebrovascular Diseases. 2012;21(8):910.e13-910.e16. DOI: 10.1016/j.jstrokecerebrovasdis.2011.11.001
  136. 136. Murray PR, Rosenthal KS, Pfaller MA. Non–spore-forming anaerobic bacteria. In: Medical Microbiology. 9th ed. Amsterdam, the Netherlands: Elsevier; 2021. pp. 318-326.e1. (Chapter 31)
  137. 137. Bourgault AM, Rosenblatt JE, Fitzgerald RH. Peptococcus magnus: A significant human pathogen. Annals of Internal Medicine. 1980;93(2):244-248. DOI: 10.7326/0003-4819-93-2-244
  138. 138. Brook I. Recovery of anaerobic bacteria from clinical specimens in 12 years at two military hospitals. Journal of Clinical Microbiology. 1988;26(6):1181-1188. DOI: 10.1128/jcm.26.6.1181-1188.1988
  139. 139. Higaki S, Kitagawa T, Kagoura M, Morohashi M, Yamagishi T. Characterization of Peptostreptococcus species in skin infections. The Journal of International Medical Research. 2000;28(3):143-147. DOI: 10.1177/147323000002800305
  140. 140. Gonzales Zamora JA, Espinoza LA. Pyogenic brain abscess caused by Peptostreptococcus in a patient with HIV-1 infection. Diseases. 2017;5(4):26. DOI: 10.3390/diseases5040026
  141. 141. Hughes JM, Wilson ME, Wertheim HFL, Nghia HDT, Taylor W, Schultsz C. Streptococcus suis: An emerging human pathogen. Clinical Infectious Diseases. 2009;48(5):617-625. DOI: 10.1086/596763
  142. 142. Feng Y, Zhang H, Wu Z, Wang S, Cao M, Hu D, et al. Streptococcus suis infection: An emerging/reemerging challenge of bacterial infectious diseases? Virulence. 2014;5(4):477-497. DOI: 10.4161/viru.28595
  143. 143. Jiang F, Guo J, Cheng C, Gu B. Human infection caused by Streptococcus suis serotype 2 in China: Report of two cases and epidemic distribution based on sequence type. BMC Infectious Diseases. 2020;20:223. DOI: 10.1186/s12879-020-4943-x
  144. 144. Yang QP, Liu WP, Guo LX, Jiang Y, Li GD, Bai YQ, et al. Autopsy report of four cases who died from Streptococcus suis infection, with a review of the literature. European Journal of Clinical Microbiology & Infectious Diseases. 2009;28(5):447-453. DOI: 10.1007/s10096-008-0646-8
  145. 145. Henriques-Normark B, Tuomanen EI. The pneumococcus: Epidemiology, microbiology, and pathogenesis. Cold Spring Harbor Perspectives in Medicine. 2013;3(7):a010215. DOI: 10.1101/cshperspect.a010215
  146. 146. Nunes S, Sá-Leão R, Carriço J, Alves CR, Mato R, Avô AB, et al. Trends in drug resistance, serotypes, and molecular types of Streptococcus pneumoniae colonizing preschool-age children attending day care centers in Lisbon, Portugal: A summary of 4 years of annual surveillance. Journal of Clinical Microbiology. 2005;43(3):1285-1293. DOI: 10.1128/JCM.43.3.1285-1293.2005
  147. 147. Sandgren A, Sjostrom K, Olsson-Liljequist B, Christensson B, Samuelsson A, Kronvall G, et al. Effect of clonal and serotype-specific properties on the invasive capacity of Streptococcus pneumoniae. The Journal of Infectious Diseases. 2004;189(5):785-796. DOI: 10.1086/381686
  148. 148. Benton AH, Marquart ME. The role of pneumococcal virulence factors in ocular infectious diseases. Interdisciplinary Perspectives on Infectious Diseases. 2018;2018:2525173. DOI: 10.1155/2018/2525173
  149. 149. Crum NF, Barrozo CP, Chapman FA, Ryan MA, Russell KL. An outbreak of conjunctivitis due to a novel unencapsulated Streptococcus pneumoniae among military trainees. Clinical Infectious Diseases. 2004;39(8):1148-1154. DOI: 10.1086/424522
  150. 150. McNeil JC, Hulten KG, Mason EO Jr, Kaplan SL. Serotype 19A is the most common Streptococcus pneumoniae isolate in children with chronic sinusitis. The Pediatric Infectious Disease Journal. 2009;28(9):766-768. DOI: 10.1097/INF.0b013e3181a24557
  151. 151. Bergenfelz C, Hakansson AP. Streptococcus pneumoniae otitis media pathogenesis and how it informs our understanding of vaccine strategies. Current Otorhinolaryngology Reports. 2017;5(2):115-124. DOI: 10.1007/s40136-017-0152-6
  152. 152. Kumar S, Umadevi S, Easow JM, Joseph NM, Srirangaraj S, Kumari K, et al. Anterior abdominal wall abscess caused by Streptococcus pneumoniae in a patient with self-inflicted stab injury: An unusual presentation. Journal of Infection in Developing Countries. 2011;5(4):307-309. DOI: 10.3855/jidc.1384
  153. 153. Asghar MU, Kommineni K, Mehta SS, Patti RK. Pneumococcus a rare cause of cellulitis. American Journal of Medical Case Reports. 2018;6(12):247-248. DOI: 10.12691/ajmcr-6-12-5
