There are some key features characterizing pneumonias, such as fever, cough, and fatigue. Fever will give some information about possible organisms: above 39.5 °C most likely this is caused by a viral infection, whereas bacterial pneumonias present with temperatures between 38 and 39 °C. Cough can be productive with either serous or purulent expectoration. Laboratory evaluation will show inflammatory parameters, such as leukocytosis, etc.

Radiologically the lung will show ground glass opacities and consolidations, depending on the age of the inflammatory infiltrate. Clinically pneumonias are separated into typical and atypical pneumonia. Atypical pneumonia can have different meanings, either an atypical infiltration pattern on CT scans or atypical presentation with rare infectious organisms.

Although infectious pneumonia is a common disease, biopsies and surgical resections are rarely seen in pathologic practice. Most of these cases are diagnosed clinically and treated accordingly by antibiotics. If biopsied or resected, these cases usually turn out as unusual pneumonia caused by unusual organisms. Pneumonias are commonly seen at autopsy. The evaluation of infectious organisms will be discussed after the granulomatous pneumonias.

Clinically acute interstitial pneumonia (AIP, also adult respiratory distress syndrome (ARDS)) is characterized by an acute onset of severe hypoxia, with the radiological appearance of white lung. Histologically there is edema and fibrinous exudate, widened edematous alveolar septa (see also below acute fibrinous pneumonia). Later on hyaline membranes are formed – this was called diffuse alveolar damage (DAD) (Fig. 8.8). Depending on the cause of DAD, scattered neutrophilic and/or eosinophilic granulocytes can be found in bacterial, toxic, or drug-induced DAD, or few lymphocytes are seen in viral and rickettsia infections, respectively [15, 16]. Inflammatory infiltrates may be even absent such as in various kinds of shock. Rarely cases of “idiopathic AIP” have been reported. Probably some of these cases represent cases of undiagnosed SLE or drug toxicity. In the author’s experience in all cases sent for consultation and primarily labeled as idiopathic DAD, an etiology could finally be established. So it might be questioned if idiopathic DAD does exist [17].

Hamman-Rich described an interstitial pneumonia with fulminant course leading to death in their six cases within 6 months. In the author’s description, there was no hyaline membrane mentioned but a proliferation of fibroblasts. Since the tissues from these cases were all lost, this disease cannot be reconstructed and remains an enigma [18].

The sequence of events in DAD is largely dependent on the cause: Toxic metabolites of drugs or released collagenase and elastase from necrotizing pancreatitis will cause endothelial damage, followed by leakage of the small peripheral blood vessels. This causes edema, followed by pneumocyte cell death due to hypoxia. Serum proteins will pass into the alveolar lumina, coagulate there, and by the breathing movements are compressed into hyaline membranes (Figs. 8.9 and 8.10). In case of airborne disease, e.g., infection or inhaled toxins, pneumocytes type I die followed by type II. Due to the lack of surfactant lipids, the alveoli collapse. The basement membrane is either preserved or also destroyed (especially in viral infection). This again causes leakage of capillaries, edema with/without bleeding, protein extravasation into the alveoli, and finally formation of hyaline membranes.

The lethality of DAD is still high despite improvements, which have been made in the past decade. In some cases the progression of the disease might be blocked by antiprotease treatment [19]. In more recent time extracorporeal oxygenation or NO treatment has shown some benefit. If the patient survives the acute phase, DAD will be organized, which is essentially an organizing pneumonia, by some authors also labeled organizing DAD: granulation tissue grows into the alveoli and hyaline membranes are incorporated into the plugs. Remnants of hyaline membranes can be demonstrated several weeks after the initial injury (Figs. 8.11, 8.12, and 8.13). If a tissue biopsy or an autopsy specimen is available early on in the course of the disease, the etiology might be elaborated: in viral infection inclusion bodies can be seen, which can present either as nice large inclusion bodies (CMV, RSV) or by red-violet stained nucleic acids forming ill-defined speckles in nuclei and/or cytoplasm (adenovirus) [20]. This is followed by atypical proliferation and transformation of pneumocytes type II (Fig. 8.14). Typically the infected cell shows enlargement, an atypical large bizarre nucleus, and an accentuated nuclear membrane due to increased nucleic acid traffic induced by the virus. These cellular features can last for several months. In contrast to atypical pneumocyte hyperplasia (AAH), these atypical cells are singles and do not form a continuous layer along the alveolar wall. Rickettsia infection results in less pronounced proliferation of pneumocytes. In shock and drug-induced DAD, the endothelia will undergo apoptosis and necrosis, and fibrin cloths might be seen in capillaries (Fig. 8.10). In these cases the alveolar septa are widened and edematous. Inflammatory cells are scarce or absent. In later stages of drug pneumonia, scattered eosinophils are encountered – their function being completely unknown.

