patient 1 was a 74-year - old italian man who came to the emergency department ( ed ) of vittorio emanuele hospital in catania , italy , in july 2012 .
patient 2 was 65-year - old german woman who arrived in rome from frankfurt in march 2011 and came directly from the airport to the ed of the university of rome medical center .
patient 3 was a 40-year - old japanese man who came to the ed of the catholic university medical center in rome in february 2012 , 3 days after arriving in the city .
all 3 patients had sudden - onset hemoptysis , dyspnea , and fever ( temperature 37.538.5c ) , which had rapidly worsened over 23 h. their medical histories were unremarkable .
all 3 patients had acute respiratory failure requiring ventilator support and hemoconcentration ; hyponatremia ; increased levels of serum creatinine , lactate dehydrogenase , lactic acid , and brain natriuretic peptides ; leukocytosis ( 7,0008,000 cells / mm , 3,2004,000 neutrophils ) ; and increased levels of c - reactive protein ( > 400 mg / ml ) and d - dimer ( > 2,000 g / ml ) . computed tomography of
the chest showed patchy opacification throughout the lungs and multifocal confluent parenchymal opacities ( figure , panel a ) .
bronchoalveolar lavages were bright red and contained numerous erythrocytes , gram - positive cocci resembling streptococci , and no polymorphonuclear leukocytes . in spite of aggressive supportive care and empirical therapy with ceftriaxone ( 2 g intravenously ) and levofloxacin ( 500 mg intravenously ) , the conditions of the patients deteriorated rapidly , and all 3 died of massive pulmonary hemorrhage 12 h after symptom onset .
a ) computed tomographic image of the chest of a 74-year - old patient ( patient 1 ) with fatal hemorrhagic pneumonia , catania , italy , showing multifocal confluent parenchymal opacities .
c ) microscopic evidence of necrosis and bacteria in the lungs ( original magnification 40 ) .
autopsy specimens showed bilateral hemorrhagic pleural effusions ( 1,5002,000 cells / ml ) , heavy , blood - engorged lungs ( 1,6001,700 g ) , and patent hilar structures , but no thoracic or abdominal lymphadenopathy .
microscopic analysis of the lungs showed necrosis and bacteria ( figure , panel c ) .
admission blood cultures ( 3 sets / patient ) were positive at the 12-h reading .
s. pyogenes was identified by using matrix - assisted laser desorption ionization  time - of - flight mass spectrometry ( bruker daltonik , breman , germany ) and isolated in all culture bottles , bronchoalveolar lavage cultures ( pure colonies , 10 cfu / ml ) , and postmortem lung tissue cultures .
all isolates were susceptible to erythromycin , tetracycline , amoxicillin , penicillin , and clindamycin by etest ( biomrieux , marcy letoile , france ) .
results were interpreted according to european committee on antimicrobial susceptibility testing breakpoints ( www.eucast.org/clinical_breakpoints ) .
results of testing for urinary legionella pneumophila and s. pneumoniae antigens , -glucan , galactomannan , and hiv and toxicology panels were negative for all 3 patients . commercially available pcrs for respiratory tract samples showed negative results for major respiratory viruses and bacterial pathogens .
the emm typing , which was performed by pcr using protocols and the database of the centers for disease control and prevention ( atlanta , ga , usa ; www.cdc.gov/ncidod/biotech/strep/m-proteingene_typing.htm ) , showed that all 3 gas strains were emm - type 1 and had identical sequences at the 5 end of the emm gene , indicative of the emm 1.0 allele .
strains were tested for multiple virulence genes ( table ) by using pcr and primers described elsewhere ( 11 ) or designed with the vectornti program ( invitrogen , carlsbad , ca , usa ) .
they were identical in terms of the spe genotype ( spea+ , speb+ , spec , speg+ , spei , spej+ , smez+ , ssa ) ; the presence of slo , saga , sagbc , and sda1 genes ; and the absence of pam , prtf , and sof genes .
multilocus sequence typing was performed as described ( http://spyogenes.mlst.net/ ) and showed an identical sequence type ( st ) ( st28/cc28 ) for the isolates from patients 1 and 3 and a new single - locus variant of st28 ( designated st648 ) for the isolate from patient 2 .
all cases were caused by gas strains harboring the emm1.0 allele and sda1 , smez , spea , speb , speg , and spej genes .  
* slo , streptolysin o ; saga / bc , streptolysin s - associated gene a protein ; smez-2 mitogenic exotoxin z ; spea , streptococcal pyrogenic toxin a ; speb , streptococcal cysteine protease ; spec , streptococcal pyrogenic toxin c ; speg , streptococcal pyrogenic toxin g ; spei , streptococcal pyrogenic toxin i ; spej ; streptococcal pyrogenic toxin j ; prtf , fibronectin - binding protein ; pam , plasminogen - binding protein ; sof serum opacity factor ; ssa streptococcal superantigen ; sda1 , streptodornase d.  primers indicated in boldface were created with the vectornt program ( invitrogen , carlsbad , ca , usa ) .
a total of 1.3%23.8% invasive gas infections involve pneumonia , but these infections are more common in developing countries ( 1,6,7,12 ) .
however , despite early aggressive supportive care and empirical antimicrobial drug therapy , which was later confirmed to be appropriate by antibiogram results , all 3 patients we describe died within 812 h of symptom onset from massive pulmonary bleeding and acute respiratory failure .
the roles of gas in the rapid progression of disease were highlighted by the abundance of gas found the lungs , extensive and severe pulmonary damage , and virulence factor profiles of the isolates , all of which included sda1 , smez , spea , speb , speg , spej , and emm-1 genes ( 4,5 ) .
invasive bacterial disease requires virulence factors that facilitate interactions of the microbe with host tissues and subvert defenses of the immune system . in the emm1 gas clone ,
progression to systemic infection is also favored by mutations in the 2-component control of virulence regulatory system , which enhances resistance to subepithelial immune defenses and facilitates deep - tissue penetration .
these mutations markedly alter transcription profiles of invasive gas isolates than those of pharyngeal mucosal isolates ( 35,8 ) , strongly upregulating sda1 transcription and markedly downregulating expression of the gene encoding cysteine protease speb ( 612 ) .
the sda1 gene facilitates avoidance of neutrophil extracellular traps by the pathogen and serves as a selective force for a control of virulence regulatory system mutation ( 7,13 ) .
speb protease enables accumulation and activation of broad - spectrum host protease plasmin on the microbial cell surface , thereby promoting infection spread to normally sterile sites ( 2,3,14 ) .
invasive gas strains also produce increased levels of toxins , including some that destroy immune cells , and superantigens ( e.g. , spea , spej ) that dysregulate the immune response of the host ( 3 ) .
host factors also affect clinical presentation and disease progression , which explains why diseases of different severity can be caused by genetically indistinguishable emm1 strains with no evidence of regulatory gene mutation ( 2,4,7 ) .
elucidation of these host and bacterial factors involved in the pathogenesis of these rare but life - threatening infections may be useful for improving disease prognosis ( 6 ) .
 we report 3 cases of fulminant hemorrhagic pneumonia in previously health patients . 
 sudden - onset hemoptysis and dyspnea developed ; all 3 patients and died < 12 h later of massive pulmonary bleeding , despite aggressive supportive care . 
 postmortem analysis showed that the illnesses were caused by group a streptococcus 
 emm1/sequence type 28 strains . 
The Study
Conclusions