  154. 154. Newman N, Dagan R, Reuveni H, Cohen Z, Melamed R, Greenberg D. Superficial skin infection caused by Streptococcus pneumoniae in children. Pediatric Infectious Disease Journal. 2005;24(10):937-939. DOI: 10.1097/01.inf.0000180974.44754.41
  155. 155. Patel M, Ahrens JC, Moyer DV, DiNubile ML. Pneumococcal soft-tissue infections: A problem deserving more recognition. Clinical Infectious Diseases. 1994;19:149-151. DOI: 10.1093/clinids/19.1.149
  156. 156. Hakeem L, Urolagin M, Bhattacharyya DN, Griffiths G. Haemorrhagic bullous Streptococcus pneumoniae cellulitis in type 2 diabetes mellitus. British Journal of Diabetes & Vascular Disease. 2008;8:75-79. DOI: 10.1177/1474651408100353
  157. 157. Mook-Kanamori BB, Geldhoff M, van der Poll T, van de Beek D. Pathogenesis and pathophysiology of pneumococcal meningitis. Clinical Microbiology Reviews. 2011;24(3):557-591. DOI: 10.1128/CMR.00008-11
  158. 158. van de Beek D, Brouwer M, Hasbun R, Koedel U, Whitney CG, Wijdicks E. Community-acquired bacterial meningitis. Nature Reviews. Disease Primers. 2016;2:16074. DOI: 10.1038/nrdp.2016.74
  159. 159. Engelen-Lee JY, Brouwer MC, Aronica E, van de Beek D. Pneumococcal meningitis: Clinical-pathological correlations (meningene-path). Acta Neuropathologica Communications. 2016;4:26. DOI: 10.1186/s40478-016-0297-4
  160. 160. Inamasu J, Shizu N, Tsutsumi Y, Hirose Y. Infected epidural hematoma of the lumbar spine associated with invasive pneumococcal disease. Asian Journal of Neurosurgery. 2015;10(1):58-61. DOI: 10.4103/1793-5482.151527
  161. 161. Said MA, Johnson HL, Nonyane BA, Deloria-Knoll M, O'Brien KL, AGEDD Adult Pneumococcal Burden Study Team. Estimating the burden of pneumococcal pneumonia among adults: A systematic review and meta-analysis of diagnostic techniques. PLoS One. 2013;8(4):e60273. DOI: 10.1371/journal.pone.0060273
  162. 162. Alsaleh M, Aljeshi M, Alghamdi Y, Althumair A, Alghareeb A, Aldeailj S, et al. A comprehensive review study on pneumococcal pneumonia and its association with global mortality and morbidity. Journal of Lung, Pulmonary & Respiratory Research. 2018;5(6):185-190. DOI: 10.15406/jlprr.2018.05.00190
  163. 163. Jain V, Vashisht R, Yilmaz G, Bhardwaj A. Pneumonia pathology. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021
  164. 164. Daudin M, Tattevin P, Lelong B, Flecher E, Lavoué S, Piau C, et al. Characteristics and prognosis of pneumococcal endocarditis: A case–control study. Clinical Microbiology and Infection. 2016;22(572):e5-572.e8. DOI: 10.1016/j.cmi.2016.03.011
  165. 165. Périer A, Puyade M, Revest M, Tattevin P, Bernard L, Lemaignen A, et al. Prognosis of Streptococcus pneumoniae endocarditis in France, a multicenter observational study (2000–2015). International Journal of Cardiology. 2019;288:102-106. DOI: 10.1016/j.ijcard.2019.04.048
  166. 166. Naito R, Miyazaki T, Kajino K, Daida H. Fulminant pneumococcal infection. BMJ Case Reports. 2014;2014:bcr2014205907. DOI: 10.1136/bcr-2014-205907
  167. 167. Yu VL, Chiou CC, Feldman C, Ortqvist A, Rello J, Morris AJ, et al. An international prospective study of pneumococcal bacteremia: Correlation with in vitro resistance, antibiotics administration, and clinical outcome. Clinical Infectious Diseases. 2003;37:230-237. DOI: 10.1086/377534
  168. 168. Waghorn DJ, Mayon-White RT. A study of 42 episodes of overwhelming post-splenectomy infection: Is current guideline for asplenic individuals being followed? The Journal of Infection. 1997;35:289-294. DOI: 10.1016/s0163-4453(97)93232-1
  169. 169. Hale AJ, LaSalvia M, Kirby JE, Kimball A, Baden R. Fatal purpura fulminans and Waterhouse-Friderichsen syndrome from fulminant Streptococcus pneumoniae sepsis in an asplenic young adult. IDCases. 2016;6:1-4. DOI: 10.1016/j.idcr.2016.08.004
  170. 170. Theilacker C, Ludewig K, Serr A, Schimpf J, Held J, Bögelein M, et al. Overwhelming postsplenectomy infection: A prospective multicenter cohort study. Clinical Infectious Diseases. 2016;62:871-878. DOI: 10.1093/cid/civ1195
  171. 171. Murph RC, Matulis WS, Hernandez JE. Rapidly fatal pneumococcal sepsis in a healthy adult. Clinical Infectious Diseases. 1996;22:375-376. DOI: 10.1093/clinids/22.2.375
  172. 172. Zarrabi MH, Rosner F. Serious infections in adults following splenectomy for trauma. Archives of Internal Medicine. 1984;144(7):1421-1424. DOI: 10.1001/archinte.1984.00350190109020

Written By

Yutaka Tsutsumi

Submitted: 06 June 2022 Reviewed: 13 June 2022 Published: 15 July 2022