Acute fibrinous and organizing pneumonia (AFOP) was recently described as a variant of DAD: the dominant pattern is accumulation of intra-alveolar fibrin and concomitant organizing pneumonia [21]. Also pneumocyte type II hyperplasia, edema, and inflammatory infiltrates were described. Clinically the symptoms were identical to ARDS/AIP. The main difference stated by the author was the absence of hyaline membranes and the presence of fibrin cloths. The underlying causes were similar to classical DAD/AIP, so the author concluded that this might be a variant of DAD. However, some aspects have never been clarified: Fibrin exudation and clothing is seen early in DAD (see also Fig. 8.9), so the earliest phase of DAD does not present with hyaline membranes – these are formed later on due to respiration, which compresses fibrin into hyaline membranes. Rarely DAD might also present with a multifocal pattern, which includes a timely heterogeneity: acute fibrinous exudation in one, organizing DAD in another area [22]. Within the underlying cause, similar diseases as in DAD were found, including rare cases of acute hypersensitivity pneumonia [21, 23].

LIP almost vanished from the literature in the last 5 years. The major problem is the separation from NSIP. When NSIP was described, it was never clearly separated from LIP [24]. When comparing my own cases and reports from the literature, it becomes evident that differences do exist: in LIP the lymphocytic and plasmacytic infiltration is dense, hyperplasia of the bronchus-associated lymphoid tissue (BALT) is common, and within lymph follicles germinal centers are usually present [24]. The infiltration in LIP is more diffuse, architectural distortion is common, and scarring does occur. Histiocytic and monocytic cellular infiltrations are much less pronounced compared to NSIP. Lymphoepithelial lesions do occur similar to lymphomas, in some entities aggressively infiltrating and destroying the epithelium; in other cases no epithelial disruption does occur. In contrast to NSIP, the architecture of the peripheral lung is remodeled, especially in later stages (Fig. 8.15).

The clinical presentation depends on the underlying disease, and the CT scan usually shows ground glass opacities, in subacute and chronic stages, and also areas of fibrosis.

On gross morphology scattered areas of consolidations are seen.

Within the etiologic spectrum, similar diseases are found as in NSIP: autoimmune diseases especially collagen vascular diseases, allergic diseases as extrinsic allergic alveolitis/hypersensitivity pneumonia (EAA/HP) (acute and subacute), allergic drug reactions, HIV infection, and in children different types of immunodeficiency (T-cell defect, NK-cell defect). The most important differential diagnoses, however, are extranodal marginal zone lymphoma of MALT/BALT type and lymphomatoid granulomatosis type I. In all cases the clonality has to be evaluated and a lymphoma needs to be excluded by proof of multiclonality.

LYG type I can be difficult to separate: large blasts are rare and can be obscured within a dense infiltrate by small lymphocytes. The lymphocytic infiltration is polyclonal, so this does not help in the separation. Therefore a search for EBV-positive blasts is essential. Also it is important to exclude posttransplant lymphoproliferative disease [25], which can present in a similar pattern (large lymphoid cells usually EBV positive). However, it should be reminded that some of the autoimmune diseases have a high propensity of developing non-Hodgkin lymphomas later in the course [26]. Within the autoimmune diseases, Sjøgren’s disease most often presents with LIP pattern [27, 28].

GIP has a quite narrow etiologic spectrum either being caused by hard metal dust or by viral infection. The former will be discussed later. Several viruses can cause GIP, the classical one being measles virus. However, in contrast to pneumoconiosis in infections, the giant cells are mixed epithelial as well as macrophagocytic. The epithelial giant cells (Hecht cells) are transformed pneumocytes type II in whom nuclear division was not followed by cell division giving rise to multinucleation [29]. The additional features are identical to DAD as described above. Especially within the epithelial cells, viral inclusion bodies can be found (Fig. 8.16). Besides measles, also respiratory syncytial virus (RSV) can present with this picture predominantly in children [30].

Alveolar and interstitial pneumonias can be induced by a wide variety of organisms. According to that they can be classified as bacterial, viral, rickettsia, or parasitic. Parasitoses will be covered in eosinophilic pneumonias (Chap. 10).

Infectious pneumonias in childhood are quite common but are rarely biopsied. There are some differences in so far as the density of leukocytic infiltrations is much less compared to the adult form.

Opportunistic infections as part of the infectious pneumonias in immunocompromised patients will be mentioned in the tables under the different organisms and in the chapter on transplantation pathology. Disorders related to therapeutic intervention, chemotherapeutic drug, and radiation injury will be discussed in toxic reaction due to drugs and inhalation.

Bacterial pneumonias are most often purulent; the dominant inflammatory cell is the neutrophil. In early stages the infiltration starts with macrophages and fibrin exudation followed by infiltration by neutrophils. Abscess formation is common; cavitation is induced by some bacteria and most likely is induced by vasculitis and thrombosis. A few bacteria cause DAD and fibrinous pneumonia, other lymphocytic pneumonia – these tissue reactions can point to the underlying type of infection (Table 8.1). A scattered type of neutrophilic infiltration is seen in some infections such as Nocardia or Legionella pneumonia (Fig. 8.17) and a mixed infiltration of leukocytes but dominated by macrophages seen in such rare bacterial infections as listeriosis (Fig. 8.18, Table 8.1).

Fungal pneumonias are caused by a variety of fungal organisms. Most often fungal infection does not proceed into infections of deep organs, but stay confined to the skin, oral cavity, or the upper respiratory tract. In immunocompromised patients or in infants, however, fungal infections can cause lethal widespread multiorgan infections (Figs. 8.19 and 8.20). Since many of the fungi have developed some capsular structures and also can undergo different developmental stages, the host tissue often needs to develop different strategies to keep the infection under control. In the normal host, fungi are usually controlled by an influx of neutrophils, which are capable of eliminating the fungi before they can cause pneumonia. In conditions where the fungi cannot be controlled, such as in bronchiectasis, the lung encases the infection by granulation tissue, starting as an organizing pneumonia, and later on a fibrous capsule separates the infectious focus from the normal lung – a mycetoma has been formed (Fig. 8.21). Normally there is a steady-state situation, i.e., no invasion of the fungus in deep areas of the lung occur, but the lung cannot get rid of the fungus. However, there are rare conditions where invasion does occur and a chronic slowly progressing pneumonia develops – called chronic necrotizing mycosis. A few fungi pathogenic in humans can cause life-threatening infections: an example is mucormycosis. Again infection most often occurs in immunocompromised patients. The patients develop cough, occasionally mild hemorrhage, fever and shortness of breath is common. The major problem is that this fungus does not respond to many antifungal drugs therefore amphotericin B is applied, which has many toxic side effects. Pneumonia in Mucor infection presents with an infiltration of macrophages and neutrophils, necrosis is widespread, pleura is often involved, or the infection can even enter the pleural cavity (Fig. 8.22, Table 8.2).

Finally the reaction of the lung tissue against some specific forms of fungi can also be granulomatous. This reaction can be an innate immune reaction with histiocytes, macrophages, and foreign body giant cells or develop into a specific immune reaction with lymphocytes and epithelioid granuloma formation. However, this specific immune reaction depends on a functioning non-impaired immune system capable of producing different types of T lymphocytes (see below). Many fungi exhibit an angioinvasive growth behavior, i.e., their hyphae will grow toward arteries and veins directed by increase of pO₂ and immediately will invade through the vessels wall, resulting in sepsis. There exist also an allergic mycosis, called allergic bronchopulmonary mycosis (ABPA, ABPM), which is based on a sensitization against fungal proteins; this will be discussed in Chap. 10.

Respirotropic viruses and Rickettsia cause viral and rickettsial pneumonias. One of the most common tissue reactions is DAD with hyaline membranes. In virus infections only scattered lymphocytes are seen in tissue sections, but in BAL there can be a lymphocytosis with up to 30 % of lymphocytes, predominantly CD8⁺ ones. Some viruses such as influenza type A strains can destroy the basal lamina of the epithelial layer and the capillaries by their enzymes. In these cases diffuse hemorrhage is seen with bleeding from capillaries, giving the macroscopic surface of the mucosa a dark red color. The distribution of inflammatory changes is also important: influenza virus usually causes trachea-broncho-pneumonia, whereas adenovirus is more likely causing bronchiolo-pneumonia. In cases of less virulent types of strains of viruses, a lymphocytic interstitial pneumonia can be seen (Figs. 8.23, 8.24, and 8.25). As a rule one should always try to find viral inclusion bodies. They can be prominent and easily seen as in CMV or HSV infection, whereas in adenovirus infection this can be difficult, because of intracytoplasmic bodies. Since the virions are very small and invisible, the package is ill defined. Viral inclusion bodies are stained violet red due to their high content of either DNA or RNA, and viral inclusions change the internal structure of a nucleus: the nuclear membrane is less sharp, and the chromatin structure is blurred.

Bronchopulmonary dysplasia is a specific condition found in premature children. Inflammation is a major contributor to the pathogenesis of BPD, which is often initiated by a respiratory distress response and exacerbated by mechanical ventilation and exposure to supplemental oxygen [41]. Similar to Wilson-Mikity syndrome, infectious organisms such as ureaplasma and CMV have been reported to cause BPD [34, 42, 43]. In BPD sometimes remnants of infant DAD can be seen (hyaline membranes; Fig. 8.28), but the characteristic feature is interstitial fibrosis (Fig. 8.29).

Aspiration in children can be seen in two different forms: meconium aspiration during delivery causing severe respiratory distress and postnatal aspiration, most often as silent nocturnal aspiration in breast-fed babies. Risk factors for severe meconium aspiration are fetal distress and birth asphyxia [44, 45]. The diagnosis is most often made at autopsy. In addition to DAD, also a foreign body granulomatous reaction might be seen, depending on the time the child has survived. In silent nocturnal aspiration, children swallow milk from breast-feeding and aspirate small amounts. This causes scattered ground glass opacities on CT scan and lipid pneumonia on histology. However, the diagnosis can be made by bronchoalveolar lavage: macrophages laden with lipid droplets in their cytoplasm in more than 10 % are diagnostic in this setting (Fig. 8.30).

HIV infection transmitted by HIV-positive mothers can cause also HIV in the child. It has been shown that HIV-infected women as well as HIV-infected family members coinfected with opportunistic pathogens might transmit these infections more likely to their infants than women without HIV infection, resulting in increased acquisition of such infections in the young child [46]. Otherwise HIV infection in children is morphologically similar to that in adults. Within the spectrum of opportunistic infections, Pneumocystis jirovecii is the most common.

The name granuloma is derived from the Latin word granulum, which means grain. The ending -oma is a Greek ending, used to designate a nodular swelling. Therefore granuloma is a nodular, well-circumscribed macroscopic lesion. With the invention of microscopy, this term has been extended to small nodular aggregates of cells. Over the decades the definition has undergone different interpretations. Some use granuloma strictly for well-circumscribed lesions, whereas others also designate a more loose aggregate of inflammatory cells as granuloma.

Epithelioid cell granulomas originally were recognized as a granulomatous inflammatory reaction elicited by infectious organisms. The first organisms identified were Mycobacterium tuberculosis and bovis and Treponema pallidum [47]. In the nineteenth century, Schaumann, Besnier, and Boeck recognized another epithelioid cell granulomatosis, which, due to the macroscopic resemblance to dermal sarcoma, they called sarcoidosis [48]. In the following decades, various epithelioid cell granulomatoses have been added, and even in the 1990s, new diseases have been reported, like zirconiosis [49–52].

The formation of epithelioid cell granulomas requires a combination of at least two different sets of stimulants: (a) stimulants for granuloma formation and (b) stimulants for epithelioid and Langhans cell differentiation. So what are the driving forces?

Granuloma formation is an old phylogenetic process by which complex organisms protect themselves against invading organisms or toxic substances. The invader or a toxic substance is isolated by granulation tissue or is phagocytosed and degraded simply by macrophages as part of the innate immune system. If these cells can kill the invading organism, no further defense line is required. If the invader cannot be ingested and degraded by these cells, histiocytes and macrophages can form foreign body giant cells, which are more efficient in phagocytosis and degradation. These cells together form foreign body granulomas. In every case the invading organism cannot be killed by phagocytosis, another defense line is activated, which includes immune mechanisms. This more powerful line of defense is the epithelioid cell granuloma. The driving forces, which induce granuloma formation, are the macrophages, the antigen-presenting cells, such as Langerhans and dendritic reticulum cells, and the T and B lymphocytes [53–56]. Among the different cytokines released are interleukins 1β, 2, 3, 8, 10, 12, 17, macrophage migration inhibitory factor 1 (MIF1), IFNγ, and TNFα. How these factors act and interact is still not understood; however, macrophages and lymphocytes are activated and immobilized. This is followed by the cytokine-induced transformation of macrophages into epithelioid and foreign body giant cells [57–62]. Giant cells can be either formed by fusion of macrophages or by nuclear division without cell division. Foreign body giant cells further on differentiate into Langhans giant cells. This process of transformation is maintained by the same secretory factors, which are produced in larger quantities by the epithelioid cells and by infiltrating lymphocytes [63].

But why do we find non-necrotizing and necrotizing epithelioid cell granulomas even in the presence of the same organism?

Different substances either actively liberated from mycobacteria or passively by degradation can induce granuloma formation. Among them are trehalose-6,6′-dimycolate, lipoarabinomannan, and 65 kDa antigen of mycobacterial capsule (a chaperonin) [61, 62]. These products stimulate granuloma formation by the induction of cytokine gene expression, mainly IL1β or TNFα. In addition they have other effects, like induction of apoptosis, enhancing coagulation, and together release TNFα, which subsequently induce necrosis by occlusion of small blood vessels. The mycobacterial chaperonin also stimulates monocytes to express mRNA for TNFα and to release IL6 and IL8, cytokines which are chemoattractants for lymphocytes. In some patients necrotizing and non-necrotizing epithelioid cell granulomas, induced by M. tuberculosis, can be found side by side. The underlying mechanism is not completely understood. One possible explanation might be the mycobacterial burden: large amounts of mycobacteria release large quantities of coagulation factors and thus induce infarct-like necrosis. Another explanation is within the interaction of virulent stains of mycobacteria and host defense cells [63].

When we go back to morphology, we can see three different settings, in which we encounter necrosis: M. tuberculosis escape the immune defense, multiply, invade vessel walls, and are in part degraded by leukocytes, and by this a massive liberation of capsule constituents occurs; epithelioid cell granulomas develop in vessels walls and obstruct or occlude the vessel lumen, and ischemic necrosis follows; an imbalance of the virulence of the mycobacteria and the immune defense capability of the host is in favor of the invading organism. These factors together might lead to higher concentration of TNFα, as well as trehalose-6,6′-dimycolate, lipoarabinomannan, and chaperonin. In addition vasculitis-associated and released thrombogenic factors may synergistically act together to induce this characteristic caseous necrosis (Fig. 8.31).

When classifying granulomatous pneumonias, we will discern epithelioid from histiocytic granulomas and as a second step differentiate infectious from noninfectious forms.

Epithelioid cell granulomas are a specific form of granulomas, composed of epithelioid cells, giant cells, and lymphocytes (epithelioid: epithel = the stem of epithelium and oid = similar to). This type of granuloma can be induced by a variety of quite different stimuli. Epithelioid and giant cells are specialized members of the monocyte/macrophage lineage, the first a differentiated secretory cell (Fig. 8.32) and the second a specialized phagocytic cell (Fig. 8.33). Giant cells can be either formed by cell fusion or by incomplete cell division (no cytoplasmic division). Both ways have been proven experimentally [56, 64, 65]. First foreign body giant cells are formed, which later reorganize into Langhans cells. These are characterized by a nuclear row opposite to the phagocytic pole of the cell. Lymphocytes are usually layered at the outer granuloma shell and can be numerous or sparse. Phenotypically these are T lymphocytes, whereas B lymphocytes are loosely arranged outside the granulomas. T-helper-1 and T-helper-2 and cytotoxic T lymphocytes (CD8⁺) can be present in the granulomas, with the composition depending on the type of underlying disease. This will be discussed later.

We can encounter different stages of granuloma formation: first we see a loose aggregation of macrophages, histiocytes, lymphocytes, and even neutrophils. During each step the granuloma becomes more compact, and the margins are better circumscribed. During aging, epithelioid cell granulomas might undergo fibrosis and hyalinization (Figs. 8.34, 8.35, and 8.36). However, in some diseases like extrinsic allergic alveolitis, the epithelioid cell granulomas remain less well delineated and tend to be more loosely arranged. Also a spillover of lymphocytes into adjacent alveolar septa is seen.

A very important finding is central necrosis, defining the necrotizing epithelioid cell granuloma. Small necrobiotic foci or few apoptotic cells are not regarded as necrosis. The necrosis is either stained eosinophilic with minimal amounts of nuclear debris, or may contain larger amounts of nuclear debris, or stained blue violet by H&E. In early necrosis neutrophils can be found. The descriptive term caseous necrosis is often used; however, it should be reminded that this term was invented to describe these necroses macroscopically: a caseous necrosis is characterized by a yellowish color and soft, cheese-like consistency (Fig. 8.31).

Pathologists usually differentiate granulomatoses by their morphologic appearance: if there is an epithelioid cell granuloma with necrosis, primarily infectious diseases are to be discussed, whereas in non-necrotizing granulomas, other diagnoses are to be added. Although this rule will be true in most cases, it should be reminded that sometimes necrosis is not associated with infection, as in necrotizing sarcoid granulomatosis and some cases of bronchocentric granulomatosis.

The distribution pattern of the granulomas may assist in sorting out specific diseases: the distribution of granulomas along lymphatic vessels is quite characteristic in sarcoidosis, whereas an airspace-oriented pattern is seen in most infectious epithelioid cell granulomatoses. However, the distribution pattern might not be apparent in transbronchial biopsies.